IMPROVEMENTS IN ANTISENSE OLIGOMERS, DELIVERY OF ANTISENSE OLIGOMERS, AND IDENTIFICATION OF ANTISENSE OLIGOMER TARGETS

Abstract: Antisense oligomers which possess improved properties over those taught in the prior art are disclosed. Preferably, oligomers for delivery to a cell comprising at least one nucleomonomer having a silicon-based 2'OH protecting group, e.g., a tertbutyl dimethyl-silyl group. Oligomers of between about 7 and about 12 nucleomonomers in length which are complementary to a site on an RNA target molecule selected from the group consisting of: the extreme 5' terminus of the RNA molecule, a 5' splice junction of the RNA molecule, and a 3' splice junction of the RNA molecule are provided. Oligomers comprising a neutral backbone which have been modified to comprise at least one charged group are also disclosed. In addition, methods of identifying an oligomer complementary to a cellular gene involved in a physiological process are provided.

Description: IMPROVEMENTS IN ANTISENSE OLIGOMERS, DELIVERY OF ANTISENSE OLIGOMERS, AND IDENTIFICATION OF ANTISENSE OLIGOMER TARGETS Related Applications This application claims priority to U.S. provisional application Serial No. 60/146,857 filed on August 3, 1999 , the contents of which is entirely incorporated herein by reference. Background of the Invention Antisense oligomers are promising therapeutic agents and useful research tools in elucidating gene function. Antisense oligomers can be designed, for example, to work by steric inhibition or by activating RNAse H. In addition, ribozymes, which are catalytic RNA molecules with ribonuclease activity can be used to cleave a single-stranded nucleic acid to which they have a complementary region. Many different means of stabilizing antisense oligomers have been developed. For example, oligonucleotides with phosphorothioate linkages have been shown to be effective in inhibiting the synthesis of proteins in several cell types, however, phosphorothioate oligonucleotides are highly negatively charged and, therefore, interact nonspecifically with cellular and viral proteins (Taylor et al. 1996. J. Biol. Chem. 271 : 17445). Gapmer or chimeric antisense oligomers that have a short stretch of phosphorothioate DNA (5-12 nucleotides) have been used to obtain RNase-H mediated cleavage of target RNAs, while reducing the number of phosphorothioate linkages (Dagle, J.M., Walder, J.A. & Weeks, D.L. Nucleic Acids Res 18, 4751-7 (1990); Agrawal, S., Mayrand, S.H., Zamecnik, P.C. & Pederson, T. Proc Natl Acad Sci USA 87, 1401-5 (1990)). Usually, in a gapmer oligomer a central region that forms a substrate for RNase is flanked by hybridizing "arms" comprised of modified nucleotides that do not form substrates for RNase H. Alternatively, the substrate for RNase H that forms the "gap" can be on the 5' or 3' side of the oligomer (B. P. Monia, et a\., Biol Chem 268, 14514-22 (1993)). The "arms" which do not form substrates for RNase H have three relevant properties. First, they hybridize to the target providing the necessary duplex affinity to achieve antisense inhibition. Second, as discussed above, they reduce the number of phosphorothioate DNA linkages in the oligomer, thus reducing non-specific effects. Third, they limit the region that forms a substrate for RNase H, thus adding to the target specificity of the oligomer. Chimeric oligomers have also been synthesized with methylphosphonate and phosphoramidate linkages in the arms (Dagle, J.M., Walder, J.A. & Weeks, D.L. Nucleic Acids Res 18, 4751-7 (1990): Agrawal, S., Mayrand, S.H., Zamecnik, P.C. & Pederson, T. Proc Natl Acad Sci USA S7, 1401-5 (1990). While these compounds functioned well in buffer systems and Xenopus oocytes, the arms decreased the hybrid affinity. This decrease in affinity dramatically reduces the activity of oligomers in mammalian cell culture. Another strategy for chemical modification has been to alter the ribose moieties. Morpholino oligomers are uncharged molecules comprising a morpholino group in place of the ribose moiety (Summerton and Weller. 1993. U.S. Patent 5,185,444). Oligonucleotides comprising morpholino modifications have been found to be effective in certain cell types (Taylor et al. 1996. J. Biol. Chem. 271 :17445' Taylor et al. 1997. Cytokine. 9:672). However, neutral oligomers such as these are difficult to transfect because they do not interact with cationic lipids used for transfection. In addition, neutral and/or radically modified backbone chemistries are often difficult and expensive to synthesize. 2' modified sugars (e.g., -O-alkyl and fluoro and other 2' modifications) have excellent hybrid affinity, and thus are well suited for use in the "arms" of chimeric oligomers. In an earlier patent application by Monia (WO 94/08003 Figure 15), oligomers are described that have 2'-O-methyl hybridizing "arms" without phosphorothioates in the "arms". While Monia shows that these oligomers may function in some cases (WO 94/08003, see, e.g., Figure 15), oligomers of this type have reduced activity in cellular systems. This may be due to exonuclease degradation of the 2'-O-methyl phosphodiester linkages. In order to maximize therapeutic activity of antisense oligomers, it would be of great benefit to improve upon the prior art oligomers by optimizing their ability to permeate cells, their ease of synthesis and purification, their specificity, their activity, and their nuclease resistance. Summary of the Invention The instant invention is based, at least in part, on the discovery that modifications to the prior art antisense oligomers result in improved properties. In addition, improved methods for facilitating uptake of oligomers and for identifying target genes for oligomers have been developed. The invention improves upon the prior art antisense oligomers, inter alia, by optimizing their ability to permeate cells, their ease of synthesis and purification, their specificity, their activity, and their nuclease resistance. Accordingly, the invention provides optimized antisense oligomer compositions, methods for making and using both in in vitro systems, ex vivo and therapeutically, and methods for identifying target genes and for verifying the function of target genes. In one aspect, the invention pertains to an oligomer for delivery to a cell comprising at least one nucleomonomer having a silicon-based 2'OH protecting group. In one embodiment, the silicon-based protecting group is a tertbutyl dimethyl-silyl group. In another aspect, the invention pertains to a method of inhibiting expression of a protein in a cell comprising contacting a cell with an oligomer of claim 1. such that expression of a protein in the cell occurs. In another embodiment, the invention pertains to a method of enhancing the uptake of a neutral oligomer by a cell, comprising modifying the neutral oligomer to comprise at least one charge, such that enhanced uptake of the oligomer occurs. In one embodiment, the uptake of the oligomer is facilitated by electroporation. In another embodiment, the uptake of the oligomer is facilitated by positively charged transduction reagent. In yet another embodiment, the uptake of the oligomer is facilitated by cationic lipids. In another aspect, the invention pertains to a method of inhibiting the expression of a protein in a cell comprising contacting a cell with an oligomer which is complementary to a target nucleic acid molecule, said oligomer having a region comprising a neutral backbone and having at least one negatively charged group such that inhibition of expression of a protein occurs. In one embodiment, the neutral backbone is a morpholino or peptide backbone. In another embodiment, the negatively charged group is covalently linked to the oligomer. In another embodiment, the covalent linkage is a phosphodiester linkage. In another embodiment, the negatively charged group is non-covalently linked to the oligomer. In another embodiment, the negatively charged group is present on a charged molecule which complexes with the oligomer. In another aspect, the invention pertains to a method of screening for an oligomer complementary to a cellular gene involved in a physiological process comprising: contacting a cell with an oligomer comprising at least one universal nucleotide and determining the ability of the oligomer to induce a phenotypic change in the cell to thereby identify an oligomer which is complementary to a cellular gene involved in a physiological process. In yet another aspect, the invention pertains to a method of screening for an oligomer complementary to a cellular gene involved in a physiological process comprising: contacting a cell with a first oligomer comprising at least one universal nucleotide and determining the ability of the first oligomer to induce a phenotypic change in a cell: reducing the degeneracy of the first oligomer by fixing at lest one of the universal bases to thereby make a second oligomer; and determining the ability of the second oligomer to induce a phenotypic change in a cell to thereby identify an oligomer which is complementary to a cellular gene involved in a physiological process. In yet another embodiment, the invention pertains to a method for determining the sequence of a cellular gene which is involved in a physiological process comprising: determining the sequence of an oligomer identified in a screening assay and identifying cellular gene sequences which are complementary to the oligomer. Drawings Figure 1 illustrates the expression of ras luciferase values normalized to control luciferase. Figure 2 illustrates the transfection of A549 cells with charged morpholino oligomers. Detailed Description of the Invention The instant invention advances the prior art by providing optimized antisense oligomer compositions for use in techniques and therapies and by providing methods of making and using the improved antisense oligomer compositions. Before further description of the invention, certain terms are, for convenience, defined here. Definitions The term "oligomer" includes two or more nucleomonomers covalently coupled to each other by linkages or substitute linkages. An oligomer may comprise, for example, between a few (e.g. 7, 10, 12, 15) or a few hundred ( e.g., 100 or 200) nucleomonomers. For example, an oligomer of the invention preferably comprises between about 10 and about 50 nucleomonomers , between about 15 and about 40, or between about 20 and about 30 nucleomonomers. More preferably, an oligomer comprises about 25 nucleomonomers. Oligomers may comprise, for example, oligonucleotides, oligonucleosides, polydeoxyribonucleotides (containing 2'-deoxy-D-ribose) or modified forms thereof, e.g., DNA, polyribonucleotides (containing D-ribose or modified forms thereof), RNA, or any other type of polynucleotide which is an N-glycoside or C-glycoside of a purine or pyrimidine base, or modified purine or pyrimidine base. The term oligomer includes compositions in which adjacent nucleomonomers are linked via phosphorothioate, amide, or other linkages (e.g., Neilsen, P.E., et al. 1991. Science. 254:1497). Oligomers comprise one or more regions which are complementary to and can bind to a target nucleic acid sequence, e.g., by Watson/Crick or Hoogsteen binding. Preferably, oligomers of the invention are substantially complementary to a target RNA sequence. By substantially complementary it is meant that no loops greater than about 8 nucleotides are formed by areas of non-complementarity between the oligomer and the target. In a preferred embodiment, the antisense oligomers of the invention are complementary to a target RNA sequence over at least about 80% of the length of the oligomer. In a more preferred embodiment, antisense oligomers of the invention are complementary to a target RNA sequence over at least about 90-95 % of the length of the oligomer. In a more particularly preferred embodiment, antisense oligomers of the invention are complementary to a target RNA sequence over the entire length of the oligomer. The ability of an oligomer to bind to a target sequence is primarily a function of the bases in the oligomer. Accordingly, elements ordinarily found in oligomers, such as the furanose ring and/or the phosphodiester linkage can be replaced with any suitable functionally equivalent element. The term "oligomer" includes any structure that serves as a scaffold or support for the bases of the oligomer, where the scaffold permits binding to the target nucleic acid molecule in a sequence-dependent manner. The term "nucleomonomer" includes bases covalently linked to a second moiety. Nucleomonomers include, for example, nucleosides and nucleotides. Nucleomonomers can be linked to form oligomers that bind to target nucleic acid sequences in a sequence specific manner. The term "second moiety" as used herein includes substituted and unsubstituted cycloalkyl moieties, e.g. cyclohexyl or cyclopentyl moieties, and substituted and unsubstituted heterocychc moeities, e.g. 6-member morpholino moeities or, preferably, sugar moieties. Sugar moieties include natural sugars, e.g. monosaccharides (such as pentoses, e.g. ribose), modified sugars and sugar analogs. Possible modifications include, for example, replacement of one or more of the hydroxyl groups with a halogen, a heteroatom, an aliphatic group, or the functionalization of the group as an ether, an amine, a thiol, or the like. For example, modified sugars include D-ribose, 2'-O-alkyl, 2'-amino 2'-S-alkyl, 2'halo, 2'-O- methyl, 2'-ftuoro, 2'-methyoxy, 2'-ethyoxy, 2'-methoxyethoxy, 2'-allyloxy (- OCH2CH=CH2), 2' propyl, ethynyl, ethenyl, propenyl, and cyano and the like. In one embodiment, the sugar moiety can be a hexose and incorporated into an oligomer as described (Augustyns, K., et al., Nucl. Acids. Res. 1992. 18:4711). Exemplary nucleomonomers can be found, e.g., in US Patent 5,849,902. The term "base" includes the known purine and pyrimidine heterocychc bases, deazapurines, and analogs (including heterocycl substituted analogs, e.g. aminoethyoxy phenoxazine), derivatives (e.g. 1-alkenyl-, 1-alkynyl-, heteroaromatic- and 1-alkynyl derivatives) and tautomers thereof. Examples of purines include adenine, guanine, inosine, diaminopurine, and xanthine and analogs (e.g., 8-oxo-N°methyladenine or 7-diazaxanthine) and derivatives thereof. Pyrimidines include, for example, thymine, uracil, and cytosine, and their analogs (e.g., 5-methylcytosine, 5-methyluracil, 5-(l-propynyl)uracil, 5-(l- propynyl)cytosine and 4,4-ethanocytosine). Other examples of suitable bases include non- purinyl and non-pyrimidinyl bases such as 2-aminopyridine and triazines. The term "nucleoside" includes bases which are covalently attached to a sugar moiety, preferably ribose or deoxyribose. Examples of preferred nucleosides include ribonucleosides and deoxyribonucleosides. Nucleosides also include bases linked to amino acids and/or amino acid analogs which may comprise free carboxyl groups, free amino groups, or protecting groups. Suitable protecting groups are well known in the art (see: T.W. Greene, "Protective Groups in Organic Synthesis", Wiley, New York, 1981 ; J.F.W. McOmie (ed.), "Protective Groups in Organic Chemistry", Plenum, New York, 1973). The term "nucleotide" includes nucleosides which further comprise a phosphate group or a phosphate analog. As used herein, the term "linkage" includes a naturally occurring, unmodified phosphodiester moiety (-O-P(O)(O)-O-) that covalently couples adjacent nucleomonomers. As used herein, the term "substitute linkage" includes any analog or derivative of the native phosphodiester group that covalently couples adjacent nucleomonomers. Substitute linkages include phosphodiester analogs, e.g., such as phosphorothioate, phosphorodithioate, and P- ethyoxyphosphodiester, p-ethoxyphosphodiester, p alkyloxyphosphotriester, methylphosphnate, and nonphosphorus containing linkages, e.g., such as acetals and amides. Such substitute linkages are known in the art (e.g., Bjergarde et al. 1991. Nucleic Acids Res. 19:5843; Caruthers et al. 1991. Nucleosides Nucleotides. 10:47). Oligomers of the invention comprise 3' and 5' termini. The 3' and 5' termini of an oligomer can be substantially protected from nucleases e.g., by modifying the 3' and/or 5' linkages (e.g., WO 93/13121). For example, oligomers can be made resistant to nucleases by the inclusion of a "blocking group." The term "blocking group" as used herein refers to substituents (e.g., other than OH groups) that can be attached to oligomers or nucleomonomers, either as protecting groups or coupling groups for synthesis (e.g., hydrogen phosphonate, phosphoramidite, or PO3 ~ 2). "Blocking groups" also include "end blocking groups" or "exonuclease blocking groups" which protect the 5' and 3' termini of the oligomer, including modified nucleotides and non-nucleotide exonuclease resistant structures. Exemplary end-blocking groups include cap structures (e.g., a 7-methylguanosine cap), inverted nucleomonomers, e.g., with 3'-3' and/or 5'-5' end inversions (see e.g., Ortiagao et al. 1992. Antisense Res. Dev. 2:129), methylphosphonate, phosphoramidite, non-nucleotide groups (e.g., non-nucleotide linkers, amino linkers, conjugates) and the like. The 3' terminal nucleomonomer can comprise a modified sugar moiety. The 3' terminal nucleomonomer comprises a 3'-O that can optionally be substituted by a blocking group that prevents 3'- exonuclease degradation of the oligonucleotide. For example, the 3'-hydroxyl is esterified to a nucleotide through a 3'-»3' internucleotide linkage. For example, the alkyloxy radical can be methoxy, ethoxy, or isopropoxy, and preferably, ethoxy. Optionally, the 3 '— »3' linked nucleotide at the 3' terminus can be linked by a substitute linkage. To reduce nuclease degradation, the 5' most 3'— >5' linkage can be a modified linkage, e.g., a phosphorothioate or a P-alkyloxyphosphotriester linkage. Preferably, the two 5' most 3'— >5' linkages can be modified linkages. Optionally, the 5' terminal hydroxy moiety can be esterified with a phosphorus containing moiety, e.g., phosphate, phosphorothioate, or P-ethoxyphosphate. As used herein, the terms "peptide nucleic acids" or "PNAs" refer to nucleic acid mimics, e.g., DNA or RNA mimics, in which the deoxyribose phosphate backbone is replaced by a pseudopeptide backbone and only the four nucleobases (natural or modified) are retained. The neutral backbone of PNAs has been shown to allow for specific hybridization to DNA and RNA under conditions of low ionic strength. The synthesis of PNA oligomers can be performed using standard solid phase peptide synthesis protocols as described in Hyrup B. et al. (1996) supra; Perry-O'Keefe et al. Proc. Natl. Acad. Sci. 93: 14670-675. The term "chimeric oligomer" includes oligomers which comprise different component parts or regions which impart a desired quality to the oligomer. For example, specific regions of the oligomer (i.e., segments of the oligomer comprising at least one nucleomonomer) can provide stability against endonucleases, stability against exonucleases, complementarity with the target sequence, RNase H recruitment and activation, or the like. Regions may be multifunctional, e.g., providing more than one quality to the oligomer, e.g., complementarity and stability or RNase activation and complementarity. In addition, those of skill in the art will recognize that there may be more than one region imparting the same quality to one oligomer. The term "chimeric oligomer" includes oligomers having an RNA- like and a DNA-like region. The language "RNase H activating region" includes a region of an oligomer, e.g. a chimeric oligomer, that is capable of recruiting RNase H to cleave the target RNA strand to which the oligomer binds. Typically, the RNase activating region contains a minimal core (of at least about 3-5, typically between about 3-12, more typically, between about 5-12, and more preferably between about 5-10 contiguous nucleomonomers) of DNA or DNA-like nucleomonomers. More preferably, the RNase H activating region comprises about nine deoxyribose containing nucleomonomers. Preferably, the contiguous nucleomonomers are linked by a substitute linkage, e.g., a phosphorothioate linkage. The language "non-activating region" includes a region of an oligomer, e.g. a chimeric oligomer, that does not recruit or activate RNase H. Preferably, a non-activating region does not comprise phosphorothioate DNA. In one embodiment a non-activating region can comprise between about 10 and about 30 nucleomonomers. The non-activating region can be stabilized against nucleases and/or can provide specificity for the target by being complementary to the target and forming hydrogen bonds with the target nucleic acid molecule, preferably an mRNA molecule, which is to be bound by the oligomer. The term "alkyl" includes saturated aliphatic groups, including straight-chain alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.), branched-chain alkyl groups (isopropyl, tert-butyl, isobutyl, etc.), cycloalkyl (alicyclic) groups (cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. The term alkyl further includes alkyl groups, which can further include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone. In an embodiment, a straight chain or branched chain alkyl has 10 or fewer carbon atoms in its backbone (e.g., C,-C ]0 for straight chain, C 3 -C 10 for branched chain), and more preferably 6 or fewer. Likewise, preferred cycloalkyls have from 4-7 carbon atoms in their ring structure, and more preferably have 5 or 6 carbons in the ring structure. Moreover, the term alkyl includes both "unsubstituted alkyls" and "substituted alkyls", the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkyl sulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Cycloalkyls can be further substituted, e.g., with the substituents described above. An "alkylaryl" or an "aralkyl" moiety is an alkyl substituted with an aryl (e.g., phenylmethyl (benzyl)). The term "alkyl" also includes the side chains of natural and unnatural amino acids. Examples of halogenated alkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, perfluoromethyl, perchloromethyl, perfluoroethyl, perchloroethyl, etc. The term "aryl" includes groups, including 5- and 6-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, phenyl, pyrrole, furan, thiophene, thiazole, isothiaozole, imidazole, triazole, tetrazole, pyrazole, oxazole, isooxazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. Furthermore, the term "aryl" includes multicyclic aryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, napthridine, indole, benzofuran, purine, benzofuran, deazapurine, or indolizine. Those aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles", "heterocycles," "heteroaryls" or "heteroaromatics". The aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl groups can also be fused or bridged with alicyclic or heterocychc rings which are not aromatic so as to form a polycycle (e.g., tetralin). The term "alkenyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond. For example, the term "alkenyl" includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc.), branched- chain alkenyl groups, cycloalkenyl (alicyclic) groups (cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), alkyl or alkenyl substituted cycloalkenyl groups, and cycloalkyl or cycloalkenyl substituted alkenyl groups. The term alkenyl further includes alkenyl groups which include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone. In certain embodiments, a straight chain or branched chain alkenyl group has 6 or fewer carbon atoms in its backbone (e.g., C2-Cg for straight chain, C3-C6 for branched chain). Likewise, cycloalkenyl groups may have from 3-8 carbon atoms in their ring structure, and more preferably have 5 or 6 carbons in the ring structure. The term C 2 -C 6 includes alkenyl groups containing 2 to 6 carbon atoms. Moreover, the term alkenyl includes both "unsubstituted alkenyls" and "substituted alkenyls", the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. The term "alkynyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, the term "alkynyl" includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, etc.), branched- chain alkynyl groups, and cycloalkyl or cycloalkenyl substituted alkynyl groups. The term alkynyl further includes alkynyl groups which include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone. In certain embodiments, a straight chain or branched chain alkynyl group has 6 or fewer carbon atoms in its backbone (e.g., C2-Cg for straight chain, C3-C6 for branched chain). The term C 2 -C 6 includes alkynyl groups containing 2 to 6 carbon atoms. Moreover, the term alkynyl includes both "unsubstituted alkynyls" and "substituted alkynyls", the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. The terms "alkoxyalkyl", "alkylaminoalkyl" and "thioalkoxyalkyl" include alkyl groups, as described above, which further include oxygen, nitrogen or sulfur atoms replacing one or more carbons of the hydrocarbon backbone, e.g., oxygen, nitrogen or sulfur atoms. The term "alkoxy" includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups and may include cyclic groups such as cyclopentoxy. The term "amine" or "amino" includes compounds where a nitrogen atom is covalently bonded to at least one carbon or heteroatom. The term "alkyl amino" includes groups and compounds wherein the nitrogen is bound to at least one additional alkyl group. The term "dialkyl amino" includes groups wherein the nitrogen atom is bound to at least two additional alkyl groups. The term "arylamino" and "diarylamino" include groups wherein the nitrogen is bound to at least one or two aryl groups, respectively. The term "alkylarylamino," "alkylaminoaryl" or "arylaminoalkyl" refers to an amino group which is bound to at least one alkyl group and at least one aryl group. The term "alkaminoalkyl" refers to an alkyl, alkenyl, or alkynyl group bound to a nitrogen atom which is also bound to an alkyl group. The term "amide" or "aminocarboxy" includes compounds or moieties which contain a nitrogen atom which is bound to the carbon of a carbonyl or a thiocarbonyl group. The term includes "alkaminocarboxy" groups which include alkyl, alkenyl, or alkynyl groups bound to an amino group bound to a carboxy group. It includes arylaminocarboxy groups which include aryl or heteroaryl moieties bound to an amino group which is bound to the carbon of a carbonyl or thiocarbonyl group. The terms "alkylaminocarboxy," "alkenylaminocarboxy," "alkynylaminocarboxy," and "arylaminocarboxy" include moieties wherein alkyl, alkenyl, alkynyl and aryl moieties, respectively, are bound to a nitrogen atom which is in turn bound to the carbon of a carbonyl group. The term "carbonyl" or "carboxy" includes compounds and moieties which contain a carbon connected with a double bond to an oxygen atom, and tautomeric forms thereofExamples of moieties which contain a carbonyl include aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, etc. The term "carboxy moiety" or "carbonyl moiety" refers to groups such as "alkylcarbonyl" groups wherein an alkyl group is covalently bound to a carbonyl group, "alkenylcarbonyl" groups wherein an alkenyl group is covalently bound to a carbonyl group, "alkynylcarbonyl" groups wherein an alkynyl group is covalently bound to a carbonyl group, "arylcarbonyl" groups wherein an aryl group is covalently attached to the carbonyl group. Furthermore, the term also refers to groups wherein one or more heteroatoms are covalently bonded to the carbonyl moiety. For example, the term includes moieties such as, for example, aminocarbonyl moieties, (wherein a nitrogen atom is bound to the carbon of the carbonyl group, e.g., an amide), aminocarbonyloxy moieties, wherein an oxygen and a nitrogen atom are both bond to the carbon of the carbonyl group (e.g., also refered to as a "carbamate"). Furthermore, aminocarbonylamino groups (e.g., ureas) are also include as well as other combinations of carbonyl groups bound to heteroatoms (e.g., nitrogen, oxygen, sulfur, etc. as well as carbon atoms). Furthermore, the heteroatom can be further substituted with one or more alkyl, alkenyl, alkynyl, aryl, aralkyl, acyl, etc. moieties. The term "thiocarbonyl" or "thiocarboxy" includes compounds and moieties which contain a carbon connected with a double bond to a sulfur atom. The term "thiocarbonyl moiety" includes moieties which are analogous to carbonyl moieties. For example, "thiocarbonyl" moieties include aminothiocarbonyl, wherein an amino group is bound to the carbon atom of the thiocarbonyl group, furthermore other thiocarbonyl moieties include, oxythiocarbonyls (oxygen bound to the carbon atom), aminothiocarbonylamino groups, etc. The term "ether" includes compounds or moieties which contain an oxygen bonded to two different carbon atoms or heteroatoms. For example, the term includes "alkoxyalkyl" which refers to an alkyl, alkenyl, or alkynyl group covalently bonded to an oxygen atom which is covalently bonded to another alkyl group. The term "ester" includes compounds and moieties which contain a carbon or a heteroatom bound to an oxygen atom which is bonded to the carbon of a carbonyl group. The term "ester" includes alkoxycarboxy groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxy carbonyl, pentoxy carbonyl, etc. The alkyl, alkenyl, or alkynyl groups are as defined above. The term "thioether" includes compounds and moieties which contain a sulfur atom bonded to two different carbon or hetero atoms. Examples of thioethers include, but are not limited to alkthioalkyls, alkthioalkenyls, and alkthioalkynyls. The term "alkthioalkyls" include compounds with an alkyl, alkenyl, or alkynyl group bonded to a sulfur atom which is bonded to an alkyl group. Similarly, the term "alkthioalkenyls" and alkthioalkynyls" refer to compounds or moieties wherein an alkyl, alkenyl, or alkynyl group is bonded to a sulfur atom which is covalently bonded to an alkynyl group. The term "hydroxy" or "hydroxyl" includes groups with an -OH or -O " . The term "halogen" includes fluorine, bromine, chlorine, iodine, etc. The term "heteroatom" includes atoms of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur and phosphorus. The term "heterocycle" or "heterocychc" includes saturated, unsaturated, aromatic ("heteroaryls" or "heteroaromatic") and polycyclic rings which contain one or more heteroatoms. Examples of heterocycles include, for example, benzodioxazole, benzofuran, benzoimidazole, benzothiazole, benzothiophene, benzoxazole, deazapurine, furan, indole, indolizine, imidazole, isooxazole, isoquinoline, isothiaozole, methylenedioxyphenyl, napthridine, oxazole, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinoline, tetrazole, thiazole, thiophene, and triazole. Other heterocycles include morpholine, piprazine, piperidine, thiomorpholine, and thioazolidine. The heterocycles may be substituted or unsubstituted. Examples of substituents include, for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, alkylaminoacarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkyl, alkylaryl, or an aromatic or heteroaromatic moiety. Enhancing Activity of Oligomers In one embodiment, the invention is directed to oligomers which comprise nucleomonomers comprising a 2' OH protecting group to make a 2'O-X modified nucleomonomer (where X is the protecting group). 2'OH modified RNA is used extensively in antisense, because it imparts partial nuclease stability and low toxicity, as well as high hybridization affinity. Many 2'OH protecting groups have been used to protect the 2' OH group during RNA synthesis. However, 2'OH protecting groups are often bulky. The term "bulky" blocking group includes blocking groups that contain more than about 15 atoms. In some instances, bulky blocking groups have been found to interfere with hybridization to target molecules. In one embodiment, at least one nucleomonomer comprising a bulky 2'OH blocking group is used at the 5' and/or 3' end of an oligomer. In another embodiment, an oligomer of the invention comprises at least one nucleomonomer having a bulky blocking group which nucleomonomer(s) is located at a distance of no more than 5 nucleomonomers away from the 5' and/or 3' end(s) of an oligomer. In one embodiment, an oligomer comprising a bulky blocking group further comprises at least one nucleomonomer comprising a 2'OH blocking group which is not bulky, (contains less than about 15 atoms) e.g., a 2'O-methyl blocking group. In one embodiment, a 2'OH protecting group is a silicon-based protecting group. As used herein, the term "silicon-based protecting group" includes groups of the formula - SiR]R 2 R 3 , wherein R, and R 2 and R 3 are substituted or unsubstituted, branched or unbranched alkyl, alkenyl, or alkynyl groups. Preferrably, R,, R 2 , and R 3 are lower alkyl, such as methyl, ethyl, or butyl. Rl, R2, and R3 can contain cyclic groups and may be linked to each other to form silicon containing heterocycles. In one embodiment, Rl, R2, and R3 are substituted with hydrophobic groups, such a halogens. Suitable silicon-based protecting groups are known in the art (see, for example, J.F. Klebe, Advances in Organic Chemistry, Method and Results, Vol. 8, E.C. Taylor (ed.) Wiley-Interscience, New York, 1972, pp. 97-178; A.E. Pierce, Silylation of Organic Compounds, Pierce Chemical Company, Rockford, Illinois, 1968). Examples of silicon-based protecting groups include trimethylsilyl (TMS), and perferrably, t-butyldimethylsilyl (TBDMS). TBDMS In a preferred embodiment, a 2'OH protecting group is a precursor protecting group. As used herein, the term "precursor protecting group" includes 2'OH protecting groups present on nucleomonomers which are meant to be removed from the 2'OH prior to the delivery of an oligomer to a cell. Although such nucleomonomers are intended for use as precursors, i.e., the protecting groups are meant to be removed in a deprotecting step, the instant examples demonstrate that such oligomers can be incorporated into oligomers for delivery to a cell. Surprisingly, the instant examples demonstrate that oligomers having nucleomonomers comprising 2'OH precursor protecting groups with bulky substituents, which would be predicted to have decreased affinity and reduced activity relative to control oligomers without such substituents (e.g., having only 2'-O-methyl nucleomonomers and exonuclease blocking groups), have been found to be more potent than such control oligomers. This surprising discovery imparts several advantages to the oligomers of the instant invention. For example, it is convenient to use 2' -O-X modified nucleomonomers comprising precursor protecting groups (e.g., where X is a silicon-based protecting group) because such protected RNA nucleomonomers are used widely for RNA synthesis and are readily available. In addition, such nucleomonomers are relatively inexpensive (compared to other 2'-O-X modified nucleomonomers) and have well characterized coupling conditions. In one embodiment, at least one (e.g., between at least one and about 20, between at least one and about 10, or between at least one and about 5) 2'OH protecting groups are included on at least one end of an oligomer of the invention. In another embodiment, an oligomer comprises 2'OH protecting groups on both the 3' end and the 5' end of the oligomer. In a preferred embodiment, at least about 3 2' OH protecting groups are placed on at least one end of the oligomer. It will be understood that the oligomers of the invention which comprise nucleomonomers having 2'OH protecting groups, e.g., TBDMS groups, can further comprise nucleomonomers which comprise other 2'OH protecting groups, e.g., 2'O-methyl groups. In a preferred embodiment, an oligomer of the invention comprising a 2'OH protecting group is configured as shown in the representative example shown below: A«B«B'«C (where A represents a region of the oligomer which activates RNase H (e.g., comprising between about 5 to about 12 nucleomonomers linked by modified linkages (e.g., comprising a region of nucleomonomers linked by phosphorothioate or phosphorodithioate linkages, a region linked by both phosphorothioate or other alternative linkages and unmodified linkages, or a region containing mostly phosphorothioate linkages with some unmodified linkages); B represents a region of the oligomer comprising nucleomonomers having at least one 2' -O-methyl RNA (e.g., comprising between about 1 to about 20 nucleomonomers comprising 2'O-methyl); B' represents a region of the oligomer comprising nucleomonomers having 2'-OH silicon-based protecting groups (e.g., comprising between about 1 to about 20 nucleomonomers comprising silicon-based protecting groups); C represents an exonuclease blocking group (e.g., a phosphorothioate linkage, an inverted nucleomonomer, or a propyl linker group as a blocking group (e.g., available from TriLink Biotechnologies, Inc.; San Diego, CA) or another blocking group known in the art. In another embodiment, an oligomer of the invention is configured as depicted in the representative examples below which rely on steric blocking of target sequences, rather than RNase activation: B' In yet another embodiment, an oligomer of the invention is configured, as depicted in the representative examples below which are RNase H activating antisense oligomers protected from exonucleases by B' or C. A«B* A«B'»C C*B'«A B'»A B'»B»A C»B'« B«A Enhanced Identification of Genes Involved In Physiological Processes In another aspect, the invention provides a method to identify genes involved in a physiological or pathological process, and validate their involvement in such process. Antisense oligomers are capable of targeting partially mismatched (or perfectly matched) sites that are not the original intended target site (Woolf, T.M., et al. 1992. Proc. Natl. Acad. Sci, 89, 7305). This can occur if an oligomer is of sufficiently high affinity to bind to partially matched sequences and inactivate those sequences. If the oligomer is short enough, and of high enough affinity (e.g., between about 7 to about 15 nucleotides), identical matches to unintended targets will occur frequently. These unintended hybridization events are normally thought of as disadvantageous when designing antisense oligomers as specific target validation or gene function analysis tools (Woolf, T.M., et al. 1992 Proc. Natl. Acad. Sci, 89, 7305-7309). However, this potential lack of specificity can be used to make a single oligomer that is likely to inhibit more than one target gene (e.g., preferably from between about 5 to about 500 target genes). By increasing the number of target sites to which an oligomer binds, one can maximize their chances of identifying a target of interest. Preferably, the maximum number of target genes will be kept below 500 to avoid toxicity to the target cell. In order to perform such a screen, many oligomers of different sequences are synthesized. In one embodiment, such sequences are arbitrary, i.e., randomly generated, but fixed, i.e., unchanging. In another embodiment, such sequences are designed to target at least one known gene. In yet another embodiment, the antisense oligomers can also be targeted to a known region of high sequence conservation, to make them more likely to cross-hybridize. Optionally, highly conserved regions of genes likely to be good targets for therapeutic intervention could be chosen (kinases, G protein coupled receptors, channels...etc). The affinity characteristics (>60 degrees C) and RNase H activation characteristics of the oligomer chemistry, sequence, and length, are designed to make the oligomer cross-hybridize to from between about 5 to about 500 targets. This can be accomplished by altering the affinity of the oligomer for its complementary sequence. For example, if the affinity of the oligomer is increased, the number of partial mismatched genes that have enough affinity to bind to the oligomer. The affinity of an oligomer can also be altered by using an oligomer chemistry that activates RNase H, which tends to be less specific than other types of oligomers, because with RNase H activating oligomers even transient, or low affinity binding can lead to irreversible cleavage of the target RNA (Woolf, T.M., et al. 1992. Proc. Natl. Acad. Sci. 89, 7305-7309). In one embodiment, the affinity of the oligomer can be increased by any number of approaches known in the art, including incorporation of the following modifications, while retaining from about 6 to about 12 phosphorothioate linked DNA nucleomonomers to activate RNase H. For example, such nucleomonomers can comprise: 2'- modifications such as 2' -O-methyl, 2' fluro, or 2' methoxyethoxy.( e.g., US patent 5,849,902); propyne C and U modifications ( Flanagan, W.M. and Wagner, R.W. 1997. Molecular and Cellular Biochemistry, 112, 213-225.); Morpholino modifications; and/or PNA modifications as known in the art. In one embodiment, the specificity of the oligomer can be reduced by incorporating "universal" nucleomonomers. The term "Universal nucleomonomers" as used herein include those which bind to more than one or to all four of the target bases (i.e., A, C, U and G). Such universal nucleomonomers are known in the art, and include, e.g., deoxyinosine and deoxynebularin. In particular, the "universal" nucleomonomers could be used in the all or part of the phosphorothioate region which activates RNase H. The term "cross-hybridizing oligomers: as used herein includes a collection of cross- hybridizing oligomers, (i.e., a collection of oligomers having universal nucleomonomers at various positions (e.g., between about 100 to about 10,000 oligomers)) can be separately delivered to a cell line (e.g., by transfection). This can be accomplished, for example, using multi-well plates. In one embodiment, the transfection conditions can be optimized using commercially available cationic lipids (e.g., Lewis, J., et al. 1996. Proc Natl Acad Sci USA, 93, 3176-81) or other methods, and a fluorescent control oligomer of the same chemistry. Preferably, the control oligomer targets a known accessible antisense target in a control gene. The control serves the purpose of confirming inhibition of the control gene (e.g., beta-actin). The cross-hybridizing oligomers can be used in an assay (e.g., set up in a high throughput format) to identify physiologically relevant genes. For example, if one desired to find genes which, when inhibited, would inhibit production of a given molecule (e.g., IgE) a collection of cross-hybridizing nucleomonomers can be separately delivered to a cell that makes IgE, (previously or subsequently stimulated to make IgE) and an ELISA for IgE could be done on the cellular supernatants. Individual oligomers which inhibit IgE production can be identified and characterized. As another example, to inhibit the secretion or processing of an Alzheimer's plaque forming protein (e.g., by targeting an RNA encoding an upstream gene in the cascade of Alzheimer's protein processing), one could screen for oligomers which inhibit expression of this protein. In one embodiment, a luciferase reporter gene, with its expression driven by a cellular promoter of interest could be used as a readout. Once an active cross-hybridizing (ACH) oligomer is identified with the desired phenotype (i.e., which has the desired physiological or pathological effect), the genes for which the ACH oligomer may inhibit are identified. In making oligomers having "universal" bases, the degeneracy of the oligomer can be reduced one or two bases at a time by fixing one or two of the universal bases in a re- synthesis of the ACH for use in a secondary screen. This would require 4 or 16 resynthesized oligomers, respectively. Each of these oligomers could then be individually transfected into cells and the phenotype of the cell analyzed. In this second round of screening, oligomers identified as ACH represent a less degenerate oligomer (i.e., a more specific oligomer). This process is illustrated by example below. This screening process can be reiterated by changing the remaining universal base positions, until a single ACH sequence (or small number of ACH sequences) is/are determined. For example, if the ACH sequence is: Primary screen: NNNNNNATCCGGATTACCAAACCATCA (SEQ ID NO:l) (where N is a universal base) One could synthesize the following oligomers, and test for their ability to alter the phenotype of the cell in the same manner as the parent oligomer above. Secondary screen: 1)NNNNNAATCCGGATTACCAAACCATCA (SEQ ID NO:2) 2)NNNNNTATCCGGATTACCAAACCATCA (SEQ ID NO:3) 3)NNNNNCATCCGGATTACCAAACCATCA (SEQIDNO:4) 4)NNNNNGATCCGGATTACCAAACCATCA (SEQ ID NO:5) If oligomer number 2 in the secondary screen list above (i.e., comprising a T at nucleomonomer position 6) showed the best inhibition (e.g., produced the most intense phenotype or produced the phenotype at the lowest dose), one would then fix this base at T, and make four more oligomers: Tertiary screen: NNNNATATCCGGATTACCAAACCATCA (SEQ ID NO:6) NNNNTTATCCGGATTACCAAACCATCA (SEQ ID NO:7) NNNNCTATCCGGATTACCAAACCATCA (SEQ ID NO:8) NNNNGTATCCGGATTACCAAACCATCA (SEQ ID NO:9) This process would be reiterated at each degenerate position, until the most active fixed sequence(s) are defined. The most active sequence could then be used for identification of the actual gene which is inhibited, e.g., by using computer homology searches or hybridization techniques. For example, in one embodiment, computer searches for homology of the ACH sequences to nucleotide databases (e.g., using BLAST or BLAST 2, on the National Institutes of Health server) can be performed. If using an oligomer that activates RNase H, then introns, coding regions and the 5' and 3' UTR must be searched for homologies. If using an oligomer that works by steric inhibition, then only the splice junctions, and 5' UTR and start codon region need be checked for homology. All genes identified as having substantial homology to the oligomer, i.e., sufficient homology to allow the oligomer to bind tightly (e.g., about 80% nucleotide sequence identity), are candidates for the gene targeted by the oligomer. The percent identity between two sequences is a function of the number of identical positions shared by two sequences (i.e., % identity = # of identical positions/total # of positions in the oligomer x 100). Algorithms are also often used to optimally align and compare two nucleotide or amino acid sequences to define the percent identity between the two sequences. A preferred, non-limiting example of a mathematical algorithm utilized for the comparison of two sequences is the algorithm of Karlin and Altschul (1990) Proc. Natl. Acad. Sci. USA 87:2264-68, modified as in Karlin and Altschul (1993) Proc. Natl. Acad. Sci. USA 90:5873-77. Such an algorithm is incorporated into the NBLAST and XBLAST programs of Altschul, et al. (1990) J. Mol. Biol. 215:403-10. When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used. See http://www.ncbi.nlm.nih.gov. The search for genes targeted by oligomerscan be further limited, e.g., using data from expression profiling technology (e.g., oligomer gene chips, SAGE, or others, which identify genes expressed in certain cell types) to limit the search to genes expressed in the cell type of interest. In addition, the search can be further limited by only examining potential candidate genes preliminarily identified using a different process (e.g., differential display or bioinformatics). In another embodiment, candidate genes can be identified by experimental methods such as hybridization of the labeled (radioactive or non-radioactive) ACH to arrays or libraries of cloned DNA at physiological stringency. The stringency conditions can be determined empirically by comparing the effect of nucleotide mismatches between antisense oligomers and target nucleic acid molecules on the ability of an antisense molecule to modulate transcription in a cell. In general, physiological stringency is roughly 150-300mM salt at 37°C. Candidate genes can be validated by synthesizing a number of antisense oligomers and control oligomers targeting different sites on the candidate gene, delivering these oligomers to cells, and confirming that the antisense, but not control oligomers produce the desired change in phenotype. Enhanced Uptake of oligomers by cells In one embodiment, the uptake of short oligomers by cells is enhanced. Short oligomers (e.g., from between about 7 to about 12 nucleomonomers) have been shown to have high enough hybrid affinity to be active in cell culture ( Flanagan, W.M. and Wagner, R.W. (1997) Molecular and Cellular Biochemistry, 172, 213-225.). The propyne modified phosphorothioate oligomers used in the art formed substrates for RNase H and cleaved the target RNA. A problem with the prior art oligomers that are shorter than about 12 to about 25 nucleotides, however, is that they may activate RNase-H at unintended sites within the RNA in cell and lead to non-specific cleavage (Woolf, T.M., et al. 1992. Proc. Natl. Acad. Sci., 89 , 7305-7309). There are many advantages of short oligomers, e.g., they are more readily synthesized and purified, thus greatly reducing costs. In addition, they allow the possibility of cell permeation without using transfection reagents (Flanagan, W., et al. 1999. Nature Biotechnology, 17, 48-52). The short oligomers or the prior art did not work if they were further modified to render them unable to activate RNase-H (Flanagan, W.M. and Wagner, R.W. (1997) Molecular and Cellular Biochemistry, 172, 213-225; Flanagan, W., et al. 1999. Nature Biotechnology, 17, 48-52). However, in one embodiment of the invention, oligomers are rendered unable to activate RNase H, i.e., such that they act by steric inhibition (Flanagan, W., et al. 1999. Nature Biotechnology, 17, 48-52.; Woolf, T.M. (\995) Antisense Res Dev, 5, 227-32). This steric blocking mechanism is inherently much more specific than the RNase activating mechanism because steric blocking is not generally effective if an oligomer inadvertently binds to the coding region or the introns or 3' UTR of an RNA molecule. In general, steric blocking oligomers are only active at splice junctions and the 5' UTR and start codon region of an RNA. In fact, in cell culture experiments negatively charged oligomers that function via a steric blocking mechanism may not work at any site in the 5' UTR, but rather are further limited to the extreme 5' of a message as an active site. (Monia, B. Cambridge Healthtech Institute antisense conference (Fairmont Hotel, San Francisco, CA, June 21-23 1998). In one embodiment, the instant oligomers are short (e.g., 7-12 nucleomonomers), are of high affinity, and target the extreme 5' terminus (e.g., within 5 nucleotides or the 5' cap), or target the 5' or 3' splice junctions (e.g., within 20 nucleotides of a splice junction or other site necessary for splicing). Using oligomers designed in this manner, the instant invention provides for enhanced cell permeation , enhanced ease of synthesis and purification, high specificity (i.e., the oligomers do not activate RNase H and are only active in limited regions of target or untargeted RNA), high activity, and nuclease resistance. As such, the instant oligomers are ideal for therapeutic use. In one embodiment the oligomers of the invention are modified to be more lipophilic for enhanced uptake. Such modification can be made using one or more of the following techniques: the incorporation of Propyne bases (Flanagan, W.M. and Wagner, R.W. (1997) Molecular and Cellular Biochemistry, 172, 213-225); the substitution of phenoxazine for some or all uridines; the incorporation of neutral backbones (such as PNA, morpholino, or methyl phosphonate). See also ( Flanagan, W., Wagner, R., Grant, D., Lin, K. and Matteucci, M. (1999) Nature Biotechnology, 17, 48-52.) In another embodiment, the oligomers of the invention do not activatet RNAse H. For examle, such an oligomer may incorporate a neutral backbone (such as PNA, moφholino, or methyl phosphonate); may incoφorate virtually any other sugar or backbone modification; and/or may incoφorate 2' -O-X modifications (where X is, e.g., an alkyl group. (Because such a modification will also increase the lipophilicity of the oligomer. In a preferred embodiment, the oligomer would also be modified to comprise only phosphorothioate linkages to block exonucleases)). In another embodiment, such an oligomer can be modified to dramatically enhance affinity, e.g., using one or more of the following modifications: a propyne modification, the inclusing of a G-Clamp (Flanagan et al. (1999) Proc. Natl. Acad, Sci, 96, 3513-8; the inclusion of intercalating agent; or by the inclusion of another art recognized group which is known to enhance hybrid affinity dramatically (e.g., such that a 7-12 nucleotide oligomer is capable of forming a thermodynamically stable hybrid at 37° C. To illustrate, an exemplary oligomer could be a 9 mer comprising a phosphorothioate backbone. In addition, the oligomer could be a 2'-propoxy oligomer comprising phenoxazine (Flanagan, W., et al. 1999 Nature Biotechnology, 17 , 48-52). The oligomer could comprise propyne modified C's as replacements for U's (Wagner, R.W., et al. 1993. Science, 260, 1510-3). Another exemplary oligomer is a PNA with propyne C's (Wagner, R.W., et al. 1993. Science, 260, 1510) and phenoxazine replacing the U's, and which targets the extreme 5' end of the message. In another aspect, the invention provides for enhanced uptake of neutral oligomers. Neutral oligomers are difficult to deliver to cells, e.g., by transfection, because they do not interact with cationic lipids commonly used for transfection. However, neutral backbone oligomers are desirable because they are highly nuclease resistant, and have very high specificity and low toxicity (Taylor, M. F., et al. 1996. J Biol Chem, 271(29), 17445-52. The instant invention provides for neutral backbone oligomers which are modified to include a one or more charged groups (e.g., positive or negative charges). Such charges can be used, e.g., to facilitate loading into cationic lipid vesicles, particles, or liposomes. The negative (or positive charge) also facillitates the electroporation of neutral compounds. The addition of charges does not adversely affect the low toxicity or activity of the otherwise neutral oligomers. Any charged group known in the art can be used in the instant methods. For example, exemplary negatively charged groups include, but are not limited to: carboxylate, phosphate, sulfate, nitrate, nitrite, hydroxyl, sulfite, bicarbonate, nitro, and other species which are anionic at physiological pH. Exemplary positively charged groups include amines and other species which are cationic at physiological pH. In one embodiment, one or more charged groups can be attached to the neutral backbone oligomers by a covalent linkage. The covalent linkage may be attached to any atom of the oligomer which allows the oligomer of the invention to perform its intended function. Covalent linkages include chains of 0-50 atoms, 0-40 atoms, 0-30 atoms, 0-20 atoms, 0-10 atoms, 1-9 atoms, 1-8 atoms, 1-7 atoms, 1-6 atoms, 1-5 atoms, 1-4 atoms, or 1-3 atoms. The atoms of the chain can be substituted or unsubstituted carbon, nitrogen, oxygen, phosphorous or sulfur atoms. The covalent linkage may include, for example, phosphate linkages, peptidic linkages, alkyl linkages, ester linkages, ether linkages, thioether linkages, phosphothionate, thioester linkages, etc. The covalent linkage can be any combination of atoms which allow the composition of the invention to perform its intended function. The chain may further comprise any substituents which allow the composition of the invention to perform its intended function. Examples of substituents of the covalent linkage include, but are not limited to, halogens (e.g., fluorine, chlorine, iodine, bromine, etc.), alkoxy (e.g., methoxy, ethoxy, isopropoxy, n-propyloxy, n-butyloxy, pentoxy, cyclopentoxy, arylalkyloxy, etc.) hydroxy, alkylcarbonyl, cyano, nitro, thiol, alkenyl, alkynyl (e.g., ethynyl, etc.), alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, trifluoromethyl, azido, heterocyclyl, alkylaryl, heteroaryl, alkyl, alkenyl, alkynyl, aryl, or combinations thereof. Further examples of substituents include the side chains of amino acids. Other examples include charged moieties and moities which enhance the ability of the composition of the invention to perform its function. In a further embodiment, one or more charges can be attached by a covalent linkage which is labile, e.g., enzymatically or chemically. Such a linkage can be cleaved within cells (e.g., the linkage can be a phosphodiester linkage). Example of moieties which are labile include peptidic, phosphodiester, phosphorothioate, or phosphodithionate linkages which can be cleaved in vivo. Other examples of labile moieties include thioesters, amides, carbamates, ureas, and other moieties known to those of ordinary skill in the art. The covalent linkages may be attached to the oligomer of the invention through derivitization of a functional group on the oligomer' s backbone. Examples of groups which can be derivitized include hydroxyl groups, thiol groups, phosphonate groups, amino groups, and carbonxylate groups. These groups are able to be easily reacted with compounds known in the art to form the covalent linkages discussed above. Examples of compounds which can be used to derivitize the oligomers of the invention include acid chlorides, halogenated compounds, etc. Derivatives of the oligomers can be synthesized by methods well known in the art (see, for example, March, Advanced Organic Chemistry, J. Wiley & Sons, New York, 1992). In an embodiment, the derivatives of the oligomers of the invention, enhance the ability of the oligomer to perform its intended function, e.g., by enhancing the ability of the compound to penetrate membranes, etc. In one embodiment, a carboxylate moiety (COO- or COOH) of the oligomer of the invention is derivatized with a carboxyl protecting group, which when cleaved in vivo, yields the free carboxyl groups. Examples of carboxyl protecting groups include prodrugs and their uses, which are well known in the art (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19). Other examples of carboxyl protecting groups include unsubstituted, branched or unbranched lower alkyl ester moieties, (e.g., ethyl esters), lower alkenyl esters, di-lower alkyl-amino lower-alkyl esters (e.g., dimethylaminoethyl ester), acylamino lower alkyl esters, acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters (phenyl ester), aryl-lower alkyl esters (e.g., benzyl ester), substituted (e.g., with methyl, halo, or methoxy substituents) aryl and aryl-lower alkyl esters, amides, lower-alkyl amides, di-lower alkyl amides, and hydroxy amides. Carboxylate groups can be converted into esters via treatment with an alcohol in the presence of a catalyst. One preferred example of a carboxyl protecting groups is succinate. The negative charges be linked using any method known in the art, but phosphodiester or phosphorothioate linkages are preferred. The linkages can be at any position on the oligomer, although linkages at the termini of the oligomer are preferred. Given the teachings above, standard methods can be used to prepare such oligomers. Once a charge or several charges are added to the otherwise neutral oligomer, standard transfection protocols with cationic lipids can be used to deliver the oligomer to a cell. The subject oligomers can incoφorate any neutral backbone, but moφholino and peptide backbones are preferred. One or more charges can also be noncovalently associated with the neutral oligomer, e.g., by complexing the otherwise neutral oligomer with a molecule comprising one or more negative charges. The negatively charged molecule and the neutral oligomer would have some affinity for each other in order to make a stable or transiently stable complex (i.e., the otherwise neutral oligmer and the charged molecule would bind or hybridize to each other, (for example, through hydrogen bonding or Van der Waals interactions). In one embodiment, the interaction is based on basepairing. In a preferred embodiment, the charged molecule is an oligomer bearing at least one charge. If base pairing is used to bind the negativley charged compound to the neutral oligomer, then the negatively charged compound could be natural or modified DNA or RNA with a phosphodiester or phosphorothioate containing backbone. The RNA could also be modified (e.g., 2'-O-methyl RNA). In another embodiment the charged molecule may be a lipophilic molecule and the lipophilic molecule and the otherwise neutral oligomer may interact via a hydrophobic interaction between a neutral portion of the negatively charged molecule, and the neutral oligomer. In one embodiment, the charged molecule binds only to a portion of the neutral oligomer, rather than across its entire length. The use of charged molecules which bind to the entire length of the neutral oligomer would eliminate the need to synthesize a different charged molecule for each different neutral oligomer made. Instead, a standard sequence (i.e., a single charged molecule) could be used. In a preferred embodiment, the charged molecule ios rich in G and C nucleotides, so that a short sequence cbe used to stably to the neutral oligomer. Preferably, an otherwise neutral oligomer that has been modified to comprise a charge as described herein is taken up by a cell more efficiently than a control, unmodified neutral oligomer. Such increased efficiency can be measured, e.g., by directly assaying for the presence of the oligomer (e.g., using a tagged molecule) or by assaying for increased inhibition of the target protein. Delivery of Oligomers to Cells Oligomers need to be delivered to, e.g., contacted with and taken up by, one or more cells. The term "cells" refers to prokaryotic and eukaryotic cells, preferably vertebrate cells, and, more preferably, mammalian cells. In a preferred embodiment, oligomers of the invention are contacted with human cells. Oligomers can be contacted with cells in vitro or in vivo. Oligomers are taken up by cells at a slow rate by endocytosis, but endocytosed oligomers are generally sequestered and not available for hybridization to target RNA. In other embodiments, delivery of oligomers into cells can be facilitated by suitable art recognized methods including calcium phosphate, DMSO, glycerol or dextran, electroporation, or by transfection, e.g., using cationic, anionic, and/or neutral lipid compositions or liposomes using methods known in the art (see e.g., WO 90/14074; WO 91/16024; WO 91/17424; U.S.Patent No. 4,897,355; Bergan et al. 1993. Nucleic Acids Research. 21 :3567). Enhanced delivery of oligomers can also be mediated by the use of viruses, polyamine or polycation conjugates using compounds such as polylysine, protamine, or Nl, N12-bis (ethyl) spermine (see e.g., Bartzatt, R. et al.1989. Biotechnol. Appl Biochem. 11 :133; Wagner E. et al. 1992. Proc. Natl. Acad. Sci. 88:4255). In one embodiment, oligomers can be derivitized or chemically modified to facilitate cellular uptake. For example, covalent linkage of a cholesterol moiety to an oligomer can improve cellular uptake by 5- to 10- fold which in turn improves DNA binding by about 10- fold (Boutorin et al., 1989, FEBS Letters 254:129-132). Similarly, derivatization of oligomers with poly-L-lysine can aid oligomer uptake by cells (Schell, 1974, Biochem. Biophys. Acta 340:323, and Lemaitre et al., 1987, Proc. Natl. Acad. Sci. USA 84:648). Certain protein carriers can also facilitate cellular uptake of oligomers, including, for example, serum albumin, nuclear proteins possessing signals for transport to the nucleus, and viral or bacterial proteins capable of cell membrane penetration. Therefore, protein carriers are useful when associated with or linked to the oligomers. Accordingly, the present invention contemplates derivatization of oligomers with groups capable of facilitating cellular uptake, including hydrocarbons and non-polar groups, cholesterol, poly-L-lysine and proteins, as well as other aryl or steroid groups and polycations having analogous beneficial effects, such as phenyl or naphthyl groups, quinoline, anthracene or phenanthracene groups, fatty acids, fatty alcohols and sesquiteφenes, diteφenes and steroids. In another embodiment, an oligomer may be associated with a carrier or vehicle, e.g., liposomes or micelles, although other carriers could be used, as would be appreciated by one skilled in the art. Such carriers are used to facilitate the cellular uptake and/or targeting of the oligomer, and/or improve the oligomer's pharmacokinetic and/or toxicologic properties. For example, the oligomers of the present invention may also be administered encapsulated in liposomes, pharmaceutical compositions wherein the active ingredient is contained either dispersed or variously present in coφuscles consisting of aqueous concentric layers adherent to lipidic layers. The oligomers, depending upon solubility, may be present both in the aqueous layer and in the lipidic layer, or in what is generally termed a liposomic suspension. The hydrophobic layer, generally but not exclusively, comprises phospholipids such as lecithin and sphingomyelin, steroids such as cholesterol, more or less ionic surfactants such as diacetylphosphate, stearylamine, or phosphatidic acid, and/or other materials of a hydrophobic nature. The diameters of the liposomes generally range from about 15 nm to about 5 microns. The use of liposomes as drug delivery vehicles offers several advantages. Liposomes increase intracellular stability, increase uptake efficiency and improve biological activity. Liposomes are hollow spherical vesicles composed of lipids arranged in a similar fashion as those lipids which make up the cell membrane. They have an internal aqueous space for entrapping water soluble compounds and range in size from 0.05 to several microns in diameter. Several studies have shown that liposomes can deliver nucleic acids to cells and that the nucleic acids remain biologically active. For example, a liposome delivery vehicle originally designed as a research tool, such as Lipofectin, can deliver intact nucleic acid molecules to cells. Specific advantages of using liposomes include the following: they are non-toxic and biodegradable in composition; they display long circulation half-lives; and recognition molecules can be readily attached to their surface for targeting to tissues. Finally, cost- effective manufacture of liposome-based pharmaceuticals, either in a liquid suspension or lyophilized product, has demonstrated the viability of this technology as an acceptable drug delivery system. Cationic lipids can also be used to deliver oligomers to cells. The term "cationic lipid" includes lipids and synthetic lipids having both polar and non-polar domains and which are capable of being positively charged at or around physiological pH and which bind to polyanions, such as nucleic acids, and facilitate the delivery of nucleic acids into cells. In general cationic lipids include saturated and unsaturated alkyl and alicyclic ethers and esters of amines, amides, or derivatives thereof. Straight-chain and branched alkyl and alkenyl groups of cationic lipids can contain, e.g., from 1 to about 25 carbon atoms. Preferred straight chain or branched alkyl or alkene groups have six or more carbon atoms. Alicyclic groups include cholesterol and other steroid groups. Cationic lipids can be prepared with a variety of counterions (anions) including, e.g., C1-, Br-, I-, F-, acetate, trifluoroacetate, sulfate, nitrite, and nitrate. Cationic lipids have been used in the art to deliver oligomers to cells (See e.g., 5,855,910; 5,851,548; 5,830,430; 5,780,053; 5,767,099; Lewis et al. 1996. Proc. Natl. Acad. Sci. USA 93:3176; Hope et al. 1998. Molecular Membrane Biology 15:1). Other lipid compositions which can be used to facilitate uptake of the instant oligomers can be used in connection with the claimed methods. In addition to those listed supra, other lipid compositions are also known in the art and include, e.g., those taught in US patent 4,235,871; US patent 4,501,728; 4,837,028; 4,737,323. In one embodiment lipid compositions can further comprise agents, e.g., viral proteins to enhance lipid- mediated transfections of oligomers (Kamata et al. 1994. Nucl. Acids. Res. 22:536). In another embodiment, oligomers are contacted with cells as part of a composition comprising an oligomer, a peptide, and a lipid as taught, e.g., in U.S. patent 5,736,392. Improved lipids have also been described which are serum resistant (Lewis et al. 1996. Proc. Natl. Acad. Sci. 93:3176) In another embodiment N-substituted glycine oligomers (peptoids) can be used to optimize uptake of oligomers. Peptoids have been used to create cationic lipid-like compounds for transfection (Muφhy et al. 1998. Proc. Natl. Acad. Sci. 95:1517). Peptoids can be synthesized usin standard methods (e.g., Zuckermann, R. N., et al. 1992. J Am. Chem. Soc. 114:10646; Zuckermann, R.N., et al. 1992. Int. J. Peptide Protein Res. 40:497). Combinations of cationic lipids and peptoids, liptoids, can also be used to optimize uptake of the subject oligomers (Hunag et al. 1998. Chemistry and Biology. 5:345). Liptoids can be synthesized by elaborating peptoid oligomers and coupling the amino terminal submonomer to a lipid via its amino group (Hunag et al. 1998. Chemistry and Biology. 5:345). Positively charged transduction reagents can be used to facilitate uptake. For example, it is known in the art that positively charged amino acids can be used for creating highly active cation lipids (Lewis et al. 1996. Proc. Natl. Acad. Sci. U.S.A. 93:3176). In one embodiment, a composition for delivering oligomers of the invention comprises a number of arginine, lysine, histadine and/or ornithine residues linked to a lipophilic moiety (see e.g., U.S. patent 5,777,153). In another, a composition for delivering oligomers of the invention comprises a peptide having from between about one to about four basic residues. These basic residues can be located, e.g., on the amino terminal, c-terminal, or internal region of the peptide. Families of amino acid residues having simila side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpola side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan) beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine phenylalanine, tryptophan, histidine). Apart from the basic amino acids, a majority or all of the other residues of the peptide can be selected from the non-basic amino acids, e.g., amino acids other than lysine, arginine, or histidine. Preferably a preponderance of neutral amino acids with long neutral side chains are used. For example, a peptide such as (N-term) His-Ile-Tφ-Leu-Ile-Tyr-Leu-Tφ-Ile- Val-(C-term) (SEQ ID NO: 10) could be used. In one embodiment such a composition can be mixe with the fusogenic lipid DOPE as is well known in the art. For example, in one embodiment, an oligomer can be contacted with cells in the presence of lipid such as cytofectin CS or GSV(available from Glen Research; Sterling, VA), GS3815, GS2888 for prolonged incubation periods as described herein. In one embodiment the incubation of the cells with the mixture comprising a lipid and the antisense construct does not reduce the viability of the cells. Preferably, after the transfection period the cells are substantially viable. In one embodiment, after transfection, the cells are between at least about 70 and at least about 100 percent viable. In another embodiment, the cells are between at least about 80 and at least about 95% viable. In yet another embodiment, the cells are between at least about 85% and at least about 90% viable. In one embodiment, oligomers are modified by attaching a peptide sequence that transports the oligomer into a cell, referred to herein as a "transporting peptide." In one embodiment, the composition includes an oligomer which is complementary to a target nucleic acid molecule encoding the protein, and a covalently attached transporting peptide. The language "transporting peptide" includes an amino acid sequence that facilitates the transport of an oligomer into a cell. Exemplary peptides which facilitate the transport of the moieties to which they are linked into cells are known in the art, and include, e.g., HIV TAT transcription factor, lactoferrin, Heφes VP22 protein, and fibroblast growth factor 2 (Pooga et al. 1998. Nature Biotechnology. 16:857; and Derossi et al. 1998. Trends in Cell Biology. 8:84; Elliott and O'Hare. 1997. Cell 88:223). For example, in one embodiment, the transporting peptide comprises an amino acid sequence derived from the antennapedia protein. Preferably, the peptide comprises amino acids 43-58 of the antennapedia protein (Arg-Gln-Ile-Lys-Ile-Tφ-Phe-Gln-Asn-Arg-Arg- Met-Lys-Tφ-Lys-Lys) (SEQ ID NO: 11) or a portion or variant thereof that facilitates transport of an oligomer into a cell (see, e.g., WO 91/1898; Derossi et al. 1998. Trends Cell Biol. 8:84). Exemplary variants are shown in Derossi et al., supra. In one embodiment, the transporting peptide comprises an amino acid sequence derived from the transportan, galanin (l-12)-Lys-mastoparan (1-14) amide, protein. (Pooga et al. 1998. Nature Biotechnology 16:857). Preferably, the peptide comprises the amino acids of the transportan protein shown in the sequence GWTLNSAGYLLGKINLKALAALAKKIL (SEQ ID NO: 12) or a portion or variant thereof that facilitates transport of an oligomer into a cell. In one embodiment, the transporting peptide comprises an amino acid sequence derived from the HIV TAT protein. Preferably, the peptide comprises amino acids 37-72 of the HIV TAT protein, e.g., shown in the sequence C(Acm)FITKALGISYGRKKRRQRRRPPQC (SEQ ID NO: 13 ) (TAT 37-60; where C(Acm) is Cys-acetamidomethyl) or a portion or variant thereof, e.g., C(Acm)GRKKRRQRRRPPQC (SEQ ID NO: 14) (TAT 48-40) or C(Acm)LGISYGRKKRRQRRPPQC (SEQ ID NO: 15) (TAT 43-60) that facilitates transport of an oligomer into a cell (Vives et al. 1997. J Biol. Chem. 272:16010). In another embodiment the peptide (G)CFITKALGISYGRKKRRQRRRPPQGSQTHQVSLSKQ (SEQ ID NO: 16)can be used. Portions or variants of transporting peptides can be readily tested to determine whether they are equivalent to these peptide portions by comparing their activity to the activity of the native peptide, e.g., their ability to transport fluorescently labeled oligomers to cells. Fragments or variants that retain the ability of the native transporting peptide to transport an oligomer into a cell are functionally equivalent and can be substituted for the native peptides. Oligomers can be attached to the transporting peptide using known techniques, e.g., (Prochiantz, A. 1996. Curr. Opin. Neurobiol. 6:629; Derossi et al. 1998. Trends Cell Biol. 8:84; Troy et al. 1996. J. Neurosci. 16:253), Vives et al. 1997. J. Biol. Chem. 272:16010). For example, in one embodiment, oligomers bearing an activated thiol group are linked via that thiol group to a cysteine present in a transport peptide (e.g., to the cysteine present in the b turn between the second and the third helix of the antennapedia homeodomain as taught, e.g., in Derossi et al. 1998. Trends Cell Biol. 8:84; Prochiantz. 1996. Current Opinion in Neurobiol. 6:629; Allinquant et al. 1995. J. Cell Biol. 128:919). In another embodiment, a Boc-Cys-(Npys)OH group can be coupled to the transport peptide as the last (N terminal) amino acid and an oligomer bearing an SH group can be coupled to the peptide (Troy et al. 1996. J. Neurosci. 16:253). In one embodiment, a linking group can be attached to a nucleomonomer and the transporting peptide can be covalently attached to the linker. In one embodiment, a linker can function as both an attachment site for a transporting peptide and can provide stability against nucleases. Examples of suitable linkers include substituted or unsubstituted C r C 20 alkyl chains, C,-C 20 alkenyl chains, C,-C 20 alkynyl chains, peptides, and heteroatoms (e.g., S, O, NH, etc.). Other exemplary linkers include bifunctional crosslinking agents such as sulfosuccinimidyl-4-(maleimidophenyl)-butyrate (SMPB) (see e.g., Smith et al. Biochem J 1991. 276: 417-2). In one embodiment, oligomers of the invention are synthesized as molecular conjugates which utilize receptor-mediated endocytotic mechanisms for delivering genes into cells (See e.g., Bunnell et al. 1992. Somatic Cell and Molecular Genetics. 18:559 and the references cited therein). Assays of Oligomer Stability The oligomers of the invention are stabilized, e.g., substantially resistant to endonuclease and exonuclease degradation. An oligomer is defined as being substantially resistant to nucleases when it is at least about 3-fold more resistant to attack by an endogenous cellular nuclease, and is highly nuclease resistant when it is at least about 6-fold more resistant than a corresponding oligomer comprised of unmodified DNA or RNA. This can be demonstrated by showing that the oligomers o the invention are substantially resistant to nucleases using techniques which are known in the art. One way in which substantial stability can be demonstrated is showing that the oligomers of the invention function when delivered to a cell, e.g., that they reduce transcription of target RNA molecules, e.g., by measuring protein levels or by measuring cleavage of mRNA. Assays which measure the stability of target RNA can be performed at about 24 hours post-transfection (e.g., using Northern blot techniques, RNase Protection Assays, or QC-PCR assays as known in the art. Alternatively, levels of the target protein can be measured. Preferably, in addition to testing the RNA and/or protein levels of interest, the RNA and/or protein levels of a control, non-targeted gene will be measured (e.g., actin, or preferably a control with sequence similarity to the target) as a specificity control. Preferably, RNA and/or protein measurements will be made using any art- recognized technique. Preferably, measurements will be made beginning at about 16-24 hours post transfection. (M. Y. Chiang, et al.. 1991. J Biol Chem. 266:18162-71; T. Fisher, et al. 1993. Nucleic Acids Research. 21 3857. Oligomer Synthesis Oligomers of the invention can be synthesized by any methods known in the art, e.g., using enzymatic synthesis and chemical synthesis. Preferably, chemical synthesis is used. Chemical synthesis of linear oligomers is well know in the art and can be achieved by solution or solid phase techniques. Preferably, synthesis is by solid phase methods. Oligomers can be made by any of several different synthetic procedures including the phosphoramidite, phosphite triester, H-phosphonate and phosphotriester methods, typically by automated synthesis methods. Oligomer synthesis protocols are well known in the art and can be found, e.g., in U.S. patent 5,830,653; WO 98/13526; Stec et al. 1984. J. Am. Chem. Soc. 106:6077; Stec et al. 1985. J. Org. Chem. 50:3908; Stec et al. J. Chromatog. 1985. 326:263; LaPlanche et al. 1986. Nuc. Acid. Res. 1986. 14:9081; Fasman G. D., 1989. Practical Handbook of Biochemistry and Molecular Biology. 1989. CRC Press, Boca Raton, Fla.; Lamone. 1993. Biochem. Soc. Trans. 21 :1 ; U.S. Patent 5,013,830; U.S. Patent 5,214,135; U.S. Patent 5,525,719; Kawasaki et al. 1993. J. Med. Chem. 36:831 ; WO 92/03568; U.S. Patent 5,276,019; U.S. Patent 5,264,423). The synthesis method selected can depend on the length of the desired oligomer and such choice is within the skill of the ordinary artisan. For example, the phosphoramidite and phosphite triester method produce oligomers having 175 or more nucleotides while the H-phosphonate method works well for oligomers of less than 100 nucleotides. If modified bases are incoφorated into the oligomer, and particularly if modified phosphodiester linkages are used, then the synthetic procedures are altered as needed according to known procedures. In this regard, Uhlmann et al. (1990, Chemical Reviews 90:543-584) provide references and outline procedures for making oligomers with modified bases and modified phosphodiester linkages. Other exemplary methods for making oligomers are taught in Sonveaux. 1994. "Protecting Groups in Oligonucleotide Synthesis"; Agrawal. Methods in Molecular Biology 26: 1. Exemplary synthesis methods are also taught in "Oligonucleotide Synthesis- A Practical Approach" (Gait, M.J. IRL Press at Oxford University Press. 1984). Moreover, linear oligomers of defined sequence can be purchased commercially. The oligomers may be purified by polyacrylamide gel electrophoresis, or by any of a number of chromatographic methods, including gel chromatography and high pressure liquid chromatography. To confirm a nucleotide sequence, oligomers may be subjected to DNA sequencing by any of the known procedures, including Maxam and Gilbert sequencing, Sanger sequencing, capillary electrophoresis sequencing the wandering spot sequencing procedure or by using selective chemical degradation of oligomers bound to Hybond paper. Sequences of short oligomers can also be analyzed by laser desoφtion mass spectroscopy or by fast atom bombardment (McNeal, et al., 1982, J. Am. Chem. Soc. 104:976; Viari, et al., 1987, Biomed. Environ. Mass Spectrom. 14:83; Grotjahn et al., 1982, Nuc. Acid Res. 10:4671). Sequencing methods are also available for RNA oligomers. The quality of oligomers synthesized can be verified by testing the oligomer by capillary electrophoresis and denaturing strong anion HPLC (SAX-HPLC) using, e.g., the method of Bergot and Egan. 1992. J. Chrom. 599:35. It will be understood that the oligomers of the invention can be synthesized to comprise one or more of the disclosed improvements. For example, in one embodiment, an oligomer of the invention comprises a nucleomonomer containing a 2'OH precursor protecting group. In another exemplary embodiment, an oligomer of the invention is a short oligomer which targets the extreme 5' terminus or 3' or 5' splice junctions of a target RNA molecule. In one embodiment, an oligomer of the invention comprises at least two of the above improvements. In one embodiment, an oligomer of the invention comprises at least three of the above improvements. One of skill in the art will recognize that given the teachings of the specification, multiple variations and combinations of these improved oligomers can be made. Uses of Oligomers The oligomers of the invention can be used in a variety of in vitro and in vitro situations to specifically degrade a target mRNA molecule, and preferably, to inhibit expression of a target protein encoded by the target mRNA molecule. The instant methods and compositions are suitable for both in vitro and in vivo use. In one embodiment, the oligomers of the invention can be used to inhibit gene function in vitro in a method for identifying the functions of genes. The transcription genes that are identified, but for which no function has yet been shown can be inhibited to determine how the phenotype of a cell is changed when the gene is not transcribed. Such methods are useful for the validation of target genes for clinical treatment with antisense oligomers or with other therapies. In one embodiment, in vitro treatment of cells with oligomers can be used for ex vivo therapy of cells removed from a subject (e.g., for treatment of leukemia or viral infection) or for treatment of cells which did not originate in the subject, but are to be administered to the subject (e.g., to eliminate transplantation antigen expression on cells to be transplanted into a subject). In addition, in vitro treatment of cells can be used in non-therapeutic settings, e.g., to study gene regulation and protein synthesis or to evaluate improvements made to oligomers designed to modulate gene expression and/or protein synthesis. In vivo treatment of cells can be useful in certain clinical settings where it is desirable to inhibit the expression of a protein. There are numerous medical conditions for which antisense therapy is reported to be suitable (see e.g., U.S. patent 5,830,653) as well as respiratory syncytial virus infection (WO 95/22553) influenza virus (WO 94/23028), and malignancies (WO 94/08003). Other examples of clinical uses of antisense oligomers are reviewed, e.g., in Glaser. 1996. Genetic Engineering News 16:1. Exemplary targets for cleavage by antisense oligomers include e.g., protein kinase Ca, ICAM-1, c-raf kinase, p53, c-myb, and the bcr/abl fusion gene found in chronic myelogenous leukemia. The optimal course of administration of the oligomers may vary depending upon the desired result or on the subject to be treated. As used herein "administration" refers to contacting cells with oligomers. Such contacting can occur in vitro (e.g., in cell cultrure) or in vivo,e e.g., in a subject (such as an animal or a human). The dosage of oligomers may be adjusted to optimally reduce expression of a protein translated from a target mRNA, e.g., as measured by a readout of RNA stability or by a therapeutic response, without undue experimentation. For example, expression of the protein encoded by the nucleic acid target can be measured to determine whether or dosage regimen needs to be adjusted accordingly. In addition, an increase or decrease in RNA and/or protein levels in a cell or produced by a cell can be measured using any art recognized technique. By determining whether transcription has been decreased, the effectiveness of the oligomer in inducing the cleavage of the target RNA can be determined. As used herein, "pharmaceutically acceptable carrier" includes appropriate solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absoφtion delaying agents, and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, it can be used in the therapeutic compositions. Supplementary active ingredients can also be incoφorated into the compositions. Oligomers may be incoφorated into liposomes or liposomes modified with polyethylene glycol or admixed with cationic lipids for parenteral administration. Incoφoration of additional substances into the liposome, for example, antibodies reactive against membrane proteins found on specific target cells, can help target the oligomers to specific cell types. Moreover, the present invention provides for administering the subject oligomers with an osmotic pump providing continuous infusion of such oligomers, for example, as described in Rataiczak et al. (1992 Proc. Natl. Acad. Sci. USA 89:1 1823-1 1827). Such osmotic pumps are commercially available, e.g., from Alzet Inc. (Palo Alto, Calif). Topical administration and parenteral administration in a cationic lipid carrier are preferred. With respect to in vivo applications, the formulations of the present invention can be administered to a patient in a variety of forms adapted to the chosen route of administration, namely, parenterally, orally, or intraperitoneally. Parenteral administration, which is preferred, includes administration by the following routes: intravenous; intramuscular; interstitially; intraarterially; subcutaneous; intra ocular; intrasynovial; trans epithelial, including transdermal; pulmonary via inhalation; ophthalmic; sublingual and buccal; topically, including ophthalmic; dermal; ocular; rectal; and nasal inhalation via insufflation. Intravenous administration is preferred among the routes of parenteral administration. Pharmaceutical preparations for parenteral administration include aqueous solutions of the active compounds in water-soluble or water-dispersible form. In addition, suspensions of the active compounds as appropriate oily injection suspensions may be administered. Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension include, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran, optionally, the suspension may also contain stabilizers. Drug delivery vehicles can be chosen e.g., for in vitro, for systemic, or for topical administration. These vehicles can be designed to serve as a slow release reservoir or to deliver their contents directly to the target cell. An advantage of using some direct delivery drug vehicles is that multiple molecules are delivered per uptake. Such vehicles have been shown to increase the circulation half-life of drugs that would otherwise be rapidly cleared from the blood stream. Some examples of such specialized drug delivery vehicles which fall into this category are liposomes, hydrogels, cyclodextrins, biodegradable nanocapsules, and bioadhesive microspheres. The described oligomers may be administered systemically to a subject. Systemic absoφtion refers to the entry of drugs into the blood stream followed by distribution throughout the entire body. Administration routes which lead to systemic absoφtion include: intravenous, subcutaneous, intraperitoneal, and intranasal. Each of these administration routes delivers the oligomer to accessible diseased cells. Following subcutaneous administration, the therapeutic agent drains into local lymph nodes and proceeds through the lymphatic network into the circulation. The rate of entry into the circulation has been shown to be a function of molecular weight or size. The use of a liposome or other drug carrier localizes the oligomer at the lymph node. The oligomer can be modified to diffuse into the cell, or the liposome can directly participate in the delivery of either the unmodified or modified oligomer into the cell. The chosen method of delivery will result in entry into cells. Preferred delivery methods include liposomes (10-400 nm), hydrogels, controlled-release polymers, and other pharmaceutically applicable vehicles, and micro injection or electroporation (for ex vivo treatments). The oligomers, especially in lipid formulations, can also be administered by coating a medical device, for example, a catheter, such as an angioplasty balloon catheter, with a cationic lipid formulation. Coating may be achieved, for example, by dipping the medical device into a lipid formulation or a mixture of a lipid formulation and a suitable solvent, for example, an aqueous-based buffer, an aqueous solvent, ethanol, methylene chloride, chloroform and the like. An amount of the formulation will naturally adhere to the surface of the device which is subsequently administered to a patient, as appropriate. Alternatively, a lyophilized mixture of a lipid formulation may be specifically bound to the surface of the device. Such binding techniques are described, for example, in K. Ishihara et al., Journal of Biomedical Materials Research, Vol. 27, pp. 1309-1314 (1993), the disclosures of which are incoφorated herein by reference in their entirety. The useful dosage to be administered and the particular mode of administration will vary depending upon such factors as the cell type, or for in vivo use, the age, weight and the particular animal and region thereof to be treated, the particular oligomer and delivery method used, the therapeutic or diagnostic use contemplated, and the form of the formulation, for example, suspension, emulsion, micelle or liposome, as will be readily apparent to those skilled in the art. Typically, dosage is administered at lower levels and increased until the desired effect is achieved. When lipids are used to deliver the oligomers, the amount of lipid compound that is administered can vary and generally depends upon the amount of oligomer agent being administered. For example, the weight ratio of lipid compound to oligomer agent is preferably from about 1 :1 to about 15:1, with a weight ratio of about 5:1 to about 10:1 being more preferred. Generally, the amount of cationic lipid compound which is administered will vary from between about 0.1 milligram (mg) to about 1 gram (g). By way of general guidance, typically between about 0.1 mg and about 10 mg of the particular oligomer agent, and about 1 mg to about 100 mg of the lipid compositions, each per kilogram of patient body weight, is administered, although higher and lower amounts can be used. The agents of the invention are administered to subjects or contacted with cells in a biologically compatible form suitable for pharmaceutical administration. By "biologically compatible form suitable for administration " is meant that the oligomer is administered in a form in which any toxic effects are outweighed by the therapeutic effects of the oligomer. In one embodiment, oligomers can be administered to subjects. The term subject is intended to include living organisms, e.g., prokaryotes and eukaryotes. Examples of subjects include mammals, e.g., humans, dogs, cats, mice, rats, and transgenic non-human animals. Administration of an active amount of an oligomer of the present invention is defined as an amount effective, at dosages and for periods of time necessary to achieve the desired result. For example, an active amount of an oligomer may vary according to factors such as the type of cell, the oligomer used, and for in vivo uses the disease state, age, sex, and weight of the individual, and the ability of the oligomer to elicit a desired response in the individual. Establishment of therapeutic levels of oligomers within the cell is dependent upon the rates of uptake and efflux degradation. Decreasing the degree of degradation prolongs the intracellular half-life of the oligomer. Thus, chemically-modified oligomers, e.g., with modification of the phosphate backbone, may require different dosing. The exact dosage of an oligomer and number of doses administered will depend upon the data generated experimentally and in clinical trials. Several factors such as the desired effect, the delivery vehicle, disease indication, and the route of administration, will affect the dosage. The expected in vivo dosage is between about 0.001-200 mg/kg of body weight/day. For example, the oligomers can be provided in a therapeutically effective amount of about 0.1 mg to about 100 mg per kg of body weight per day, and preferably of about 0.1 mg to about 10 mg per kg of body weight per day, to bind to a nucleic acid in accordance with the methods of this invention. Dosages can be readily determined by one of ordinary skill in the art and formulated into the subject pharmaceutical compositions. Preferably, the duration of treatment will extend at least through the course of the disease symptoms. Dosage regima may be adjusted to provide the optimum therapeutic response. For example, the oligomer may be repeatedly administered, e.g., several doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. One of ordinary skill in the art will readily be able to determine appropriate doses and schedules of administration of the subject oligomers, whether the oligomers are to be administered to cells or to subjects. The practice of the present invention will employ, unless otherwise indicated, conventional techniques of cell biology, cell culture, molecular biology, microbiology, recombinant DNA, and immunology, which are within the skill of the art. Such techniques are explained fully in the literature. See, for example, Molecular Cloning A Laboratory Manual, 2nd Ed., ed. by Sambrook, J. et al. (Cold Spring Harbor Laboratory Press (1989)); Short Protocols in Molecular Biology, 3rd Ed., ed. by Ausubel, F. et al. (Wiley, NY (1995)); DNA Cloning, Volumes I and II (D. N. Glover ed., 1985); Oligonucleotide Synthesis (M. J. Gait ed. (1984)); Mullis et al. U.S. Patent No: 4,683,195; Nucleic Acid Hybridization (B. D. Hames & S. J. Higgins eds. (1984)); the treatise, Methods In Enzymology (Academic Press, Inc., N. Y.); Immunochemical Methods In Cell And Molecular Biology (Mayer and Walker, eds., Academic Press, London (1987)); Handbook Of Experimental Immunology, Volumes I-IV (D. M. Weir and C. C. Blackwell, eds. (1986)); and Miller, J. Experiments in Molecular Genetics (Cold Spring Harbor Press, Cold Spring Harbor, N.Y. (1972)). The invention is further illustrated by the following examples, which should not be construed as further limiting. The contents of all references, pending patent applications and published patents, cited throughout this application are hereby expressly incoφorated by reference. Examples Example 1. Oligomers comprising 2' OH Protecting Groups Oligonucleotide Synthesis Oligonucleotides were synthesized using commercially available nucleotide monomers and phosphoramidite chemistry protocols. After the synthesis was complete the oligonucleotides were deprotected according to standard protocols. Oligonucleotides containing 2' -O-t-butyldimethylsilyl (TBDMS), a commonly used protecting group in RNA synthesis, were deprotected in a similar manner, but the second deprotection step to remove the TBDMS protecting group was omitted. The product was purified by reversed-phase HPLC using a column composed of C 18 with a triethylammonium acetate / acetonitrile gradient. After purification, the oligomer was ethanol precipitated and then resuspended in 20 mM HEPES pH=8.0. A B C A illustrates an unmodified ribonucleotide. B illustrates a 2' O-methyl modified ribonucleotide. C. illustrates a 2' -O-t-butyldimethylsilyl protected ribonucleotide. The antisense activity of modified oligonucleotides was tested in cell culture using a luciferase reporter assay. Oligonucleotides were synthesized with a combination of backbone, sugar and end group modifications all composed of the same sequence (TTGCCCACACCGACGGCGCCCACCA). This sequence (anti-ras) was designed to target the ras coding region in an antisense manner. The antisense activity of a modified oligonucleotide was assessed by transfecting cells with the anti-ras oligonucleotide and a luciferase expression vector containing a ras coding sequence inserted before the luciferase coding region. The expression of luciferase in cells treated with a control oligonucleotide was compared to cells treated with an antisense oligonucleotide. To demonstrate the exquisite specificity of the antisense oligonucleotides and to control for any non-specific antisense effects, an additional transfection was performed in which the cells were transfected with a control luciferase expression vector, a vector with no upstream ras coding sequence, after treatment with the anti-ras oligonucleotides. All of the cells were co-transfected with a renilla luciferase expression vector to control for transfection efficiency. HeLa cells were grown in 24-well plates until they reached -70% confluency in MEM media containing 10% fetal bovine serum, 2 mM L-Glutamine, 1.5 g/L sodium bicarbonate, 1 mM pyruvate, and pencillin/streptomycin. For each oligonucleotide chemistry tested a 2X solution (6.6 μg/ml) of Lipofectin (GIBCO-BRL) was prepared by adding 11.6 μl of lipofectin to 1.75 mL of opti-mem (GIBCO-BRL). Each oligonucleotide tested was diluted to 200 nM by adding 3.5 μl of a 100 μM stock solution to 1.75 ml of opti-mem. The diluted oligonucleotide was added to the lipid/opti-mem mixture, vortexed and incubated at room temperature for 15 minutes. The cells were rinsed with 0.5 ml of opti-mem and treated with 0.5 ml of lipid/oligonucleotide transfection media in six replicates. Preparation of lipid/oligonucleotide transfection media was repeated for each oligonucleotide chemistry tested and transfected in a separate 24-well plate. After incubating the HeLa cells with the lipid/oligonucleotide transfection media for 3 hours at 37°C one 24-well plate was transfected with the ras-luciferase expression vector and the renilla luciferase expression vector and the other plate was treated with the control luciferase (luc) expression vector and the renilla luciferase (luc) expression vector. Expression vector transfection media was prepared by adding 7 μl of a 20 ng/μl stock solution of the renilla luc vector and 7 μl of either the ras- or control-luc vector (100 ng/μl stock) to 1.75 ml of opti-mem. The ras- or control-luc/ renilla luc solution was added to 1.75 mL of 6.6 μg/ml Lipofectin opti-mem mixture and incubated at room temperature for 15 minutes. The lipid/oligonucleotide transfection media was aspirated and the cells were treated with 0.5 ml of expression vector transfection media. After incubating the cells at 37°C for 3 hours the ras- or control-luc and renilla luc transfection media was aspirated and replaced with full growth media. The cells were incubated overnight at 37°C, washed with phosphate-buffered saline (PBS) and harvested by adding 200 μl of passive lysis buffer (Promega) to each well. The expression of luciferase and renilla luciferase were analyzed using the Dual Reporter assay system supplied by Promega. The luciferase values (see Table 1 ) represent the average of six separate transfections in which firefly luciferase values were normalized to renilla luciferase to control for transfection efficiency. To control for non-specific antisense effects the ras-luc values were then normalized to control-luc. Negative and Positive Control Oligomers were constructed as shown below: 5' X(ps)X(ps)X(ps)X(ps)X(ps)X(ps) X(ps)X(ps)X(ps) [xxxxxxxxxxxxxxxxj (ps)(propyl) Where X represents the nucleotide sequence (the positive control was designed to target ras and the negative control oligomer was composed of a scrambled sequence); (ps) represents a phosphorothioate linkage; x represents nucleomonomers comprising nucleomonomers comprising 2'-O- Methyl blocking groups and linked by phosphodiester linkages; and (propyl) represents a propyl blocking group. The TBDMS oligomer was constructed as shown below: 5' X(ps)X(ps)X(ps)X(ps)X(ps)X(ps) X(ps)X(ps)X(ps) [xxxxxxxxxxxxx SiSiSi] Where X represents the nucleotide sequence; (ps) represents a phosphorothioate linkage; x represents nucleomonomers comprising nucleomonomers comprising 2'-O- Methyl blocking groups and linked by phosphodiester linkages; and (SI) represents a nucleomonomer comprising a TBDMS blocking group and linked by phosphodiester linkages. The results of the experiment are shown in Table 1. Table 1 : Luciferase expression values normalized to renilla luciferase. The positive anti-ras oligomer inhibited the expression of luciferase by -75% compared to cells treated with the control oligomer. Inhibition of expression by greater than 95% was seen for cells treated with the anti-ras TBDMs oligomer compared to cells treated with the control oligomer (Figure 1). Example 2. Transfection of A549 Cells with a Charged Morpholino Oligonucleotide by Electroporation In this experiment, A549 cells were harvested from T150 flasks at 80% confluence using Trypsin. The cells were washed (PB sucrose, 20 ml) pelleted three times (centrifugation at 1000 φm, 5 min.), and resuspended at cell densities of 5, 3, and 1.5 x 10 6 cells/ml in PB sucrose. 7.5 ul of carboxy-fluorescene 25 mer moφholino oligonucleotide (4mM) was added to each of nine 5 ml polystyrene tubes. (Carboxy-fluorescene contains two negative charges). 300 ul of corresponding cell suspension (5, 3, or 1.5 x 10 6 cells/ml) was added to each tube and mixed gently. The cell/oligo suspensions were transferred to electroporation cuvettes and electroporated using a BioRad GenePulser II with RF module under the following conditions: 400 V 25 kHz frequency 8 bursts 80/60/40% modulation 2 msec burst duration 100 msec burst interval 1 ml of warm (37°C) media was added to the cuvette, and the cell suspension was divided between two wells already containing 1.5 ml of A549 growth media (37°C) on a 6- well culture plate. The plates were incubated at 37°C for 20-24 hours and uptake was evaluated via fluorescence microscopy. Figure 2 shows oligomer uptake in cells by fluorescence as compared with no treatment control. Equivalents Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims: What is claimed is: 1. An oligomer for delivery to a cell comprising at least one nucleomonomer having a silicon- based 2'OH protecting group. 2. The oligomer of claim 1 wherein the silicon-based protecting group is a tertbutyl dimethyl-silyl group. 3. A method of inhibiting expression of a protein in a cell comprising contacting a cell with an oligomer of claim 1, such that inhibition of expression of the protein in the cell occurs. 4. A method of enhancing the uptake of a neutral oligomer by a cell, comprising modifying the neutral oligomer to comprise at least one charge, such that enhanced uptake of the oligomer occurs. 5. The method of claim 4, wherein the uptake of the oligomer is facilitated by electroporation. 6. The method of claim 4, wherein the uptake of the oligomer is facilitated by positively charged transduction reagent. 7. The method of claim 6, wherein the uptake of the oligomer is facilitated by cationic lipids. 8. A method of inhibiting the expression of a protein in a cell comprising contacting a cell with an oligomer which is complementary to a target nucleic acid molecule, said oligomer having a region comprising a neutral backbone and having at least one negatively charged group such that inhibition of expression of a protein occurs. 9. The method of claim 8, wherein said neutral backbone is a moφholino or peptide backbone. 10. The method of claim 8, wherein said negatively charged group is covalently linked to the oligomer. 11. The oligomer of claim 10, wherein the covalent linkage is a phosphodiester linkage. 12. The oligomer of claim 8, wherein the negatively charged group is non-covalently linked to the oligomer. 13. The oligomer of claim 12, wherein the negatively charged group is present on a charged molecule which complexes with the oligomer. 14. A method of screening for an oligomer complementary to a cellular gene involved in a physiological process comprising: contacting a cell with an oligomer comprising at least one universal nucleotide and determining the ability of the oligomer to induce a phenotypic change in the cell to thereby identify an oligomer which is complementary to a cellular gene involved in a physiological process. 15. A method of screening for an oligomer complementary to a cellular gene involved in a physiological process comprising: contacting a cell with a first oligomer comprising at least one universal nucleotide and determining the ability of the first oligomer to induce a phenotypic change in a cell; reducing the degeneracy of the first oligomer by fixing at lest one of the universal bases to thereby make a second oligomer; and determining the ability of the second oligomer to induce a phenotypic change in a cell to thereby identify an oligomer which is complementary to a cellular gene involved in a physiological process. 16. A method for determining the sequence of a cellular gene which is involved in a physiological process comprising: determining the sequence of an oligomer identified in claim 14 and identifying cellular gene sequences which are complementary to the oligomer.

Inventors: BECK TERRY B, WOOLF TOD M, BECK, TERRY, B., WOOLF, TOD, M.
Applicants: SEQUITUR INC, TRILINK BIOTECHNOLOGIES INC, SEQUITUR, INC., TRILINK BIOTECHNOLOGIES, INC.
Application year: 2000
Main classification: C12N15
IPC codes: C12N15