Source: http://www.google.com/patents/US8143221
Timestamp: 2016-10-01 15:37:01
Document Index: 699397457

Matched Legal Cases: ['Application No. 60', 'art 1', 'art 2', 'art 4', 'art 2', 'art 2', 'art 2', 'art 2', 'art 2']

Patent US8143221 - Use of ADNF polypeptides for treating peripheral neurotoxicity - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign inPatentsThis invention relates to the use of ADNF polypeptides in the treatment of neurotoxicity induced by chemical agents or by disease processes. The ADNF polypeptides include ADNF I and ADNF III (also referred to as ADNP) polypeptides, analogs, subsequences such as NAP and SAL, and D-amino acid versions...http://www.google.com/patents/US8143221?utm_source=gb-gplus-sharePatent US8143221 - Use of ADNF polypeptides for treating peripheral neurotoxicityAdvanced Patent SearchTry the new Google Patents, with machine-classified Google Scholar results, and Japanese and South Korean patents.Publication numberUS8143221 B2Publication typeGrantApplication numberUS 12/245,517Publication dateMar 27, 2012Priority dateMar 23, 2005Fee statusPaidAlso published asCA2602893A1, EP1885389A1, EP1885389A4, US7452867, US20060247168, US20090137469, WO2006099739A1Publication number12245517, 245517, US 8143221 B2, US 8143221B2, US-B2-8143221, US8143221 B2, US8143221B2InventorsIllana Gozes, James MillerOriginal AssigneeRamot At Tel-Aviv University, Allon Therapeutics, Inc.Export CitationBiBTeX, EndNote, RefManPatent Citations (36), Non-Patent Citations (58), Referenced by (2), Classifications (19), Legal Events (4) External Links: USPTO, USPTO Assignment, EspacenetUse of ADNF polypeptides for treating peripheral neurotoxicity
US 8143221 B2Abstract
This invention relates to the use of ADNF polypeptides in the treatment of neurotoxicity induced by chemical agents or by disease processes. The ADNF polypeptides include ADNF I and ADNF III (also referred to as ADNP) polypeptides, analogs, subsequences such as NAP and SAL, and D-amino acid versions (either wholly D-amino acid peptides or mixed D- and L-amino acid peptides), and combinations thereof which contain their respective active core sites.
1. A method for the treatment of cancer or neoplasia with reduced peripheral neurotoxicity, the method comprising
a) administering an anti-cancer agent to a subject in need thereof; and
b) administering, contemporaneously or sequentially with the anti-cancer agent of step a), an ADNF polypeptide in an effective amount in a pharmaceutically acceptable carrier, thereby reducing peripheral neurotoxicity associated with the anti-cancer agent, wherein the ADNF polypeptide is a member selected from the group consisting of:
(i) an ADNF I polypeptide comprising an active core site having the amino acid sequence of Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala (SEQ ID NO:1), wherein at least one amino acid in SEQ ID NO:1 is optionally a D-amino acid;
(ii) an ADNF III polypeptide comprising an active core site having the amino acid sequence of Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln (SEQ ID NO:2), wherein at least one amino acid in SEQ ID NO:2 is optionally a D-amino acid; and
(iii) a mixture of the ADNF I polypeptide of part (i) and the ADNF III polypeptide of part (ii).
2. The method of claim 1, wherein said anti-cancer agent is a vinca alkaloid.
3. The method of claim 1, wherein the ADNF polypeptide is a member selected from the group consisting of a full length ADNF I polypeptide, a full length ADNF III polypeptide (ADNP), and a mixture of a full length ADNF I polypeptide and a full length ADNF III polypeptide.
4. The method of claim 1, wherein the ADNF polypeptide is an ADNF I polypeptide of part (i).
5. The method of claim 1, wherein the active core site of the ADNF polypeptide comprises at least one D-amino acid.
6. The method of claim 1, wherein the ADNF I polypeptide has the formula (R1)x-Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala-(R2)y (SEQ ID NO:20), in which
R2 is an amino acid sequence comprising from 1 to about 40 amino acids wherein each amino acid is independently selected from the group consisting of naturally occurring amino acids and amino acid analogs; and
x and y are independently selected and are equal to zero or one.
7. The method of claim 6, wherein the ADNF I polypeptide is Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala (SEQ ID NO:1).
8. The method of claim 6, wherein the ADNF I polypeptide is selected from the group consisting of:
Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala.
9. The method of claim 6, wherein the ADNF I polypeptide comprises up to about 20 amino acids at either or both of the N-terminus and the C-terminus of the active core site.
10. The method of claim 1, wherein the ADNF polypeptide is an ADNF III polypeptide of part (ii).
11. The method of claim 10, wherein the ADNF III polypeptide has the formula (R1)x-Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln-(R2)y (SEQ ID NO:13), in which
12. The method of claim 10, wherein the ADNF III polypeptide is Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln (SEQ ID NO:2).
13. The method of claim 10, wherein the active core site of the ADNF III polypeptide comprises at least one D-amino acid.
14. The method of claim 10, wherein the ADNF III polypeptide is a member selected from the group consisting of:
15. The method of claim 10, wherein the ADNF III polypeptide comprises up to about 20 amino acids at either or both of the N-terminus and the C-terminus of the active core site.
16. The method of claim 1, wherein a mixture of the ADNF I polypeptide of part (i) and the ADNF III polypeptide of part (ii) is administered to the subject.
17. The method of claim 16, wherein either or both active core sites of the ADNF I polypeptide and the ADNF III polypeptide comprise at least one D-amino acid.
18. The method of claim 16, wherein the ADNF I polypeptide is Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala (SEQ ID NO:1), and wherein the ADNF III polypeptide is Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln (SEQ ID NO:2).
19. The method of claim 16, wherein the ADNF I polypeptide is a member selected from the group consisting of:
(SEQ ID NO : 3)
wherein the ADNF III polypeptide is selected from
the group consisting of:
20. The method of claim 16, wherein the ADNF I polypeptide comprises up to about 20 amino acids at either or both of the N-terminus and the C-terminus of the active core site of the ADNF I polypeptide, and wherein the ADNF III polypeptide comprises up to about 20 amino acids at either or both of the N-terminus and the C-terminus of the active core site of the ADNF III polypeptide.
21. The method of claim 1, wherein the ADNF polypeptide is administered intranasally, orally, intravenously or subcutaneously. Description
This application is a divisional of U.S. application Ser. No. 11/388,634, filed Mar. 23, 2006 which claims the benefit of U.S. Provisional Application No. 60/664,908, filed Mar. 23, 2005; which is herein incorporated by reference for all purposes.
This invention relates to the use of ADNF polypeptides in the treatment of neurotoxicity. The present invention also relates to the manufacture of medicaments, methods of formulation and uses thereof. The ADNF polypeptides include ADNF I and ADNF III (also referred to as ADNP) polypeptides, analogs, subsequences such as NAP and SAL (defined below), and D-amino acid versions (either wholly D-amino acid peptides or mixed D- and L-amino acid peptides), and combinations thereof which contain their respective active core sites.
NAP, an 8-amino acid peptide (NAPVSIPQ=Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln); SEQ ID NO:2), is derived from a novel protein, activity-dependent neuroprotective protein, ADNP (U.S. Pat. No. 6,613,740, Bassan et al., J. Neurochem. 72: 1283-1293 (1999); Zamostiano, et al., J. Biol. Chem. 276:708-714 (2001)). The NAP sequence within the ADNP gene is identical in rodents and humans (U.S. Pat. No. 6,613,740, Zamostiano, et al., J. Biol. Chem. 276:708-714 (2001)).
In cell cultures, NAP has been shown to have neuroprotective activity on cells of the central nervous system (CNS) at femtomolar concentrations (Bassan et al., 1999; Offen et al., Brain Res. 854:257-262 (2000)). Several animal models have also demonstrated NAP activity on diseases of the CNS. In animal models simulating parts of the Alzheimer's disease pathology, NAP was protective (Bassan et al., 1999; Gozes et al., J. Pharmacol. Exp. Ther. 293:1091-1098 (2000); see also U.S. Pat. No. 6,613,740). In normal aging rats, intranasal administration of NAP improved performance in the Morris water maze. (Gozes et al., J. Mol. Neurosci. 19:175-178 (2002). NAP reduced infarct volume and motor function deficits Mol. Neurosci. 19:175-178 (2002). NAP reduced infarct volume and motor function deficits after ischemic injury, by decreasing apoptosis (Leker et al., Stroke 33:1085-1092 (2002)) and reducing damage caused by closed head injury in mice by decreasing inflammation (Beni Adani et al., J. Pharmacol. Exp. Ther. 296:57-63 (2001); Romano et al., J. Mol. Neurosci. 18:37-45 (2002); Zaltzman et al., NeuroReport 14:481-484 (2003)). NAP has been shown to provide protective intervention in a model of fetal alcohol syndrome, reducing fetal demise and growth restrictions. (Spong et. al., J Pharmacol Exp Ther. 297:774-9 (2001)). Additionally, long term nasal NAP application in mice resulted in decreased anxiety (Alcalay et al., Neurosci Lett. 361(1-3):128-31 (2004)).
ADNF polypeptides, including NAP and SAL, and uses thereof in neuroprotection against disorders of the central nervous system, are the subject of patents and patent applications including PCT WO 1/92333; U.S. Ser. No. 07/871,973 filed Apr. 22, 1992, now U.S. Pat. No. 5,767,240; U.S. Ser. No. 08/342,297, filed Oct. 17, 1994 (published as WO96/11948), now U.S. Pat. No. 6,174,862; U.S. Ser. No. 60/037,404, filed Feb. 7, 1997 (published as WO98/35042); U.S. Ser. No. 09/187,330, filed Nov. 11, 1998 (published as WO00/27875); U.S. Ser. No. 09/267,511, filed Mar. 12, 1999 (published as WO00/53217); U.S. Pat. No. 6,613,740, U.S. Ser. No. 60/149,956, filed Aug. 18, 1999 (published as WO01/12654); U.S. Ser. No. 60/208,944, filed May 31, 2000; and U.S. Ser. No. 60/267,805, filed Feb. 8, 2001; PCT/IL2004/000232, filed Mar. 11, 2004 (published as WO 2004/080957) herein each incorporated by reference in their entirety.
In one aspect, the present invention provides a method for treating peripheral neurotoxicity in a subject, the method comprising administering a therapeutically effective amount of an ADNF polypeptide to a subject in need thereof.
In another embodiment, the ADNF III polypeptide comprises up to about 20 amino acids at least one of the N-terminus and the C-terminus of the active core site.
FIG. 1: Rota-rod tests were performed on rats receiving 0.175 mg/kg vincristine, and similar rats receiving vincristine plus subcutaneous NAP. Rota-rod test shows vincristine and NAP treated animals (n=10) perform better than vincristine treated alone (n=10). (**p<0.01).
FIGS. 3, 4 and 5: Time spent with new odors: olfaction capacity. The time spent with each odor over the three consecutive tests was recorded. FIG. 3, for control rats, FIG. 4 for vincristine treated rats and FIG. 5 for vincristine and 25 microgram/kg NAP-treated rats. While the vincristine-treated rats did not show any initial interest in the new smell, a trend toward increased interest toward a new odor was observed in the control and the vincristine-NAP-treated rats.
FIG. 6: Comparison between time periods spent with a certain odor after exchanging for a former scent-odor discrimination test: The figure depicts 4 points, point 1=water (ddw) trial 3; point 2=odor #1, trial #1; point 3=odor #1, trial 3; point 4=odor #2, trial 1. Results showed a significant difference in the time taken to sniff the third odor when comparing control to vincristine-treated rats or vincristine-treated rats with vincristine+25 microgram/kg NAP (P<0.05).
The phrase “ADNF polypeptide” refers to one or more activity dependent neurotrophic factors (ADNF) that have an active core site comprising the amino acid sequence of SALLRSIPA (SEQ ID NO:1) (referred to as “SAL”) or NAPVSIPQ (SEQ ID NO:2) (referred to as “NAP”), or conservatively modified variants thereof that have neurotrophic/neuroprotective activity as measured with in vitro cortical neuron culture assays described by, e.g., Hill et al., Brain Res. 603:222-233 (1993); Brenneman & Gozes, J. Clin. Invest. 97:2299-2307 (1996), Gozes et al., Proc. Natl. Acad. Sci. USA 93, 427-432 (1996). An ADNF polypeptide can be an ADNF I polypeptide, an ADNF III polypeptide, their alleles, polymorphic variants, analogs, interspecies homolog, any subsequences thereof (e.g., SALLRSIPA (SEQ ID NO:1) or NAPVSIPQ (SEQ ID NO:2)) or lipophilic variants that exhibit neuroprotective/neurotrophic action on, e.g., neurons originating in the central nervous system either in vitro or in vivo. An “ADNF polypeptide” can also refer to a mixture of an ADNF I polypeptide and an ADNF III polypeptide.
The term “ADNF I” refers to an activity dependent neurotrophic factor polypeptide having a molecular weight of about 14,000 Daltons with a pI of 8.3�0.25. As described above, ADNF I polypeptides have an active site comprising an amino acid sequence of Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala (SEQ ID NO:1) (also referred to as “SALLRSIPA” or “SAL” or “ADNF-9”). See Brenneman & Gozes, J. Clin. Invest. 97:2299-2307 (1996), Glazner et al., Anat. Embryol. ((Berl). 200:65-71 (1999), Brenneman et al., J. Pharm. Exp. Ther., 285:619-27 (1998), Gozes & Brenneman, J. Mol. Neurosci. 7:235-244 (1996), and Gozes et al., Dev. Brain Res. 99:167-175 (1997). Unless indicated as otherwise, “SAL” refers to a peptide having an amino acid sequence of Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala (SEQ ID NO:1), not a peptide having an amino acid sequence of Ser-Ala-Leu. A full length amino acid sequence of ADNF I can be found in WO 96/11948.
The phrase “ADNF III polypeptide” or “ADNF III” also called activity-dependent neuroprotective protein (ADNP) refers to one or more activity dependent neurotrophic factors (ADNF) that have an active core site comprising the amino acid sequence of NAPVSIPQ (SEQ ID NO:2) (referred to as “NAP”), or conservatively modified variants thereof that have neurotrophic/neuroprotective activity as measured with in vitro cortical neuron culture assays described by, e.g., Hill et al., Brain Res. 603, 222-233 (1993); Gozes et al., Proc. Natl. Acad. Sci. USA 93, 427-432 (1996). An ADNF polypeptide can be an ADNF III polypeptide, allelelic or polymorphic variant, analog, interspecies homolog, or any subsequences thereof (e.g., NAPVSIPQ; SEQ ID NO:2) that exhibit neuroprotective/neurotrophic action on, e.g., neurons originating in the central nervous system either in vitro or in vivo. ADNF III polypeptides can range from about eight amino acids and can have, e.g., between 8-20, 8-50, 10-100 or about 1000 or more amino acids.
Full length human ADNF III has a predicted molecular weight of 123,562.8 Da (>1000 amino acid residues) and a pI of about 6.97. As described above, ADNF III polypeptides have an active site comprising an amino acid sequence of Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln (SEQ ID NO:2) (also referred to as “NAPVSIPQ” or “NAP”). See Zamostiano et al., J. Biol. Chem. 276:708-714 (2001) and Bassan et al., J. Neurochem. 72:1283-1293 (1999). Unless indicated as otherwise, “NAP” refers to a peptide having an amino acid sequence of Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln (SEQ ID NO:2), not a peptide having an amino acid sequence of Asn-Ala-Pro. Full-length amino acid and nucleic acid sequences of ADNF III can be found in WO 98/35042, WO 00/27875, U.S. Pat. No. 6,613,740. The Accession number for the human sequence is NP—852107, see also Zamostiano et al., infra.
1) Alanine (A), Glycine (G); 2) Serine (S), Threonine (T); 3) Aspartic acid (D), Glutamic acid (E); 4) Asparagine (N), Glutamine (Q); 5) Cysteine (C), Methionine (M); 6) Arginine (R), Lysine (K), Histidine (H); 7) Isoleucine (1), Leucine (L), Valine (V); and 8) Phenylalanine (F), Tyrosine (Y), Tryptophan (W). (see, e.g., Creighton, Proteins (1984)). One of skill in the art will appreciate that many conservative variations of the nucleic acid and polypeptide sequences provided herein yield functionally identical products. For example, due to the degeneracy of the genetic code, “silent substitutions” (i.e., substitutions of a nucleic acid sequence that do not result in an alteration in an encoded polypeptide) are an implied feature of every nucleic acid sequence that encodes an amino acid. Similarly, “conservative amino acid substitutions,” in one or a few amino acids in an amino acid sequence are substituted with different amino acids with highly similar properties (see the definitions section, supra), are also readily identified as being highly similar to a disclosed amino acid sequence, or to a disclosed nucleic acid sequence that encodes an amino acid. Such conservatively substituted variations of each explicitly listed nucleic acid and amino acid sequences are a feature of the present invention.
The term “subject” refers to any mammal, in particular human, at any stage of life.
The term “contacting” is used herein interchangeably with the following: combined with, added to, mixed with, passed over, incubated with, flowed over, etc. Moreover, the ADNF III polypeptides or nucleic acids encoding them of the present invention can be “administered” by any conventional method such as, for example, parenteral, oral, topical, and inhalation routes. In some embodiments, parenteral and nasal inhalation routes are employed.
“Neurotoxicity” as used herein is defined as adverse effects on the structure or functioning of the cells of the nervous system that result from exposure to chemical substances or to disease processes. Among other things, neurotoxicants can cause morphological changes that lead to generalized damage to nerve cells (neuronopathy), injury to axons (axonopathy), or destruction of the myelin sheath (myelinopathy). It is well established that exposure to certain chemotherapeutic agents, agricultural and industrial chemicals can damage the nervous system, resulting in neurological and behavioral dysfunction. Symptoms of neurotoxicity include muscle weakness, loss of sensation and motor control, tremors, alterations in cognition, and impaired functioning of the autonomic nervous system. Neurotoxicological assessments use a battery of functional and observational tests. Neurotoxicity in humans is most commonly measured by neurological tests that assess cognitive, sensory, and motor function.
“Peripheral neurotoxicity” refers to neurotoxicity of the peripheral nervous system (PNS). The PNS includes all the nerves not in the brain or spinal cord, and includes the dorsal root ganglia (DRG). These nerves carry sensory information and motor impulses. Damage to the nerve fibers of the PNS can disrupt communication between the CNS and the rest of the body. Peripheral neurotoxicity is also sometimes referred to in the literature as peripheral neuropathy, and can include hundreds of identifiable conditions, as further described below. “Peripheral neuropathy” encompasses a wide range of conditions in which the nerves outside of the brain and spinal cord have been damaged, and may include crush injury and section.
“Central nervous system” or “CNS” means the brain and spinal cord.
The terms “polypeptide,” “peptide” and “protein” are used interchangeably herein to refer to a polymer of amino acid residues. Generally, a peptide refers to a short polypeptide. The terms apply to amino acid polymers in which one or more amino acid residue is an analog or mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers.
As used herein ‘treatment’ includes preventative treatment or prophylaxis, such as treatment for prevention of disease progression or onset of further symptoms, or for avoidance or reduction of side-effects or symptoms of a disease.
As used herein, ‘disease’ includes an incipient condition or disorder or symptoms of a disease, incipient condition or disorder.
The terms “isolated,” “purified” or “biologically pure” refer to material that is substantially or essentially free from components that normally accompany it as found in its native state.
“An amount sufficient” or “an effective amount” or a “therapeutically effective amount” is that amount of an ADNF polypeptide that exhibits the activity of interest or which provides either a subjective relief of a symptom(s) or an objectively identifiable improvement as noted by the clinician or other qualified observer. In therapeutic applications, the ADNF polypeptides of the invention are administered to a patient in an amount sufficient to reduce or eliminate symptoms of the disease. An amount adequate to accomplish this is defined as the “therapeutically effective dose.” The dosing range varies with the ADNF polypeptide used, the route of administration and the potency of the particular ADNF polypeptide, as further set out below, and as described in patents CA Patent 2202496, U.S. Pat. No. 6,174,862 and U.S. Pat. No. 6,613,740.
“Inhibitors,” “activators,” and “modulators” of expression or of activity are used to refer to inhibitory, activating, or modulating molecules, respectively, identified using in vitro and in vivo assays for expression or activity, e.g., ligands, agonists, antagonists, and their homologs and mimetics. The term “modulator” includes inhibitors and activators. Inhibitors are agents that, e.g., inhibit expression of a polypeptide or polynucleotide of the invention or bind to, partially or totally block stimulation or enzymatic activity, decrease, prevent, delay activation, inactivate, desensitize, or down regulate the activity of a polypeptide or polynucleotide of the invention, e.g., antagonists. Activators are agents that, e.g., induce or activate the expression of a polypeptide or polynucleotide of the invention or bind to, stimulate, increase, open, activate, facilitate, enhance activation or enzymatic activity, sensitize or up regulate the activity of a polypeptide or polynucleotide of the invention, e.g., agonists. Modulators include naturally occurring and synthetic ligands, antagonists, agonists, small chemical molecules and the like. Assays to identify inhibitors and activators include, e.g., applying putative modulator compounds to cells, in the presence or absence of a polypeptide or polynucleotide of the invention and then determining the functional effects on a polypeptide or polynucleotide of the invention activity. Samples or assays comprising a polypeptide or polynucleotide of the invention that are treated with a potential activator, inhibitor, or modulator are compared to control samples without the inhibitor, activator, or modulator to examine the extent of effect. Control samples (untreated with modulators) are assigned a relative activity value of 100%. Inhibition is achieved when the activity value of a polypeptide or polynucleotide of the invention relative to the control is about 80%, optionally 50% or 25-1%. Activation is achieved when the activity value of a polypeptide or polynucleotide of the invention relative to the control is 110%, optionally 150%, optionally 200-500%, or 1000-3000% higher.
This invention discloses the surprising finding that an ADNF polypeptide that was shown previously to be neuroprotective of the CNS and to provide cognitive enhancement can alternatively be used in the treatment of peripheral neurotoxicity induced by chemical agents or disease processes. The invention is supported by the findings set out in the Examples that in vivo administration of NAP peptide significantly reduces peripheral neurotoxicity induced by chemical agents.
ADNF Polypeptides: Composition and Synthesis
In one embodiment, the ADNF polypeptides of the present invention comprise the following amino acid sequence: (R1)x-Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln-(R2)y (SEQ ID NO:13) and conservatively modified variations thereof. In this designation, R1 denotes the orientation of the amino terminal (NH2 or N-terminal) end and R2 represents the orientation of the carboxyl terminal (COOH or C-terminal) end.
In the above formula, R1 is an amino acid sequence comprising from 1 to about 40 amino acids, wherein each amino acid is independently selected from the group consisting of naturally occurring amino acids and amino acid analogs. The term “independently selected” is used herein to indicate that the amino acids making up the amino acid sequence R1 may be identical or different (e.g., all of the amino acids in the amino acid sequence may be threonine, etc.). Moreover, as previously explained, the amino acids making up the amino acid sequence R1 may be either naturally occurring amino acids, or known analogues of natural amino acids that functions in a manner similar to the naturally occurring amino acids (i.e., amino acid mimetics and analogs). Suitable amino acids that can be used to form the amino acid sequence R1 include, but are not limited to, those listed in Table I, infra. The indexes “x” and “y” are independently selected and can be equal to one or zero.
As used herein, “NAP” or “NAP peptide” refers to the formula above where x and y both equal 0. “NAP related peptide” refers to any of the other variants of NAP which are described the formula.
R1 and R2 are independently selected. If R1 R2 are the same, they are identical in terms of both chain length and amino acid composition. For example, both R1 and R2 may be Val-Leu-Gly-Gly-Gly (SEQ ID NO:14). If R1 and R2 are different, they can differ from one another in terms of chain length and/or amino acid composition and/or order of amino acids in the amino acids sequences. For example, R1 may be Val-Leu-Gly-Gly-Gly (SEQ ID NO:14), whereas R2 may be Val-Leu-Gly-Gly (SEQ ID NO:15). Alternatively, R1 may be Val-Leu-Gly-Gly-Gly (SEQ ID NO:14), whereas R2 may be Val-Leu-Gly-Gly-Val (SEQ ID NO:16). Alternatives, R1 may be Val-Leu-Gly-Gly-Gly (SEQ ID NO:14), whereas R2 may be Gly-Val-Leu-Gly-Gly (SEQ ID NO:17).
Within the scope of the above formula, certain NAP and NAP related polypeptides are preferred, namely those in which x and y are both zero (i.e. NAP). Equally preferred are NAP and NAP related polypeptides in which x is one; R1 Gly-Gly; and y is zero. Also equally preferred are NAP and NAP related polypeptides in which is one; R1 is Leu-Gly-Gly; y is one; and R2 is -Gln-Ser. Also equally preferred are NAP and NAP related polypeptides in which x is one; R1 is Leu-Gly-Leu-Gly-Gly- (SEQ ID NO:18); y is one; and R2 is -Gln-Ser. Also equally preferred are NAP and NAP related polypeptides in which x is one; R1 is Ser-Val-Arg-Leu-Gly-Leu-Gly-Gly- (SEQ ID NO:19); y is one; and R2 is -Gln-Ser. Additional amino acids can be added to both the N-terminus and the C-terminus of the active peptide without loss of biological activity.
As used herein, “SAL” or “SAL peptide” refers to the formula above where x and y both equal 0. “SAL related peptide” refers to any of the other variants of SAL which are described the formula.
R1 and R2 are independently selected. If R1 R2 are the same, they are identical in terms of both chain length and amino acid composition. Additional amino acids can be added to both the N-terminus and the C-terminus of the active peptide without loss of biological activity.
Peripheral neurotoxicity may be identified and diagnosed in a subject by a variety of techniques. Typically it may be measured by motor dysfunction, muscle wasting, or a change in sense of smell, vision or hearing, or changes in deep tendon reflexes, vibratory sense, cutaneous sensation, gait and balance, muscle strength, orthostatic blood pressure, and chronic or intermittent pain. In humans these symptoms are also sometimes demonstrative of toxic effects in both the PNS and the CNS. Ultimately, there are hundreds of possible peripheral neuropathies that may result from neurotoxicity. Reflecting the scope of PNS activity, symptoms may involve sensory, motor, or autonomic functions. They can be classified according to the type of affected nerves and how long symptoms have been developing.
As mentioned previously, certain disease processes can also result in peripheral neurotoxicity. For example, the diabetes/peripheral neuropathy link has been well established. A typical pattern of diabetes-associated neuropathic symptoms includes sensory effects that first begin in the feet. The associated pain or pins-and-needles, burning, crawling, or prickling sensations form a typical “stocking” distribution in the feet and lower legs.
Use of ADNF Polypeptides to Treat Tauopathy and Related Diseases
Tauopathy means the accumulation of microtubule-associated protein tau in the neuronal and glial cytoplasm. This terminology is relatively new, but it relates to neurodegenerative diseases evidencing widespread accumulation of tau epitopes both in neurons and glia, sometimes without deposition of amyloid beta protein. Tauopathy is now considered to be one of the primary causes of neuronal degeneration, with about one third of the very elderly presenting with deposition of abnormally phosphorylated tau proteins with relative paucity of amyloid beta protein (Abeta). In the course of neurofibrillary tangle formation (including tau aggregates), the major proteinaceous components of these lesions undergo post-translational modifications. In the case of tau, these include phosphorylation of mainly serine and threonine, but also tyrosine residues. In addition, tau is subject to ubiquitination, nitration, truncation, prolyl isomerization, association with heparan sulfate proteoglycan, glycosylation, glycation and modification by advanced glycation end-products (AGEs). Human tauopathies include Alzheimer's disease and frontotemporal dementia with parkinsonism linked to chromosome 17 (Chen et al. Curr Drug Targets. 5(6):503-15 (2004)). Furthermore, recent studies have shown that as a consequence of chemotherapy there was an increase in cerebrospinal fluid tau, which is a marker of neurodegeneration (Van Gool et al. Leukemia. 14:2076-84 (2000); Lee et al., Biochem. Biophys Acta. 1739: 251-9 (2005))
ADNF polypeptides of the invention are generally administered in a pharmaceutical formulation. Suitable formulations for use in the present invention are found in Remington's Pharmaceutical Sciences (17th ed. 1985). In addition, for a brief review of methods for drug delivery, see Langer, Science 249:1527-1533 (1990).
In therapeutic applications, the ADNF polypeptides of the invention are administered to a patient in an amount sufficient to reduce or eliminate symptoms of peripheral neurotoxicity. An amount adequate to accomplish this is defined as “therapeutically effective dose.” Amounts effective for this use will depend on, for example, the particular NAP or ADNF polypeptide employed, the type of disease or disorder to be prevented, the manner of administration, the weight and general state of health of the patient, and the judgment of the prescribing physician.
It must be noted that as used herein and in the appended claims, the singular forms “a”, “and”, and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a cell” includes a plurality of such cells and equivalents thereof known to those skilled in the art, and so forth.
Intranasal Administration of NAP Decreases Peripheral Neurotoxicity Induced by Vinca Alkaloids in Rats
The present study was designed to evaluate if NAP treatment successfully reduced peripheral neurotoxicity induced by the vinca alkaloid vincristine in rats.
Rats (200-300 g), divided into 4 groups of 10, were injected with vincristine sulfate dissolved in saline. Stock concentration was 2 mg/ml, pH 4.5-5.2. Aliquots of the drug were diluted daily in saline to concentrations of 0.175 mg/ml and were administered i.p. at a dose of 0.175 mg/kg. NAP was prepared at 0.1 mg/1.3 ml in saline (0.9% NaCl) and about 0.1 ml was injected subcutaneously to a ˜300 g rat to achieve a dose of 25 microgram/kg (exact calculations were made based on the daily body weights). For 2.5 microgram/kg, the injection solution was diluted by 10 and again 0.1 ml was injected per rat. Treatments took place daily (5 days a week) for ˜3 weeks (20 days) with the dosage calculated on daily body weight. NAP was administered at the same time as the vincristine, in the dosage and the amount where indicated the following schedule.
Four groups were evaluated: 1) Control, saline (n=10), 2) Vincristine (i.p.) 0.175 mg/kg (n=10), 3) Vincristine (i.p.) 0.175 mg/kg+NAP (s.c.) 2.5 microgram/kg (n=10), and 4) Vincristine (i.p.) 0.175 mg/kg+NAP (s.c.) 25 microgram/kg (n=10).
1) Rota-Rod
Vincristine treated animals show impaired performance on the rota-rod test which evaluates muscle innervation and strength (Boyle et al., J Pharmacol Exp Ther 279: 410-415 (1996)) Here, the rota-rod test was performed on days 3, 8, 15 and 23 after the initiation of the vincristine injections.
2) Motor Evaluation
Motor examination was performed on days 6, 9, 13 and 24 after the initiation of the vincristine injections. Rats were examined after vincristine injection, with the use of a motor disability scale. (Bederson J B, et al., Stroke. 1986; 17: 472-476; Leker R R, et al., J Neurol Sci. 1999; 162: 114-119).
3) Olfactory Discrimination Test
Treatments took place daily (5 days a week) for ˜3 weeks (20 days) with the dosage calculated on daily body weight. NAP was administered subcutaneously at the same time as the vincristine was administered intraperitoneally, in the dosage and the amount indicated in the schedule above. After a week cessation of treatment a final boost of vincristine was given i.p. daily for three days and NAP at 25 microgram/kg was given intranasally to group number 4 only. The intranasal formulation followed the previous experiment (Alcalay et al., infra). An olfactory discrimination test was performed on each of the three days of NAP treatment during the final boost period. (Macknin et al., Brain Res. 1000, 174-78 (2004)) The odors tested were 1) Deionized water (ddw) and 2) Scented extracts, i.e., vanilla/almond.
If the animal can discriminate odors, then each trial of the same scent it will be less and less interested—thus the sniffing time will go down. But when the odor is replaced by a new one—the sniffing time will increase.
FIGS. 3-5 show the time spent with new odors, i.e., olfaction capacity. The time spent with each odor over the three consecutive tests was recorded. FIG. 3, for control rats (Group 1), FIG. 4 for vincristine treated rats (Group 2) and FIG. 5 for vincristine and 25 microgram/kg NAP treated rats (Group 4). While the Group 2 vincristine-treated rats did not show any initial interest in the new smell, a trend toward increased interest toward a new odor was observed in the control and the vincristine-NAP treated rats. These results were further evaluated in FIG. 6.
FIG. 6 shows a comparison between time periods spent with a certain odor after exchanging for a new scent-odor discrimination test: The figure depicts 4 points, point 1=water (ddw) trial 3; point 2=odor #1, trial #1; point 3=odor #1, trial 3; point 4=odor #2, trial 1. Results showed a significant difference in the time taken to sniff the third odor when comparing vincristine-treated rats (Group 2) to either control rats (Group 1) or to vincristine+25 microgram/kg NAP rats (Group 4) (P<0.05).
The result of these three independent tests evaluating peripheral neurotoxicity, specifically muscle innervation or strength (e.g. rota-rod test); Motor abilities (movement and circle exit); and behavioral/olfaction abilities, indicates that treatment of animals with NAP significantly reduced impairment and evidence of peripheral neurotoxicity that results from vincristine treatment.
Administration of NAP Reduces Neurotoxicity Induced by Chemotherapeutic Agents
Aim of the study: The aim of the present randomized blind study is to investigate the efficacy of NAP in reducing neurotoxicity induced by the chemotherapeutic agent vincristine in men and women with advanced carcinoma.
Initially 21 patients with advanced carcinoma are randomized between groups A and B. In group A (11 patients) NAP is administered at a dose of 15 mg/45-70 kg before vincristine infusion (1.4 mg/m2). In group B (10 patients) the same chemotherapeutic protocol is followed without administration of NAP. Before beginning of chemotherapy and after 6 chemotherapeutic cycles all patients will undergo clinical neurologic examination and nerve conduction study by a neurologist who is blind to the randomization.
Clinical neurologic examination is assessed neurotoxicity indicators such as tendon reflexes, superficial sensory perception and muscle strength, as well as neuropathic symptoms. Nerve conduction study assesses nerve conduction velocity and action potential amplitude in 7 peripheral nerves. Deterioration of nerve conduction parameters, tendon reflexes, muscle strength, superficial sensory perception, but also of patient's symptoms is significantly more severe in group B.
Concurrent NAP administration will be found to significantly reduce neurotoxicity induced by the chemotherapeutic agent vincristine in men and women with advanced carcinoma.
Randomized Trial with or without NAP to Reduce Neurotoxicity Side Effects Under Chemotherapy with Oxaliplatin (L-OHP), FA/5-FU
Aim of the study: Chemotherapy with L-OHP, FA, 5-FU has a high activity in advanced colorectal cancer (ACRC). The main dose-limiting toxicity of chemotherapy with L-OHP is a peripheral sensory neuropathy. In this study the patients (pts) will receive a chemotherapy with L-OHP, FA and 5-FU with or without NAP. The question is whether a reduction of side effects of neurotoxicity is seen after application of NAP.
We include 27 patients with ACRC. In arm A chemotherapy is applied with L-OHP 85 mg/m2 d1, FA 500 mg/m2 d1+d2 and 5-FU 4000 mg/m2 over 48 h continuous infusion as biweekly schedule. In arm B, 15 mg/45-70 kg NAP is given over 10 min i.v. before application of the same schedule of chemotherapy. Investigation of toxicity, neurological examination and a blood count is performed before every cycle. For a daily documentation of the side effects every patient receives a questionnaire. The NAP group shows a significant reduction of peripheral neurotoxicity. In the NAP group grade II/III leucopenia occurs at a lower frequency than in the control group.
Side effects such as peripheral neurotoxicity under chemotherapy including L-OHP, FA/5-FU will be reduced under supportive care with NAP.
Taxol Neurotoxicity and Protection by NAP
The present study was designed to evaluate whether NAP treatment successfully reduced peripheral neurotoxicity induced by the taxane taxol in rats.
Forty Sprague-Dawley rats (eight weeks old) were divided into four groups that received the following treatments: a) 10% Cremophor EL in Saline; b) taxol for a cumulative dose of 5.6 mg/kg; c) taxol for a cumulative dose of 5.6 mg/kg+NAP 2.5 μg/kg/Day; or d) taxol for a cumulative dose of 5.6 mg/kg+NAP 25 μg/kg/Day. The taxol was reconstituted in a vehicle of 10% Cremophor EL in Saline.
A statistically significant difference between groups was observed only in the plantar test and results are shown in FIG. 7. After the last taxol injection on day three, the taxol-treated rats exhibited thermal hyperalgesia, which was ameliorated by 2.5 μg/kg/day NAP injections. 25 ug/kg NAP did not affect the plantar test. The hyperalgesia induced by the taxol treatment diminished after 4 days. Rota-rod experiments did not show statistically significant differences between groups in this experiment.
Fifteen Sprague-Dawley Rats (seven weeks old) were randomly divided into three groups that received the following treatments: a) 10% Cremophor EL in Saline; b) taxol for a cumulative dose of 9 mg/kg; or c) taxol for a cumulative dose of 9 mg/kg+2.5 μg/kg/Day NAP. The taxol was reconstituted in a vehicle of 10% Cremophor EL in Saline.
Results are shown in FIG. 8 (Plantar test) and FIG. 9 (Rota-rod test). Taxol-treated rats exhibited a significant thermal hyperalgesia eight days after the last Taxol injection. The hyperalgesia was ameliorated by NAP treatment. At this higher dose of Taxol, a significant effect on neuromuscular function was measured using the rota-rod test five days after the first taxol injection. The neuromuscular effect was ameliorated by NAP treatment.
NAP protects against Taxol-induced neuropathy in vivo.
Patent CitationsCited PatentFiling datePublication dateApplicantTitleUS4587046May 18, 1982May 6, 1986The Regents Of The University Of CaliforniaDrug-carrier conjugatesUS5198420Jun 30, 1992Mar 30, 1993The General Hospital CorporationUse of mullerian inhibiting substance and its agonists and antagonists in the treatment of respiratory distress syndromeUS5556757Jun 7, 1995Sep 17, 1996Insight Biotek, Inc.Peptides representing epitopic sites for bacterial and viral meningitis causing agents and their CNS carrier and uses thereofUS5767240Apr 22, 1992Jun 16, 1998The United States Of America As Represented By The Department Of Health And Human ServicesActivity-dependent neurotrophic factorUS6113947Jun 13, 1997Sep 5, 2000Genentech, Inc.Controlled release microencapsulated NGF formulationUS6174862Oct 17, 1994Jan 16, 2001Ramot University Authority For Applied Research And Industrial Development, Ltd.Neurotrophic peptides of activity dependent neurotrophic factorUS6613740Nov 6, 1998Sep 2, 2003Ramot University Authority For Applied Research And Industrial Development Ltd.Activity dependent neurotrophic factor III (ADNF III)US6649411Jul 30, 1999Nov 18, 2003The United States Of America As Represented By The Department Of Health And Human ServicesMethods of inhibiting cancer cells with ADNF III antisense oligonucleotidesUS6890904 *May 25, 2000May 10, 2005Point Therapeutics, Inc.Anti-tumor agentsUS6933277Mar 12, 1999Aug 23, 2005The United States Of America As Represented By The Department Of Health And Human ServicesPrevention of fetal alcohol syndrome and neuronal cell death with ADNF polypeptidesUS7264947Jul 17, 2003Sep 4, 2007United States Of America, As Represented By The Secretary Of The Department Of Health And Human ServicesActivity dependent neurotrophic factor III (ADNF III)US7384908Aug 17, 2000Jun 10, 2008National Institute Of HealthOrally active peptides that prevent cell damage and deathUS7427590Sep 12, 2002Sep 23, 2008The United States Of America As Represented By The Secretary Of The Department Of Health And Human ServicesNeurothrophic components of the ADNF I complexUS7427598May 31, 2001Sep 23, 2008The United States Of Americas As Represented By The Secretary Of The Department Of Health And Human ServicesPost-natal administration of activity-dependent neurotrophic factor-derived polypeptides for enhancing learning and memoryUS7452867 *Mar 23, 2006Nov 18, 2008Ramot At Tel-Aviv University, Ltd.Use of ADNF polypeptides for treating peripheral neurotoxicityUS7863247Mar 10, 2000Jan 4, 2011Ramot-University Authority for Applied Research and Development Ltd.Prevention of fetal alcohol syndrome and neuronal cell death with ADNF polypeptidesUS20020111301Mar 12, 1999Aug 15, 2002Douglas E. BrennemanPrevention of fetal alcohol syndrome and neuronal cell death with adnf polypeptidesUS20030036521 *Jul 30, 1999Feb 20, 2003Illana GozesMethods of inhibiting cancer cells with adnf iii antisense oligonucleotidesUS20030166544Jun 6, 2002Sep 4, 2003Clark Abbot F.Use of ADNP for the treatment of glaucomatous optic neuropathyUS20040053313Jul 17, 2003Mar 18, 2004The Government Of The Usa As Represented By The Secretary Of The Dept. Of Health & Human ServicesActivity dependent neurotrophic factor III (ADNF III)US20070054847Mar 11, 2004Mar 8, 2007Ramot At Tel Aviv University Ltd.Use of adnf polypeptides for treating anxiety and depressionUS20080194488Apr 14, 2008Aug 14, 2008National Institute Of HealthOrally active peptides that prevent cell damage and deathUS20090124543Aug 13, 2007May 14, 2009The Govt. Of The U.S.A., As Represented By The Secretary Of The Dept. Of Health & Human ServicesActivity dependent neurotrophic factor iii (adnf iii)US20090170780Apr 20, 2006Jul 2, 2009Ramot At Tel Aviv University Ltd.Protection of the retina against laser injury by nap and related peptidesUS20090203615Aug 25, 2008Aug 13, 2009The Government of the United States of America as represented by the Secretary of the DepartmentUse of activity dependent neurotrophic factor for enhancing learning and memory: pre-and post-natal administrationUS20090247457Aug 25, 2008Oct 1, 2009The Goverment Of The United States Of America As Represented By TheNeurotrophic components of the adnf i complexUS20100216723Aug 26, 2010Ramot At Tel-Aviv University Ltd.Neuroprotection using nap-like and sal-like peptide mimeticsEP1206489B1Aug 17, 2000May 6, 2004RAMOT UNIVERSITY, AUTHORITY FOR APPLIED RESEARCH &amp; INDUSTRIAL DEVELOPMENT LTD.Orally active peptides that prevent cell damage and deathWO1992018140A1Apr 22, 1992Oct 29, 1992The United States Of America, Represented By The Secretary, Department Of Health And Human ServicesActivity-dependent neurotrophic factorWO1996011948A1Oct 16, 1995Apr 25, 1996The Government Of The United States Of America, As Represented By The Secretary Of The Department Of Health And Human ServicesNeurotrophic peptides of activity dependent neurotrophic factorWO1998035042A2Feb 6, 1998Aug 13, 1998Merav BassanActivity dependent neurotrophic factor iii (adnf iii)WO2000027875A2Nov 4, 1999May 18, 2000The Government Of The United States Of America, As Represented By The Secretary Of The Department Of Health And Human ServicesActivity dependent neurotrophic factor iii (adnf iii)WO2000053217A2Mar 10, 2000Sep 14, 2000The Government Of The United States Of America, As Represented By The Secretary Of The Department Of Health And Human ServicesPrevention of fetal alcohol syndrome and neuronal cell death with adnf polypeptidesWO2001012654A2Aug 17, 2000Feb 22, 2001Ramot University Authority For Applied Research & Industrial Development Ltd.Orally active peptides that prevent cell damage and deathWO2001092333A2May 31, 2001Dec 6, 2001The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human ServicesUse of adnf for enhancing learning and memoryWO2004080957A2Mar 11, 2004Sep 23, 2004Ramot At Tel Aviv University Ltd.Use of adnf polypeptides for treating anxiety and depression* Cited by examinerNon-Patent CitationsReference1Bassan, M. et al. "Complete Sequence of a Novel Protein Containing a Femtomolar-Activity-Dependent Neuroprotective Peptide." Journal of Neurochemistry, vol. 72, pp. 1283-1293 (1999).2Bassan, M. et al. "VIP-Induced Mechanism of Neuroprotection: The Complete Sequence of a Femtomolar-Acting Activity-Dependent Neuroprotective Protein." Regulatory Peptides, vol. 71, No. 2, (Aug. 15, 1997).3Bedikian, Agop Y., et al., "Phase II Trial of Docetaxel in Patients with Advanced Cutaneous Malignant Melanoma Previously Untreated with Chemotherapy;" Dec. 1995; Journal of Clinical Oncology; Vo. 13; No. 12; pp. 2895-2899.4Beni-Adani, L. et al. "Activity-Dependent Neurotrophic Protein is Neuroprotective in a Mouse Model of Closed Head Injury." Society for Neuroscience, 28th Annual Meeting, Los Angeles, CA, Nov. 7-12, 1998. Abstracts, vol. 23, Part 1, p. 1043 (1998).5Brenneman et al. "Neuronal Cell Killing by the Envelope Protein of HIV and Its Prevention by Vasoactive Intestinal Peptide." Nature 335:636 (1988).6Brenneman et al. "N-Methyl-D-Aspartate Receptors Influence Neuronal Survival in Developing Spinal Cord Cultures" Dev. Brain Res. 51:63 (1990).7Brenneman, D.C. and Gozes, I. "A Femtomolar-Acting Neuroprotective Peptide." Journal of Clinical Investigation, vol. 97, pp. 2299-2307 (1996).8Brenneman, D.E. et al. "Activity-Dependent Neurotrophic Factor: Structure-Activity Relationships of Femtomolar-Acting Peptides." Journal of Pharmacology and Experimental Therapeutics, vol. 285, pp. 619-627 (1998).9Brenneman, D.E. et al. "Identification of a Nine Amino Acid Core Peptide from Activity Dependent Neurotrophic Factor I." Society for Neuroscience, 27th Annual Meeting, New Orleans, LA, Oct. 25-30, 1997. Abstracts, vol. 23, Part 2, p. 2250 (1997).10Brenneman, D.E., et al.; "Protective Peptides Derived from Novel Glial Proteins;" 2000; Biochemical Society Transactions; vol. 28; Part 4; pp. 452-455.11Chiba, Tomohiro et al.; "Neuroprotective Effect of Activity-Dependent Neurotrophic Factor Against Toxicity From Familial Amyotrophic Lateral Sclerosis-Linked Mutant SOD1 in Vitro and in Vivo"; 2004, Journal of Neuroscience Research, vol. 78, pp. 542-552.12Chiba, Tomohiro, et al., "Development of a Femtomolar-Acting Humanin Derivative Named Colivelin by Attaching Activity-Dependent Neurotropic Factor to its N Terminus: Characterization of Colivelin-Mediated Neuroprotection against Alzheimer's Disease-Relevant Insults in Vitro and In Vivo;" Nov. 2, 2005; The Journal of Neuroscience; vol. 25; No. 44; pp. 10252-10261.13Davidson, A. et al. "Protection Against Developmental Retardation and Learning Impairments in Apolipoprotein E-Deficient Mice by Activity-Dependent Femtomolar-Acting Peptides." Society for Neuroscience, 27th Annual Meeting, New Orleans, LA, Oct. 25-30, 1997. Abstracts, vol. 23, Part 2, p. 2250 (1997).14Dibbern, D.A., Jr. et al. "Inhibition of Murine Embryonic Growth by Human Immunodeficiency Virus Envelope Protein and Its Prevention by Vasoactive Intestinal Peptide and Activity-Dependent Neurotrophic Factor." Journal of Clinical Investigation, vol. 99, pp. 28377-2841 (1997).15Divinski, Inna, et al ., "A Femtomolar Acting Octapeptide Interacts with Tubulin and Protecots Astrocytes Against Zinc Intoxication;" The Journal of Biological Chemistry; Jul. 2, 2004; vol. 279, No. 27; pp. 28531-28538.16Furman, Sharon, et al.; "Subcellular Localization and Secretion of Activity-Dependent Neuroprotective Protein in Astrocytes;" 2004; Neuron Gilia Biology; vol. 1; pp. 193-199.17GenBank Accession No. AB018327 from the DNA Data Bank of Japan (DDBJ) (released Nov. 17, 1998).18Giladi, E. "Protection Against Developmental and Learning Impairments in Apolipoprotein E-Deficient Mice by Activity-Dependent Femtomolar-Acting Peptides." Neuroscience Letters, Supplement 48 S1-S60, P. S19 (1997).19Glazner, G.W. et al. "A 9 Amino Acid Peptide Fragment of Activity-Dependent Neurotrophic Factor (ADNF) Protects Neurons from Oxidative Stress-Induced Death." Society for Neuroscience, 27th Annual Meeting, New Orleans, LA, Oct. 25-30, 1997. Abstracts, vol. 23, Part 2, p. 2249 (1997).20Glazner, G.W. et al. "Activity Dependent Neurotrophic Factor: A Potent Regulator of Embryonic Growth." Anat. Embryol. 200:65-71 (1999).21Gozes I. et al. "Antiserum to Activity-Dependent Neurotrophic Factor Produces Neuronal Cell Death in CNS Cultures: Immunological and Biological Specificity." Developmental Brain Research, vol. 99, pp. 167-175 (1997).22Gozes, et al., "A Novel Signaling Molecule for Neuropeptide Action: Activity-dependent Neuroprotective Protein"; Annals of the New York Academy of Sciences, 897:125-135 (1999).23Gozes, I. and Brenneman, D.E. "Activity-Dependent Neurotrophic Factor (ADNF)." Journal of Molecular Neuroscience, vol. 7, pp. 235-244 (1996).24Gozes, I. et al. "Activity-dependent neurotrophic factor: Intranasal administration of femtomolar-acting peptides improve performance in a water maze" Journal of Pharmacology and Experimental Therapeutics, vol. 293, pp. 1091-1098 (2000).25Gozes, I. et al. "Neuroprotective Strategy for Alzheimer Disease: Intranasal Administration of a Fatty Neuropeptide." Proc. Natl. Acad. Sci. USA, vol. 93, pp. 427-432 (1996).26Gozes, I. et al. "Protection Against Developmental Retardation in Apolipoprotein E-Deficient Mice by a Fatty neuropeptide: Implications for Early Treatment of Alzheimer's Disease." Journal of Neurobiology, vol. 33, pp. 329-342 (1997).27Gozes, I. et al. "Stearyl-Norleucine-Vasoactive intestinal Peptide (VIP): A novel VIP Analog for Noninvasive Impotence Treatment." Endocrinology, vol. 134, pp. 2125 (1994).28Gozes, I. et al. "Superactive Lipophilic Peptides Discriminate Multiple Vasoactive intestinal Peptide Receptors." Journal of Pharmacology and Experimental Therapeutics, vol. 273, pp. 161-167 (1995).29Gozes, I. et al. "The cDNA Structure of a Novel Femtomolar-Acting Neuroprotective Protein: Activity-Dependent-Neurotrophic Factor III (ADNFIII)." Society for Neuroscience, 27th Annual Meeting, New Orleans, LA, Oct. 25-30, 1997. Abstracts, vol. 23, Part 2, p. 2250 (1997).30Gozes, I. et al. A Femtomolar-Acting Activity-Dependent Neuroprotective Protein (ADNP). Neuroscience Letters, Supplement 48 S1-S60, p. S21 (1997).31Gozes, Illana and Divinski, Inna; "The Femtomolar-Acting NAP Interacts with Microtubules: Novel Aspects of Astrocyte Protection;" 2004; Journal of Alheimer's Disease; vol. 6; pp. S37-S41.32Gozes, Illana, "Tubulin in the Nervous System;" 1982; Neurochemistry International; vol. 4; No. 23; pp. 101-120.33Gozes, Illana, et al.; "From Vasoactive Intestinal Peptide (VIP) Through Activity-Dependent Neuroprotective Protein (ADNP) to NAP;" 2003; Journal of Molecular Neuroscience; vol. 20; pp. 315-322.34Gozes, Illana; "Tau as a Drug Target in Alzheimer's Diseaase;" 2002; Journal of Molecular Neuroscience; vol. 19; pp. 337-338.35Gressens, P. et al. "Growth Factor Function of Vasoactive Intestinal Peptide in Whole Cultured Mouse Embryos." Nature 362:155-58 (1993).36Hannigan, J.H. and Berman, R.F. "Amelioration of Fetal Alcohol-Related Neurodevelopmental Disorders in Rats: Exploring Pharmacological and Environmental Treatments." Neurotoxicol. & Teratol. 22(1):103-111 (2000).37Hausheer et al., "Diagnosis, Management, and Evaluation of Chemotherapy-Induced Peripheral Neuropathy," Semin. Oncol. 33:15-49 (2006).38Hill, J.M. et al. "Learning Impairment in Adult Mice Produced by Early Embryonic Administration of Antiseum to Activity-Dependent Neurotrophic Factor (ADNF)." Society for Neuroscience, 27th Annual Meeting, New Orleans, LA, Oct. 25-30, 1997. Abstracts, vol. 23, Part 2, p. 2250 (1997).39Lagreze, Wolf A., et al.; "The Peptides ADNF-9 and NAP Increase Survival and Neurite Outgrowth of Rat Retinal Ganglion Cells in Vitro;" Mar. 2005; Investigative Opthalmology & Visual Science; vol. 46; No. 3; pp. 933-938.40Lee, Virginia M.-Y., et al., "Transgenic Animal Models of Taupathies;" 2005; Biochimica et Biophysica Acta; vol. 1739; pp. 251-259.41Lilling, G. et al. "Inhibition of Human Neuroblastoma Growth by a Specific VIP Antagonist." Journal of Molecular Neuroscience, vol. 5, pp. 231-239 (1995).42Mahato et al. "Development of Targeted Delivery Systems for Nucleic Acid Drugs." J. of Drug Targeting 4(6):337-357 (1997) [Abstract].43McKune, S.K. et al. "Localization of mRNA for Activity-Dependent Neurotrophic Factor III (ADNF III) in mouse Embryo and Adult CNS." Society for Neuroscience, 27th Annual Meeting, New Orleans, LA, Oct. 25-30, 1997. Abstracts, vol. 23, Part 2, p. 2249 (1997).44Nagase, et al, "Prediction of the Coding Sequences of Unidentified Human Genes. XI. The Complete Sequences of 100 New cDNA Clones from Brain Which Code for Large Proteins in vitro"; DNA Research 5:5:277-286 (1998).45Nelbock, P. et al. A cDNA for a Protein that Interacts with the Human Immunodeficiency Virus Tat Transactivator. Science, vol. 248, pp. 1650-1653 (1990).46Oberdoester, J. et al. "The Effects of Ethanol on Neuronal Cell Death: Implication for the Fetal Alcohol Syndrome." FASEB Journal 12(4):A134 (Mar. 17, 1998).47Pelsman, A. et al. "In Vitro Degeneration of Down Syndrome neurons is Prevented by Activity-Dependent Neurotrophic Factor-Derived Peptides." Society for Neuroscience, 28th Annual Meeting, Los Angeles, CA, Nov. 7-12, 1998. Abstracts, vol. 24, p. 1044 (1998).48Skolnick, J. and Fetrow, J.S. "From Genes to Protein Structure and Function: Novel Applications of Computational Approaches in the Genomic Era." Trends in Biotech. 18(1):34-39 (2000).49Smith, A.E. "Viral Vectors in Gene Therapy." Ann. Rev.Microbiol. 49:807-838 (1995) [Abstract].50Smith-Swintosky, Virginia L., et al., "Activity-Dependent Neurotrophic Factor-9 and NAP Promote Neurite Outgrowth in Rat Hippocampal and Cortical Cultures;" 2005, Journal of Molecular Neuroscience; vol. 25; pp. 225-237.51Spinney, L. "New Peptides Prevent Brain Damage." Molecular Medicine Today 5(7):282 (Jul. 1999).52Spong et al. "Prevention of Fetal Alcohol Syndrome by Novel Peptides." FASEB Journal 13(5):A881 (Mar. 15, 1991).53Spong et al. "Prevention of Fetal Demise and Growth Restriction in a Mouse Model of Fetal Alcohol Syndrome" The Journal of Pharmacology and Experimental Therapeutics 297:774-779 (2001).54Stillman and Cata, "Management of Chemotherapy-Induced Peripheral Neuropathy," Curr. Pain Headache Rep. 10:279-287, abstract only (2006).55Van Gool, S.W., et al.; "Disease-and Treatment-Related Elevation of the Neurodegenerative Market Tau in Children with Hematological Malignancies;" Leukemia; vol. 14; pp. 2076-2084.56Voet et al. Biochemistry, 2nd Ed., p. 67.57Wilkemeyer et al. "Differential effects ethanol antagonism and neuroprotection in peptide fragment NAPVSIPQ prevention of ethanol-induced development toxicity" PNAS 100:8543-8548 (2003).58Zemlyak, Ilona, et al.; "A Novel Peptide Prevents Death in Enriched Neuronal Cultures;" 2000; Regulatory Peptides; vol. 96; pp. 39-43.Referenced byCiting PatentFiling datePublication dateApplicantTitleUS8618043 *Apr 5, 2011Dec 31, 2013Ramot At Tel-Aviv UniversityUse of ADNF polypeptides for treating anxiety and depressionUS20120015878 *Jan 19, 2012Ramot At Tel Aviv University Ltd.Use of adnf polypeptides for treating anxiety and depression* Cited by examinerClassifications U.S. Classification514/18.2, 514/17.7, 514/19.3, 514/21.6, 514/21.7, 514/21.5, 514/21.4, 514/19.2International ClassificationA61K38/08, A61K38/10Cooperative ClassificationG01N2800/52, G01N2500/00, A61K49/0004, G01N33/6896, A61K38/18European ClassificationA61K49/00H, A61K38/16, A61K38/18, G01N33/68V2Legal EventsDateCodeEventDescriptionNov 2, 2010ASAssignmentOwner name: ISAR PHARMA K/S, DENMARKFree format text: SECURITY AGREEMENT;ASSIGNOR:ALLON THERAPEUTICS INC.;REEL/FRAME:025232/0577Effective date: 20101029May 23, 2013ASAssignmentOwner name: ALLON THERAPEUTICS INC., CANADAFree format text: RELEASE BY SECURED PARTY;ASSIGNOR:ISAR PHARMA K/S;REEL/FRAME:030486/0710Effective date: 20130521Mar 4, 2014ASAssignmentOwner name: RAMOT AT TEL-AVIV UNIVERSITY LTD., ISRAELFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:ALLON THERAPEUTICS INC.;REEL/FRAME:032348/0260Effective date: 20140214Sep 8, 2015FPAYFee paymentYear of fee payment: 4RotateOriginal ImageGoogle Home - Sitemap - USPTO Bulk Downloads - Privacy Policy - Terms of Service - About Google Patents - Send FeedbackData provided by IFI CLAIMS Patent Services