Federal Register / Vol. 65, No. 225 / Tuesday, November 21, 2000 / Notices 69947

the BBA to require the CPAC to submit

a report on the following topics:

• Incorporation of original Medicare

fee-for-service into the demonstration.

• Requirements of quality activities

under the demonstration.

• Inclusion of a rural area in the

demonstration.

• Requirements of a benefit structure

under the demonstration.

The CPAC will also develop

recommendations for how it should

proceed in the future to carry out its

responsibilities under the BBA.

Individuals or organizations that wish

to make 5-minute oral presentations on

the agenda issues should contact the

Executive Director, by 12 noon,

December 7, 2000, to be scheduled. The

number of oral presentations may be

limited by the time available. A written

copy of the oral remarks should be

submitted to the Executive Director, no

later than 12 noon, December 11, 2000.

Anyone who is not scheduled to speak,

may submit written comments to the

Executive Director, by 12 noon,

December 11, 2000.

The meeting is open to the public, but

attendance is limited to the space

available. Individuals requiring sign

language interpretation for the hearing

impaired or other special

accommodation should contact the

Executive Director at least 10 days

before the meeting.

(Section 4012 of the Balanced Budget Act of

1997, Public Law 105–33 (42 U.S.C.1395w–

23 note) and section 10(a) of Public Law 92–

463 (5 U.S.C. App.2, section 10(a))

(Catalog of Federal Domestic Assistance

Program No. 93.773, Medicare—Hospital

Insurance; and Program No. 93.774,

Medicare—Supplementary Medical

Insurance Program)

Dated: November 6, 2000.

Michael M. Hash,

Acting Administrator, Health Care Financing

Administration.

[FR Doc. 00–29754 Filed 11–20–00; 8:45 am]

BILLING CODE 4120–01–U

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

National Institutes of Health

National Cancer Institute: Opportunity

for a Cooperative Research and

Development Agreement (CRADA)

Collaboration in the Identification,

Characterization and Development of

Inhibitors of the Smad3 Signaling

Protein for Use in the Treatment of

Wounds and Fibrotic Diseases

Characterized by Chronic Inflammation

AGENCY: National Institutes of Health,

PHS, DHHS.

ACTION: Notice.

The National Cancer Institute’s

Laboratory of Cell Regulation and

Carcinogenesis (LCRC) has

characterized the role of the Smad3

signaling molecule in wound healing

and has developed several mouse

models of fibrosis. NCI would like to

use its expertise of Smad3 biology in a

collaboration with an outside party to

identify and characterize inhibitors of

Smad3 activity.

SUMMARY: The National Cancer Institute

(NCI) seeks a Cooperative Research and

Development Agreement (CRADA)

Collaborator to aid NCI in the

identification and development of

inhibitors of the function of the Smad3

signaling protein. Smad3 and a closely

related gene, Smad2, act as nuclear

transcriptional activators in response to

intracellular signals from the

transforming growth factor betas (TGFbetas) and activin molecules (1,2). The

existence of these genes was first

proposed after a screen for

developmental mutations in the

nematode led to the identification of

three genes, sma-2, sma-3, and sma-4,

that were homologs of Drosophila MAD,

a protein with a role in the signaling of

a TGF-beta superfamily ligand (3). The

Smad2 and Smad3 signaling pathways

play important roles in the cellular

proliferation, differentiation and

migration crucial to cutaneous wound

healing and the induction of fibrosis in

diseases characterized by chronic

inflammation (4).

NCI has generated a line of mice that

are homozygously deleted in the Smad3

gene (Smad3ex8⁄ex8 mice). These mice

have made it possible for NCI to

examine the contribution of Smad3 in

cutaneous wound healing. Smad3ex8⁄ex8

mice survive into adulthood and show

accelerated cutaneous wound healing

characterized by an increased rate of reepithelialization and a reduced local

inflammatory infiltrate of monocytes

and neutrophils. Thus, Smad3 appears

to mediate in vivo signaling pathways

that mediate key aspects of wound

healing including influx of

inflammatory cells and control of

epithelial cell proliferation and

migration. NCI’s studies indicate that

inhibitors of Smad3 function, such as

specific, small molecule or antisenserelated compounds, may accelerate

cutaneous wound healing and may even

be beneficial to other processes such as

the treatment of extensive burns, the

suppression of radiation-induced

scarring, the growth of autologous skin

grafts and the treatment of fibrotic

diseases characterized by chronic

inflammation.

NCI is looking for a CRADA

Collaborator with a demonstrated record

of success in the isolation and

characterization of small molecule

protein inhibitors. The proposed term of

the CRADA can be up to five (5) years.

DATES: Interested parties should notify

this office in writing of their interest in

filing a formal proposal no later than

January 22, 2001. Potential CRADA

Collaborators will then have an

additional thirty (30) days to submit a

formal proposal. CRADA proposals

submitted thereafter may be considered

if a suitable CRADA Collaborator has

not been selected.

ADDRESSES: Inquiries and proposals

regarding this opportunity should be

addressed to Holly Symonds Clark,

Ph.D., Technology Development

Specialist (Tel. #301–496–0477, FAX

#301–402–2117), Technology

Development and Commercialization

Branch, National Cancer Institute, 6120

Executive Blvd., Suite 450, Rockville,

MD 20852. Inquiries directed to

obtaining patent license(s) for the

technology NIH reference No. E–070–

00/0, filed May 19, 2000 for ‘‘Inhibition

of Smad3 to Prevent Fibrosis and to

Improve Wound Healing’’ (Roberts and

Ashcroft), should be addressed to

Marlene Shinn M.S., J.D., Technology

Licensing Specialist, Office of

Technology Transfer, National Institutes

of Health, 6011 Executive Blvd., Suite

325, Rockville, MD 20852, (Tel. 301–

496–7056, ext. 285; FAX 301–402–

0220).

SUPPLEMENTARY INFORMATION: A

Cooperative Research and Development

Agreement (CRADA) is the anticipated

joint agreement to be entered into with

NCI pursuant to the Federal Technology

Transfer Act of 1986 and Executive

Order 12591 of April 10, 1987 as

amended by the National Technology

Transfer Advancement Act of 1995. NCI

is looking for a CRADA partner to aide

NCI in the characterization and

development of inhibitors of the

function of the Smad3 signaling protein.

The expected duration of the CRADA

would be from one (1) to five (5) years.

The members of the transforming

growth factor-beta (TGF-beta)

superfamily are multi-functional growth

factors that are responsible for a variety

of biological processes in tissue

homeostasis, differentiation,

morphogenesis and development of

multicellular animals (for reviews see 5,

6). They transduce their signals from the

plasma membrane to nuclei of target

cells through distinct combinations of a

family of serine/threonine kinase

receptors. Once activated by specific

phosphorylation events, these receptors

69948 Federal Register / Vol. 65, No. 225 / Tuesday, November 21, 2000 / Notices

transduce their signals through

intercellular effectors known as the

Smad proteins. In response to TGF-beta,

specific Smad proteins become

inducibly phosphorylated, form

heteromers with a common partner,

Smad4, and undergo nuclear

accumulation where the complexes

function as transcription factors (for

reviews, see 7, 8, 9, 10). Two of the

Smad proteins, Smad3 and its closely

related homologue, Smad2, are

downstream mediators of signals from

TGF-betas 1, 2, 3 and activin, each of

which has been implicated as an

important factor in the cellular

proliferation, differentiation and

migration critical for cutaneous wound

healing (11, 12).

Recently, animal models for a loss of

Smad function have provided insight

into the role of specific Smads in a

variety of physiologic systems. NCI has

created a line of mice null for Smad3

(Smad3ex8/ex8). These mice survive into

adulthood and show an accelerated rate

of wound healing and an impaired local

inflammatory response (13). Following

full-thickness incisional wounds, the

rate of wound healing was markedly

accelerated in healthy Smad3ex8/ex8 mice

with complete re-epithelialization

occurring by day 2 post-wounding in

the Smad3ex8/ex8 mice versus day 5 in

wild-type mice, and with significantly

reduced wound areas and wound

widths. Total cell numbers of fibroblasts

and inflammatory cells were markedly

reduced in the wounds of the

Smad3ex8/ex8 mice, with intermediate

numbers present in the heterozygous

mice, compared with wild-type controls

(13). The results from the

characterization of the Smad3ex8/ex8 mice

implicate Smad3 in vivo both in the

inhibition of re-epithelialization, with

specific effects on keratinocyte

proliferation, and in TGF-beta-mediated

chemotaxis of monocytes and of

neutrophils (14). NCI’s results indicate

that Smad3 may mediate in vivo

signaling pathways that are inhibitory to

wound healing, as its deletion leads to

enhanced re-epithelialization and

contracted wound areas. Thus, ‘normal’

wound healing may involve the

suppression of endogenous Smad3

levels, but complete loss of this

signaling intermediate, as in the

Smad3ex8/ex8 mice, further accelerates

the wound-healing process. Through an

extensive characterization of the

Smad3ex8/ex8 mice, NCI has shown that

Smad3 is not necessary for production

of fibronectin by fibroblasts, but likely

does play a role in the elaboration of

collagens (14). Furthermore, the

improved wound healing observed in

the null mice suggests that the

inflammatory response is not critical for

re-epithelization and wound closure but

instead serves to clean wounds of

infection as well as other auxiliary

functions to the wound healing. Thus,

through the creation and

characterization of Smad3 null mice,

NCI has shown that disruption of

Smad3 in a clinical setting may be of

therapeutic benefit in accelerating all

aspects of impaired wound healing.

Preliminary studies with the Smad3

null mice indicate that they may be

resistant to the induction of fibrosis in

response to high dose radiation.

According to these results, inhibitors of

Smad3 could have clinical application

in the prevention of fibrosis, including

radiation-induced fibrosis, and scarring

as in severe trauma and burn patients.

NCI plans to explore several types of

Smad3 inhibitors including antisense

oligonucleotides to the Smad3

sequence; mutated Smad3 polypeptides

and peptide fragments; truncated or

deleted forms of Smad3; and existing

natural products or pharmaceutical

chemical compounds—all of which

could act to inhibit some aspect of

Smad3 function. NCI is looking for a

commercial partner to collaborate with

the laboratory in the identification of

novel Smad3 inhibitors and in the

analysis of existing Smad3 inhibitors for

clinical use in wound healing and in the

prevention of fibrosis and scarring.

The described methods are the subject

of a U.S. Provisional Patent Application,

filed on May 19, 2000 by the Public

Health Service on behalf of the Federal

Government. Furthermore, the initial

report and characterization of the

invention is described in two published

journal articles: Nature Cell Biology

(1999) vol. 1:260–266 and Cytokine

Growth Factor Rev. (2000) vol. 11(1–

2):125–131.

References

1. Massague, J., 1998 Annu. Rev. Biochem.

vol. 67:753–791.

2. Derynck, R. et al., 1998 Cell, vol. 95:737–

740.

3. Savage C. et al., 1996, Proc. Natl. Acad.

Sciences U.S.A., vol. 93:790–794.

4. Ashcroft and Roberts, 2000, Cytokine

Growth Factor Rev., vol. 11(1–2): 125–131.

5. Piek, E. et al., 1999, FASEB J., vol.

13:2105–2124.

6. Zimmerman, C.M. and R.W. Padgett,

2000, Gene, vol. 249:17–30.

7. Derynck and Zhang, 1996, Curr. Biol.,

vol. 6:1226–1229.

8. Massague, J., 1996, Cell, vol. 85:947–950.

9. Wrana, J. and Attisano, L., 1996, Trends

Genet., vol. 12:493–496.

10. Heldin, C–H., et al., 1997, Nature, vol.

390:465–471.

11. Roberts, A.B., 1995, Wound Repair

Regen., vol. 3:408–418

12. O’Kane, S. and Ferguson, M.W.J., 1997,

Int. J. Biochem. Cell Biol., vol. 29:63–78.

13. Ashcroft, G.S. et al, Nature Cell

Biology, vol. 1:260–266.

14. Yang, X. et al, 1999, EMBO J. vol.

18:1280–1291.

Under the present proposal, the

overall goal of the CRADA will be to

identify and characterize potential

inhibitors of Smad3 function using in

vitro assay systems and NCI’s

Smad3ex8/ex8 null mice as a preclinical

animal model. NCI speculates that the

CRADA research will have two main

phases including:

1. Identification and characterization

of inhibitors of Smad3 function, and

2. Examination of the efficacy of the

inhibitors for the treatment of various

ailments and diseases.

NCI believes that this technology may

have many applications including the

treatment of cutaneous wounds and

extensive burns and the prevention of

fibrosis and scarring in diseases

characterized by chronic inflammation.

Party Contributions

The role of the NCI in the CRADA

may include, but not be limited to:

1. Providing intellectual, scientific,

and technical expertise and experience

to the research project.

2. Providing the CRADA Collaborator

with information and data relating to

the role of the Smad3 signaling protein

in wound healing and in the

development of radiation-induced

fibrosis as determined through the NCI’s

analysis of the Smad3 null mice.

3. Providing the CRADA Collaborator

with the necessary materials to

collaborate in the identification and

characterization of the Smad3

inhibitors.

4. Planning research studies and

interpreting research results.

5. Carrying out research to analyze

potential Smad3 inhibitors.

6. Publishing research results.

7. Developing additional potential

applications of the identified Smad3

inhibitors.

The role of the CRADA Collaborator

may include, but not be limited to:

1. Providing significant intellectual,

scientific, and technical expertise or

experience to the research project.

2. Planning research studies and

interpreting research results.

3. Providing technical and/or

financial support to facilitate scientific

goals and for further design of

applications of the technology outlined

in the agreement.

4. Publishing research results.

Selection criteria for choosing the

CRADA Collaborator may include, but

not be limited to:

Federal Register / Vol. 65, No. 225 / Tuesday, November 21, 2000 / Notices 69949

1. A demonstrated record of success

in some or all of the following areas:

molecular biology, the development of

small molecule therapeutics, and high

throughput screening of compounds.

2. A demonstrated background and

expertise in growth factor and cytokine

research.

3. The ability to collaborate with NCI

on further research and development of

this technology. This ability will be

demonstrated through experience and

expertise in this or related areas of

technology indicating the ability to

contribute intellectually to ongoing

research and development.

4. The demonstration of adequate

resources to perform the research and

development of this technology (e.g.

facilities, personnel and expertise) and

to accomplish objectives according to an

appropriate timetable to be outlined in

the CRADA Collaborator’s proposal.

5. The willingness to commit best

effort and demonstrated resources to the

research and development of this

technology, as outlined in the CRADA

Collaborator’s proposal.

6. The demonstration of expertise in

the commercial development and

production of products related to this

area of technology.

7. The level of financial support the

CRADA Collaborator will provide for

CRADA-related Government activities.

8. The willingness to cooperate with

the National Cancer Institute in the

timely publication of research results.

9. The agreement to be bound by the

appropriate DHHS regulations relating

to human subjects, and all PHS policies

relating to the use and care of laboratory

animals.

10. The willingness to accept the legal

provisions and language of the CRADA

with only minor modifications, if any.

These provisions govern the distribution

of future patent rights to CRADA

inventions. Generally, the rights of

ownership are retained by the

organization that is the employer of the

inventor, with (1) the grant of a license

for research and other Government

purposes to the Government when the

CRADA Collaborator’s employee is the

sole inventor, or (2) the grant of an

option to elect an exclusive or

nonexclusive license to the CRADA

Collaborator when the Government

employee is the sole inventor.

Dated:November 12, 2000.

Kathleen Sybert,

Chief, Technology Development and

Commercialization Branch, National Cancer

Institute, National Institutes of Health.

[FR Doc. 00–29718 Filed 11–20–00; 8:45 am]

BILLING CODE 4140–01–P

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

National Institutes of Health

Government-Owned Inventions;

Availability for Licensing

AGENCY: National Institutes of Health,

Public Health Service, DHHS.

ACTION: Notice.

SUMMARY: The inventions listed below

are owned by agencies of the U.S.

Government and are available for

licensing in the U.S. in accordance with

35 U.S.C. 207 to achieve expeditious

commercialization of results of

federally-funded research and

development. Foreign patent

applications are filed on selected

inventions to extend market coverage

for companies and may also be available

for licensing.

ADDRESSES: Licensing information and

copies of the U.S. patent applications

listed below may be obtained by writing

to the indicated licensing contact at the

Office of Technology Transfer, National

Institutes of Health, 6011 Executive

Boulevard, Suite 325, Rockville,

Maryland 20852–3804; telephone: 301/

496–7057; fax: 301/402–0220. A signed

Confidential Disclosure Agreement will

be required to receive copies of the

patent applications.

Enhanced Homologous Recombination

Mediated by Lambda Recombination

Proteins

Donald L. Court, Daiguan Yu, EChaing Lee, Hilary Ellis, Nancy A.

Jenkins, Neal G. Copeland (NCI), DHHS

Reference No. E–177–00/0 filed 14 Aug

2000, Licensing Contact: Dennis Penn;

301/496–7056 ext. 211; e-mail:

pennd@od.nih.gov.

The present invention concerns

methods to enhance homologous

recombination in bacteria and

eukaryotic cells using recombination

proteins derived from bacteriophage

lambda. It also concerns methods for

promoting homologous recombination

using other recombination proteins.

Concerted use of restriction

endonucleases and DNA ligases allows

in vitro recombination of DNA

sequences. The recombinant DNA

generated by restriction and ligation

may be amplified in an appropriate

microorganism such as E. coli, and used

for diverse purposes including gene

therapy. However, the restrictionligation approach has two practical

limitations: first, DNA molecules can be

precisely combined only if convenient

restriction sites are available; second,

because useful restriction sites often

repeat in a long stretch of DNA, the size

of DNA fragments that can be

manipulated are limited, usually to less

than about 20 kilobases.

Homologous recombination, generally

defined as an exchange of homologous

segments anywhere along a length of

two DNA molecules, provides an

alternative method for engineering

DNA. In generating recombinant DNA

with homologous recombination, a

microorganism such as E. coli, or a

eukaryotic cell such as a yeast or

vertebrate cell, is transformed with an

exogenous strand of DNA. The center of

the exogenous DNA contains the desired

transgene, whereas each flank contains

a segment of homology with the cell’s

DNA. The exogenous DNA is introduced

into the cell with standard techniques

such as electroporation or calcium

phosphate-mediated transfection, and

recombines into the cell’s DNA, for

example with the assistance of

recombination-promoting proteins in

the cell.

In generating recombinant DNA by

homologous recombination, it is often

advantageous to work with short linear

segments of DNA. For example, a

mutation may be introduced into a

linear segment of DNA using

polymerase chain reaction (PCR)

techniques. Under proper

circumstances, the mutation may then

be introduced into cellular DNA by

homologous recombination. Such short

linear DNA segments can transform

yeast, but subsequent manipulation of

recombinant DNA in yeast is laborious.

It is generally easier to work in bacteria,

but linear DNA fragments do not readily

transform bacteria (due in part to

degradation by bacterial exonucleases).

Accordingly, recombinants are rare,

require special poorly-growing strains

(such as RecBCD-strains) and generally

require thousands of base pairs of

homology. This invention teaches an

improved method of promoting

homologous recombination in bacteria.

In eukaryotic cells, targeted

homologous recombination provides a

basis for targeting and altering

essentially any desired sequence in a

duplex DNA molecule, such as targeting

a DNA sequence in a chromosome for

replacement by another sequence. This

invention teaches methods useful for

treating human genetic diseases, the

creation of transgenic animals, or

modifying the germline of other

organisms.

Amelogenin Knockout Mice and Use as

Models for Tooth Disease

Dr. Ashok Kulkarni et al. (NIDCR),

DHHS Reference No. E–167–00/0,

Licensing Contact: John Rambosek; 301/