[Federal Register Volume 65, Number 225 (Tuesday, November 21, 2000)]
[Notices]
[Pages 69947-69949]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-29718]


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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.

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    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 (TGF-betas) 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 (Smad3\ex8/ex8\ mice). These mice have made it possible 
for NCI to examine the contribution of Smad3 in cutaneous wound 
healing. Smad3\ex8/ex8\ mice survive into adulthood and show 
accelerated cutaneous wound healing characterized by an increased rate 
of re-epithelialization 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 antisense-related 
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

[[Page 69948]]

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 
(Smad3<SUP>ex8/ex8</SUP>). 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 
Smad3<SUP>ex8/ex8</SUP> mice with complete re-epithelialization 
occurring by day 2 post-wounding in the Smad3<SUP>ex8/ex8</SUP> 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 
Smad3<SUP>ex8/ex8</SUP> mice, with intermediate numbers present in the 
heterozygous mice, compared with wild-type controls (13). The results 
from the characterization of the Smad3<SUP>ex8/ex8</SUP> 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 
Smad3<SUP>ex8/ex8</SUP> mice, further accelerates the wound-healing 
process. Through an extensive characterization of the 
Smad3<SUP>ex8/ex8</SUP> 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 Smad3<SUP>ex8/ex8</SUP> 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:

[[Page 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