[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
(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:
[[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