SCIENTIFIC AND COMMERCIAL DEVELOPMENT OF OLIGONUCLEOTIDES TO PROTECT NORMAL CELLS FROM TOXICITY SECONDARY TO CHEMOTHERAPY. THE OLIGONUCLEOTIDES WOULD BE USED TO TREAT SUCH CONDITIONS AS ALOPECIA (HAIR LOSS) AND MUCOSITIS.

Notice Date

November 14, 2001

Contracting Office

NIH/TDCB, 6120 Executive Blvd., Suite 450, Rockville, MD 20852

ZIP Code

20852

E-Mail Address

Click here to send a message to the CRADA point of (FrisbieS@otd.nci.nih.gov)

Description

National Cancer Institute Technology Transfer Branch CRADA Opportunity Announcement Summary: The National Cancer Institute (NCI) is currently seeking a Collaborator for a Cooperative Research and Development Agreement (CRADA) to work with investigators in the Center for Cancer Research (CCR) to develop novel oligonucleotides that can be used to treat mucositis and alopecia (hair loss) during chemotherapy. These oligonucleotides will be used clinically in the treatment of patients. Development will include formulation of these oligonucleotides for topical applications. The collaboration will involve all aspects of therapeutic development from basic scientific inquiry to late stage clinical trials that the selected sponsor will be required to partially support. Background: While chemotherapeutic agents are often very effective, there are often many side effects. Some side effects are life-threatening, some result in significant morbidity, and others are very significant from a psychosocial standpoint. Examples of these include bone marrow suppression, mucositis and alopecia. While the use of hematopoietic growth factors has substantially abrogated the concerns over neutropenia, attempts to ameliorate mucositis and alopecia have been less successful. Studies conducted at NCI have evaluated an approach to prevent or abrogate chemotherapeutic side effects including alopecia and mucositis. While the current data does not cover all chemotherapeutic agents, with minor modifications this technology is expected to be applicable to the majority, if not all, chemotherapeutic agents. The basis for this approach is that regardless of target, most drugs bind to a variety of macromolecules inside cells. For example, although DNA is often regarded to be cisplatin's principal target, more that 90% of administered cisplatin can be found in the cytosol bound to other macromolecules. The observation that certain oligonucleotides can interfere with drug activity is not unexpected. Many chemotherapeutic agents such as adriamycin, cisplatin, and etoposide bind DNA and therefore also bind oligonucleotides with variable affinities. Because such oligonucleotides are active when present in the medium of cells treated in vitro (they are charged and unable to penetrate cells) their presence in the local environment of hair follicles, for example, could prevent or abrogate drug induced cytotoxicity. It should be possible with modifications and/or formulations to enhance penetration without interfering with systemic activity of the chemotherapeutic. A relatively unstable oligonucleotide could be used to achieve high local concentrations but allow for its quick degradation if absorbed. Some oligonucleotides may have broad specificity and therefore might be used a broad-spectrum oligonucleotides when multi-agent chemotherapy is administered. Success will require the administration of small molecules locally during the period of drug exposure. This transient application would be designed to achieve sufficient local concentration to bind to and inactivate any drug that reached the target area. For example, local application to the scalp in the form of a shampoo solution, or as a liposomal formulation, or to the oral cavity in the form of an oral solution could provide high local concentrations of the small molecule antagonists. While "leaking" of such agents into the systemic circulation could theoretically result in interference with a drug's activity against a tumor, it is unlikely that the small amounts entering the circulation would result in significant antagonism. Such a concern could be addressed by appropriate in vivo models, or serum measurements in patients. While the above discussion relates principally to drugs that bind DNA, this concept is viewed as capable of being applied more broadly to include all or nearly all chemotherapeutic agents which commonly cause sided effects. A second potential approach for drugs that bind proteins, such as paclitaxel, envisions the synthesis of small peptides to which such drugs would bind with high affinities, achieving the same local effect as an administered oligonucleotide. Preliminary data indicates that such peptides can be identified and synthesized. Established screening methodologies such as Phase Display could be used to identify these peptides. Additional applications other than oncology can also be envisioned, including, for example, male pattern hair loss. Systematic experiments have been performed to date using a series of seven oligonucleotides chosen in an initial screen of this concept. The results have shown that with the right oligonucleotide of the right length, protection of as mush as 100-fold can be achieved. These experiments have provided insight into: (i) the optimal length; (ii) the optimal concentration, and (iii) the mechanism of the protective effect by demonstrating that protection is achieved by preventing drug from entering the cells. These results are favorable with regard to the possibility of development of this technology as a clinical strategy. Proposed NCI Contribution: The NCI will synthesize the initial lot of two to four oligonucleotides and conduct preclinical testing to determine the efficacy of topically administered oligonucleotide(s) in preventing hair loss following chemotherapy in an animal model. The NCI will initiate, as appropriate, collaborative phase I clinical trials under its intramural or extramural clinical trials network to determine the efficacy of a topically administered oligonucleotide(s) in preventing hair loss following chemotherapy in patients receiving chemotherapy. Proposed CRADA Collaborator Contribution: The role of the CRADA Collaborator will include, but not be limited to, formulation of the initial lot of two to four oligonucleotides for topical administration (encapsulation in liposomes is desirable), and manufacturing of the topical formulation of at least one nucleotide in sufficient quantities for use in clinical trials. Proposed Joint Contribution: The NCI and the Collaborator will jointly design a CRADA Research Plan and will jointly interpret the data generated under the Research Plan. The NCI and CRADA Collaborator will collaborate in the planning and support of preclinical and clinical development leading to FDA approval and marketing. Selection Criteria for Choosing the CRADA Collaborator May Include: 1. A demonstrated record of success in the commercial development and production of products related to this area of technology, especially experience in the topical formulation of drugs. 2. The willingness to commit best effort and demonstrated resources to the research and development of the oligonucleotides for clinical use. 3. The level of financial and staffing support the CRADA Collaborator will provide for CRADA-related activities. Willingness to cost share in preclinical and clinical studies including the funding of personnel dedicated to completion of the CRADA research project. 4. The willingness to cooperate with the NCI in the timely publication of research results. 5. The agreement to be bound by the appropriate Department of Health and Human Services (DHHS) regulations relating to human subject research and to all Public Health Service (PHS) policies relating to the use and care of laboratory animals. 6. The willingness to accept the legal provisions and language of the CRADA. 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. Response Procedure: Interested parties should notify the Technology Transfer Branch of the NCI in writing of their interest in the CRADA collaboration no later than December 6, 2001. The written notice should briefly address the selection criteria listed above. Contact Information: CRADA Contact: Suzanne M. Frisbie, Ph.D. 6120 Executive Boulevard, Suite 450 Rockville, Maryland 20852 Phone: 301-496-0477; Fax: 301-402-2117 E-mail: FrisbieS@otd.nci.nih.gov

Web Link

click here to view the standard NIH CRADA document. (http://ttb.nci.nih.gov/forms.html)

Record

Loren Data Corp. 20011116/SPMSC011.HTM (W-318 SN5129J5)