RFA-NS-02-007: GENE THERAPY FOR NEUROLOGICAL DISORDERS

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GENE THERAPY FOR NEUROLOGICAL DISORDERS Release Date: July 19, 2001 RFA: RFA-NS-02-007 National Institute of Neurological Disorders and Stroke National Institute of Child Health and Human Development National Institute on Aging National Institute of Diabetes and Digestive and Kidney Diseases National Institute on Deafness and Other Communications Disorders Letter of Intent Receipt Date: October 15, 2001 Application Receipt Date: November 16, 2001 THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. USE THE MODULAR BUDGET INSTRUCTIONS THAT BEGIN ON PAGE 13 IN THE PHS 398 (REVISION 5/2001) AVAILABLE AT http://grants.nih.gov/grants/funding/phs398/phs398.html. PURPOSE The goal of this Request for Applications (RFA) is to accelerate the translation of gene transfer methodologies into the clinic. Gene therapy holds tremendous promise for the treatment of neurological disorders. Despite recent advances in this area however, specific scientific, technological, and safety goals must be achieved before gene transfer becomes a viable therapeutic alternative. Current needs include more effective methods for controlling the expression of therapeutic transgenes in the brain, better strategies for vector delivery and monitoring transgene expression, more studies addressing the toxicity of specific vector/transgene combinations, and greater knowledge of the long term effects of expressing specific transgenes in the nervous system. This RFA is intended to encourage research projects that address these or related translational issues in the context of specific neurological disorders. RESEARCH OBJECTIVES Background Gene transfer methodologies may ultimately be used to treat a broad spectrum of diseases that affect the nervous system. These include neurodegenerative disorders (Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s disease, etc.), stroke, epilepsy, and many genetic diseases (lysosomal storage disorders, muscular dystrophies, neurofibromatosis, etc.). There is also significant potential for the application of gene therapy to the neural periphery, such as the auditory system, since a number of genes that cause sensorineural deafness have been isolated. For all these disorders, gene therapy could be used to supply gene products that prevent disease onset or progression. Gene therapy also holds great promise for the treatment of injury to the brain or spinal cord, as well as for the amelioration of chronic pain. The brain and nervous system present unique challenges to achieving successful gene transfer. Because the brain contains many distinct cell types and is regionally heterogeneous, determining how to deliver therapeutic genes effectively is critical. The presence of the blood-brain barrier, limited access to the brain, and the post-mitotic state of brain cells make introducing genes and ensuring that they are correctly expressed difficult. Finally, although the brain is comparatively isolated from immunological surveillance, immune and inflammatory responses can occur, thereby damaging neural tissue. Recent studies indicate that, despite these problems, gene transfer has great potential as a therapeutic modality. Through genetic manipulation, the identification of spontaneous mutations, and drug treatment, investigators have developed animal models for a variety of neurological disorders. Using modified viral vectors, liposomes, genetically-modified cells, or direct DNA transfer, researchers have delivered a variety of therapeutic genes into these animal models. Among these have been genes encoding growth factors, enzymes, anti-apoptotic proteins, anti-oxidant molecules, and anti- angiogenesis factors. Researchers have attempted gene replacement therapy in animals lacking a particular gene product, and have used antisense or ribozyme technologies to reduce the expression of dominantly acting gene products. Many of these pre-clinical experiments have been extremely successful. For example, in a recent NINDS-sponsored workshop (Gene Therapy for Neurological Disorders, October 23-24, 2000), investigators described the successful treatment of animal models of Parkinson’s disease and of specific lysosomal storage disorders. A summary of this meeting has been published (see Molecular Therapy 3: 3-7, 2001). Scope This RFA is intended to encourage projects that, if successful, will overcome obstacles blocking the translation of gene transfer techniques into the clinic. Proposed projects should relate directly to a neurological disorder relevant to the research missions of NINDS, NICHD, NIA, NIDCD or NIDDK. These missions are described at: http://www.ninds.nih.gov/about_ninds/plans/strategic_plan.htm (NINDS) http://www.nichd.nih.gov/strategicplan/cells (NICHD) http://www.nih.gov/nia/research/extramural/neuroscience/programs.htm and http://www.nih.gov/nia/strat-plan/2001-2005/ (NIA), http://www.nidcd.nih.gov/about/plans/strategic/health_disp.asp (NIDCD) http://www.niddk.nih.gov/fund/program/topicslist.htm (NIDDK) Projects should focus on specific scientific, technological, or safety issues that must be addressed prior to the initiation of clinical trials. Possible scientific/technological goals include, but are not limited to: O The development of improved inducible vectors that permit effective temporal control over transgene expression. O The design of vectors with regulatory elements that permit gene expression to be targeted to specific brain regions, peripheral neural tissues, or to other cell types of therapeutic interest. O The development of methods that achieve higher transduction efficiencies and high-level, stable transgene expression in the nervous system. O The development of techniques that permit improved focal or global delivery of vectors into the brain or peripheral neural tissues. O The development of improved methods for monitoring transgene expression in the brain. Safety issues, because of their paramount importance, should be addressed in all projects. Possible safety-related goals include, but are not limited to: O Toxicology studies and the determination of optimal dosage regimens for specific vector/transgene constructs. O The investigation of the long-term effects of expression of specific therapeutic transgenes. O The development of viral vectors that overcome problems of toxicity and immune response. O The use of large animal models to address safety issues. SPECIAL REQUIREMENTS Plan for Dissemination of Data and Biomaterials Sharing of data and biological materials in a timely manner is essential for the rapid progress of biomedical research. NIH policy requires that investigators make unique research resources readily available for research purposes to qualified individuals within the scientific community when they have been published (see the NIH Grants Policy Statement at http://grants.nih.gov/grants/guide/notice-files/not96-184.html) To promote the dissemination of research results, applicants who respond to this RFA must propose plans for sharing data and biomaterials generated through the grant. Rapid sharing of data and biomaterials is strongly encouraged. The Initial Review Group will evaluate the proposed sharing plan and comment on its adequacy in an administrative note in the summary statement. NIH staff will consider the adequacy of the plan in selecting grants to be awarded. National Gene Vector Laboratories An obstacle facing gene transfer investigators is obtaining high quality vectors and evaluating their safety. The National Gene Vector Laboratories (NGVLs) were established in 1995 by the NIH to produce clinical grade vectors for human gene transfer protocols and perform toxicology studies using these vectors. Where appropriate, investigators are encouraged to utilize the NGVLs (for further information, see http://www.iupui.edu/~iucc/ngvl/). MECHANISM OF SUPPORT This RFA will use the NIH individual research project grant (R01) and exploratory/developmental grant (R21) mechanisms. For this solicitation, participating NIH Institutes will use the NINDS guidelines for the R21 mechanism, which can be found at http://www.ninds.nih.gov/funding/r21guidelines.htm. As described in these guidelines, R21 proposals should have the potential for groundbreaking impact, be restricted to a maximum of $125,000/year (direct costs), and limited in duration to a maximum of two years. Applicants are encouraged to contact program staff for advice about choosing the appropriate grant mechanism. For all competing individual research project grant applications requesting up to $250,000 direct costs per year, specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined by NIH. Complete and detailed instructions and information on Modular Grant applications can be found at: http://grants.nih.gov/grants/funding/modular/modular.htm. Applications that request more than $250,000 in any year must use the standard PHS 398 (rev. 5/01) application instructions. The total project period for an application submitted in response to this RFA may not exceed five years. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. The earliest anticipated award date is July 1, 2002. For administrative reasons, all applications received in response to this solicitation will be assigned initially to NINDS. After discussions among the participating Institutes following review, applications will be reassigned to the Institute(s) that are programmatically most appropriate. Because the scope of the research proposed in response to this RFA encompasses the interests of several NIH Institutes, applications may receive dual assignments based on the established PHS guidelines. Awards will be made and managed by one of the participating NIH institutes. FUNDS AVAILABLE The participating Institutes intend to commit a total of approximately $5,000,000 in FY 2002 to fund approximately 8 to 12 new grants submitted in response to this RFA. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. Although the financial plans of the Institute provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non- profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Investigators from foreign institutions are encouraged to contact program staff before preparing applications. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or answer questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Dr. Robert Finkelstein NINDS Neuroscience Center, Rm 2143 6001 Executive Blvd. Bethesda, MD 20892-9527 Telephone: (301) 496-5745 FAX: (301) 402-1501 Email: finkelsr@ninds.nih.gov Dr. Mary Lou Oster-Granite Mental Retardation and Developmental Disabilities Branch NICHD 6100 Executive Boulevard, Rm 4B09D, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 435-6866 FAX: (301) 496-3791 E-mail: mo96o@nih.gov Dr. Bradley C. Wise Neuroscience and Neuropsychology of Aging Program NIA Gateway Building, Suite 3C307 7201 Wisconsin Avenue MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-9350 FAX: (301) 496-1494 Email: WiseB@nia.nih.gov Dr. Thomas M. Johnson Scientific Programs Branch NIDCD Executive Plaza South-400C 6120 Executive Blvd. Bethesda, MD 20892-7180 Telephone: 301-402-3461 FAS: 301-402-6251 Email: tj65y@nih.gov Dr. Catherine McKeon Division of Diabetes, Endocrinology and Metabolic Diseases NIDDK 6707 Democracy Blvd. Rm 6103, MSC 5460 Bethesda, MD 20892-5460 Telephone: (301) 594-8810 FAX: (301) 480-3503 Email: Catherine.McKeon@nih.gov Direct inquiries regarding review issues to: Dr. Lillian Pubols Scientific Review Branch NINDS Neuroscience Center, Rm 3208 Bethesda, MD 20892 Telephone: (301) 496-9223 FAX: (301) 402-0182 Email: LP28E@nih.gov Direct inquiries regarding fiscal matters to: Ms. Tina Carlisle Grants Management Branch NINDS 6001 Executive Boulevard, Rm 3290 Bethesda, MD 20892 Telephone: (301) 496-3938 Email: carlislt@ninds.nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review. The letter of intent is to be sent to Dr. Robert Finkelstein (see Inquiries) by the date listed below. SCHEDULE SUMMARY Letter of Intent Receipt Date: October 15, 2001 Application Receipt Date: November 16, 2001 Peer Review Date: February, 2002 Council Review: May, 2002 Earliest Anticipated Start Date: July 1, 2002 APPLICATION PROCEDURES The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in- time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers and NIH staff. The research grant application form PHS 398 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html is to be used in applying for these grants, with modular budget instructions beginning on page 13 of the application instructions. Applicants are permitted, however, to use the 4/1998 revision of the PHS 398 for scheduled application receipt dates until January 9, 2002. If you are preparing an application using the 4/1998 version, please refer to the step-by-step instructions for Modular Grants available at http://grants.nih.gov/grants/funding/modular/modular.htm . SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in-time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers and NIH staff. The research grant application form PHS 398 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.pdf is to be used in applying for these grants, with the modifications noted below. Applicants are permitted, however, to use the 4/1998 revision of the PHS 398 for scheduled application receipt dates until January 9, 2002. If you are preparing an application using the 4/1998 version, please refer to the step- by-step instructions for Modular Grants available at http://grants.nih.gov/grants/funding/modular/modular.htm. The RFA label available in the PHS 398 (rev. 5/2001) application form (http://grants.nih.gov/grants/funding/phs398/labels.pdf) must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. Submit a signed, typewritten original of the application, including the Checklist, and three signed, photocopies, in one package to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must be sent to: Dr. Lillian M. Pubols Scientific Review Branch, NINDS 6001 Executive Blvd. NSC Rm 3208, MSC 9529 Bethesda, MD 20892-9529 (for courier delivery use: Rockville, MD 20852) Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by NIH staff. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NINDS Scientific Review Branch in accordance with the review criteria stated below. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate National Advisory Council or Board. Review Criteria The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? (2) Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? (3) Innovation: Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? (4) Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? (5) Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? (6) Sharing plan: Has the investigator proposed an adequate plan to make all data and biological materials collected and produced as a result of the proposed research accessible in a timely manner to the biomedical research community? (7) R21 applications only: Does this project have the potential for groundbreaking impact? If successful, will this project achieve at least one of the following goals: 1) generate pilot data to assess the feasibility of a novel avenue of investigation? 2) involve high risk experiments that could lead to a breakthrough in a particular field? or 3) demonstrate the feasibility of new technologies that could have major impact in a specific area? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research. o The adequacy of the proposed protection for humans, animals or the environment, to the extent they may be adversely affected by the project proposed in the application. AWARD CRITERIA Award criteria that will be used to make award decisions include: o scientific merit (as determined by peer review) o availability of funds o programmatic priorities o adequacy of proposed sharing plan INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm. The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the Inclusion of Children as Participants in Research Involving Human Subjects that was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at: http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm Applicants may wish to place data collected under this RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. This policy announcement is found in the NIH Guide for Grants and Contracts Announcement dated June 5, 2000, at the following website: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS- led national activity for setting priority areas. This Request for Applications (RFA), Gene Therapy for Neurological Disorders, is related to many of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.853 (NINDS), 93.865 (NICHD), 93.866 (NIA), 93.173 (NIDCD), and 93.847 (NIDDK). Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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