I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information
The purpose of this Funding Opportunity Announcement (FOA) is to support the development and evaluation of novel targeting technologies to deliver anti-HIV gene therapies to specific cells or sites in vivo . There is a significant gap in knowledge of how to deliver therapies efficiently to reservoir sites or specific cell subsets in vivo (for example HIV-infected cells in tissue sanctuaries or rare central memory stem cells) for more effective treatment and/or eradication of HIV. Some of the challenges to be overcome with in vivo gene therapeutic strategies are: inefficient delivery to specific target cells and sites, selective regulation of genetic payload expression to maximize on-target efficacy and minimize off-target effects, and the potential immunogenicity of delivery vectors and the transgenes themselves.
Gene therapy holds exciting potential as a cure for numerous diseases and conditions, including HIV. HIV therapeutic targets have included both viral and host genes. Strategies being explored include protection of hematopoietic stem cells (HSCs) or T cells from infection using inhibitory modalities such as dominant-negative effectors, antisense oligonucleotides, therapeutic peptides, fusion inhibitors, RNA-based strategies (ribozymes, RNA decoys, and RNA interference), expression of fusion inhibitors or optimized versions of restriction factors. Cell-based therapies include genetically engineered chimeric antigen receptor-expressing T-cells and vectored-mediated antibody gene delivery to target and eliminate HIV-infected cells. The next generation approach to traditional vector-based delivery of anti-HIV-1 genes utilizes the delivery of nucleases (e.g., Zn finger, TALENs, homing endonucleases, CRISPR/Cas) to disrupt host or viral sequences.
Current gene therapy approaches for HIV are primarily focused on ex vivo transduction of HSC or T cells, followed by reinfusion of the modified cells. Many of these approaches show potential in vitro and in some cases in animal studies and in pilot clinical trials. Research efforts are ongoing to improve ex vivo transduction efficiency and engraftment of modified cells, as well to reduce or ameliorate graft-versus host disease (GVHD). However, the ex vivo genetic modification of cells is an inefficient and technically complex process. In vivo gene delivery by direct administration would simplify and enhance HIV gene therapy applications. Identifying delivery vectors with high specificity for the HIV reservoir is particularly important to fully realize the potential of genome editing platforms capable of excising or silencing integrated HIV proviruses in rare latently-infected cells.
In vivo gene therapy delivery would be minimally invasive, potentially more selective, and less toxic, and avoid the current poor in vivo survival and engraftment of ex vivo modified cells. The selectivity of transgene expression or activity in target cells is a key determinant of the therapeutic outcome. Uncontrolled transgene expression in non-target as well as target cells could lead to unintended adverse effects from high biological activities of transgene products and/or off-target effects of genome editing approaches. Furthermore, undesirable biodistribution as well as immune responses raised against vectors or the transgenes can lead to their loss and increase the potential for unwanted side effects. Thus, gene delivery systems that are targeted to specific organs/sites/cells are important not only for efficacy, but also for safety. For in vivo applications, there is a need for developing safe and effective mechanisms of cell-specific delivery.
Research Objectives and Scope
This FOA will support the design and development of novel approaches, technologies, tools, and methods that will result in new anti-HIV gene delivery systems capable of efficient in vivo targeting or engineering of relevant cell types. Effective gene delivery is the key pharmacologic mandate for all gene therapy interventions. While some other clinical conditions may require only localized in vivo gene therapy delivery, HIV cure approaches will require targeting cells distributed throughout the body. In addition, new gene therapy strategies such as excising or silencing HIV provirus will require targeted delivery to HIV-infected cells in anatomical sites that are not accessible for ex vivo manipulation.
Applicants are expected to have a successful therapeutic approach, with preliminary data, at the time of submission. A successful therapeutic approach in this FOA is defined as a gene therapy strategy that has shown some anti-HIV efficacy, but not necessarily specific targeting in an in vitro or ex vivo system. Projects are expected to focus on developing and optimizing delivery vehicles or cell-targeting strategies, in combination with an existing therapeutic strategy, for targeted delivery of the therapeutic following in vivo administration in an animal model context. Expression and activity of the therapeutic moiety would be studied as part of the iterative process in improving specific targeting. Applicants are also expected to leverage the growing knowledge of markers/features specific to HIV-infected cells or tissue sanctuary sites to target HIV reservoir cells.
Numerous anti-HIV gene therapeutic approaches would benefit from safe and targeted in vivo delivery. Therefore targeted in vivo delivery of a broad range of gene and cell therapies will be supported under this FOA. Such strategies may include, but are not limited to:
genome or epigenome editing strategies that directly target HIV proviral DNA in latently-infected cells
in vivo application of inhibitory modalities currently used to generate ex vivo–modified HIV-resistant cells
cell engineering strategies to equip patient cells with enhanced properties to target and eliminate latently HIV-infected cells
vectored immunotherapy for effective in vivo antibody production
Similarly, a broad range of delivery platforms will be supported under this FOA including, but not limited to: viral vectors, and non-viral methods of gene delivery such as polymer or liposome-based nanoparticles, nucleic acid complexes modified to facilitate uptake and delivery into cells, and exosomes.
Examples of activities supported by this FOA include, but are not limited to:
Development and evaluation of novel delivery technologies
Directed evolution strategies to identify vectors with enhanced cell specificity
Rational vector engineering approaches to improve cell specificity, such as retargeting strategies to direct vector to specific cell types, or detargeting modifications to specifically prevent vector entry into unwanted cell types
Optimization of in vivo gene transfer by enhancing delivery of the therapeutic gene to the nucleus, for example by increasing efficiency of nuclear targeting and uptake of genetic payloads
Strategies for temporal and quantitative control of transgene expression to regulate timing, level, and cell-specificity of transgene expression in vivo
Methodologies to reduce immunogenicity or minimize elicitation of anti-drug antibodies
Applications addressing the following topics will be deemed non-responsive and will not be reviewed:
Discovery of new gene therapeutic payloads
Studies focused exclusively on ex vivo genetic modification of cells
It is anticipated that solving the challenges of specific targeted in vivo gene delivery will involve many scientific fields, including HIV virology, pharmacology, gene therapy, chemical and biomedical engineering, and analytical chemistry, and thus teams of scientists and bioengineers are especially encouraged to apply.
NIMH will support research to develop and evaluate novel techniques to deliver anti-HIV gene therapies across the blood-brain barrier and effectively target CNS cells that harbor latent virus such as macrophages, microglia, and astrocytes with limited brain toxicity.
The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.
Issuing IC and partner components intend to commit an estimated total of $ 3.01 million to fund 5-7 awards.
Application budgets are not limited but need to reflect the actual needs of the proposed project.
The scope of the proposed project should determine the project period. The maximum project period is 5 years.
Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.
Program Directors/Principal Investigators (PD(s)/PI(s))
All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.
For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.
Robert Freund, Ph.D.
Center for Scientific Review (CSR)
6701 Rockledge Drive, Room 3216, MSC 7852
Bethesda, MD 20892-7852
Research Strategy: Provide a rational justification for the choice of in vivo target cell types, based upon the proposed therapeutic and delivery modalities. Include feasibility and proof-of-principle studies on the ability of the technologies to efficiently deliver the gene therapeutic moiety to selected cell types and to demonstrate that these technologies are effective in an animal model. Include test-of-concept studies in infected animals on suppressive antiretroviral therapy, if appropriate. Outline in vivo analytical studies, as appropriate to the therapy, to inform the biological feasibility of the approach; for example, assessment of in vivo biodistribution, bioavailability of the agent at the site of action, dosage regimen, as well as safety end-points such as immunogenicity.
Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide.
The following modifications also apply:
All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.
Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.
Delayed Onset Study
All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed.
Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.
Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.
Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.
For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII. Important reminders:
All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.
The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.
See more tips for avoiding common errors.
Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.
Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.
Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).
Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.
Does the project address an important problem or a critical barrier to progress in the field? Is there a strong scientific premise for the project? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?
Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?
Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?
Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?
If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?
Is the selection of in vivo target cell types well justified? Are the feasibility and proof of principle studies well designed and do the studies provide sufficient evidence for in vivo delivery efficiency? Do the proposed in vivo analytic studies inform the potential biological feasibility of the gene therapy delivery approach?
Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?
As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.
For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials. For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.
When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of children to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.
The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.
Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.
As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.
Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.
Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).
Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3) Genomic Data Sharing Plan (GDS).
For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.
Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.
2. Review and Selection Process
As part of the scientific peer review, all applications:
May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.
Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.
Applications will initially be assigned to NIAID and, following peer review, assignment may change to another participating NIH Institute or Center on the basis of established PHS referral guidelines . Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:
Scientific and technical merit of the proposed project as determined by scientific peer review.
Availability of funds.
Relevance of the proposed project to program priorities.
After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.
Information regarding the disposition of applications is available in the NIH Grants Policy Statement.
If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.
A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.
Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.
Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.
All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.
Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.
In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships
For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and http://www.hhs.gov/ocr/civilrights/understanding/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.
We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.
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Betty Poon, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Jeymohan Joseph, Ph.D.
National Institute of Mental Health (NIMH)
Robert Freund, Ph.D.
Center for Scientific Review (CSR)
Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.
Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.
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