Technologies and Assays for Therapeutic Genome Editing INDs (U01, Clinical Trial Not Allowed)

The purpose of this Notice Of Funding Opportunity (NOFO) is to solicit applications on the optimization and characterization of technologies and assays with the potential for utilization and adoption in regulatory submissions of genome editing therapeutics. The NIH Somatic Cell Genome Editing (SCGE) Program is funded through the NIH Common Fund, which supports cross-cutting programs that are expected to have exceptionally high impact. All Common Fund initiatives invite investigators to develop bold and innovative approaches to address problems that may seem intractable or to seize new opportunities that offer the potential for transformation of research processes. The simplicity and broad applicability of targeted and programmable genome editing approaches, including but not limited to those based on CRISPR-Cas9, raise the possibility of a fundamentally new way to treat a variety of genetic diseases. However, many challenges need to be overcome before such techniques could be widely used in the clinic. To maximize the potential of genome editing technology, the SGCE program was developed to accelerate the translation of genome editing technology into clinical applications. Based on input received from stakeholders from academia, industry, and regulatory agencies, as well as the substantial progress in the field of genome editing since the launch of the first five-year phase of the SCGE program, the second five-year phase of SCGE will focus on translating and accelerating safe and effective somatic cell genome editing therapeutics into the clinic. Specifically, SCGE Phase 2 will support the following initiatives: 1) Technologies and Assays for Therapeutic Genome Editing INDs; 2) IND-enabling Studies of Somatic Genome Editing Therapeutic Leads; 3) IND-enabling and Platform Clinical Trials of Somatic Genome Editing for Multiple Diseases and 4) Somatic Cell Genome Editing Translational Coordination and Dissemination Center (TCDC). The SCGE Program will involve collaborative research by a consortium of award recipients with differing expertise to develop, optimize and demonstrate improved candidate genome editing therapeutics as treatments for human disease. Recipients from all four SCGE program components will form a consortium, governed by a steering committee of investigators and NIH staff that will develop consensus policies and procedures for Consortium-wide activities such as data and resource sharing. Collectively, these initiatives are intended to substantially expand the number of genetic diseases treated by in vivo genome editing, ultimately allowing this technology to achieve its potential as a therapeutic platform to treat genetic disease. Program Formation and Governance The awards funded under this NOFO will be cooperative agreements (see Section VI.2. Cooperative Agreement Terms and Conditions of Award). Close interactions among the recipients and NIH will be required to maintain this complex program. The whole SCGE Program governance will rest with the SCGE Program Steering Committee in collaboration with NIH Program Officials, with advice from Program Consultants providing critical scientific and managerial insights, and subject to oversight by the NIH SCGE Working Group. The NIH SCGE Working Group consists of NIH Programmatic Staff from multiple Institutes and Centers of the NIH as well as the Office of the Director. This group will be primarily responsible for the stewardship of the SCGE Program. The SCGE Working Group is co-chaired by the Director of the National Center for Advancing Translational Sciences (NCATS) and the Director of the National Institute for Neurological Disorders and Stroke (NINDS). It reports to the Directors of the Office of Strategic Coordination/Common Fund and the Division of Program Coordination, Planning, and Strategic Initiatives for final funding decisions. Research Objectives The purpose of this 3-year U01 NOFO is to support the optimization and evaluation of IND-enabling technologies and assays to help accelerate the clinical development and evaluation of novel somatic cell genome editing therapeutics to treat a broad array of rare and common diseases. Examples of technologies and assays that would be responsive to this NOFO include those for Chemistry, Manufacturing and Controls (CMC), potency, pharmacology/toxicity, detection and measurement of on/off-target effects, immune responses, and cell tracking studies. Applicants should have an IND-enabling technology or assay to be optimized, with supportive preliminary data, at the time of submission. Projects should focus on further development and rigorous characterization of the technology and/or assay for utilization and adoption in regulatory submissions. This NOFO is intended to bring assays to the point where they could be integrated with future clinical trials/studies. Research Scope This program will support the optimization, refinement, and establishment of acceptability criteria of technologies and assays that will provide data on the efficacy and safety of somatic cell genome editing technologies and delivery systems in future regulatory submissions. In Investigational New Drug Applications (INDs) submitted to the U.S. Food and Drug Administration (FDA), sufficient CMC information should be provided to assure safety, identity, quality, purity, and strength (including potency) of the investigational product entering clinical trials. CMC activities include the establishment of manufacturing processes and product characteristics, as well as defining product testing methods to ensure that the product is safe, effective, and consistent between batches. To guide the CMC development plan, it is important to establish the Critical Quality Attributes (CQAs), a set of criteria to which a drug product should conform to be considered acceptable for its intended use. Establishing acceptable CQAs for genome editing therapeutics can be challenging due to the biological complexity of the products. Nevertheless, the risk associated with genome editing therapies can be reduced by developing appropriate analytical procedures and assays to help define suitable CQAs and ensure high-quality clinical products that meet the quality requirements for nonclinical and clinical trial materials. Process control techniques developed for protein drug production are not always applicable to cell and gene therapies. While a few in vivo somatic cell genome editing therapeutics have entered the clinic targeting the liver and eye, a comprehensive suite of technologies and assays to help define the CQAs of the genome editing product(s) have yet to be generated. Some examples of CMC challenges during the development of genome editing products include suitable potency assays to demonstrate relevant biological activity and to help determine dosage, pertinent assays to inform editing-related immunogenicity, safety and efficacy, manufacturing procedures suitable for scale-up for a multifaceted product, and other optimized bioanalytical assays to fulfill CMC-related activities. A combination of assays may be required when a single assay may not provide adequate CMC data due to a complex mechanism of action or multiple activities of a preliminary therapeutic agent. To support the clinical advancement and regulatory approval of the ever-increasing number of genome editing therapeutics, there is a need for appropriate fit-for-purpose CMC and analytical methodologies to be optimized and qualified for eventual implementation into genome editing therapeutic programs as these programs transition from research into clinical stages. Also in 2023, the FDA Modernization Act 2.0 permits the utilization of new approach methodologies (NAMs) to animal testing, including non-animal or human biology-based test methods, such as cell-based assays, microphysiological systems, or bioprinted or computer models to predict drug toxicity, metabolism, and other absorption, distribution, metabolism, and excretion (ADME) properties. NAMs can now be used to seek FDA exemptions for assessing drug safety and effectiveness during the preclinical phase. Some applicable assays have been developed by investigators in academic laboratories or small biotechnical companies for research purposes but require adaptation and/or comprehensive analysis to meet regulatory requirements during the review of clinical products. Applications responsive to this NOFO will fill this gap as these technologies and assays are critical during preclinical development and the manufacturing process, and would impact product quality, safety and efficacy during clinical application. Successful assays and associated protocols will be shared with the broader community via the Translational Coordination and Dissemination Center (TCDC) and SCGE Toolkit that will be the primary output of this collaborative Common Fund-sponsored program. Examples of product and process characterization assays supported by this NOFO include, but are not limited to: Technologies that enable more informative assessment of patient adaptive and/or innate immune (immunogenicity) responses to genome editors and vectors during clinical trials, including the presence or development of anti-drug antibodies, potential biological consequences, and whether those responses change over time or in response to redosing New approach methodologies that complement traditional animal research, including microphysiological systems, organoids, and other 3- dimensional cell models, that recapitulate critical aspects of normal human physiology and provide quantifiable and predictive measurements of genome editing effects Computer-based technologies, for example artificial intelligence or machine learning, for generating predictive models of individual or population-based biological response(s) to genome editing-based intervention Technologies to detect on and off-target editing in gene-edited animals (or humans) in a non-invasive manner, including but not limited to the use of cell-free DNA obtained from blood or other tissue compartments that can be readily accessed non-invasively (e.g. saliva, exhaled breath condensate, urine, stool) Methods to assess or predict the potential clinical impact of undesired off-target effects, including but not limited to cytotoxicity, genotoxicity, mutagenicity and tumorigenicity potential In vitro and in vivo assays for clinically relevant evaluation of the pharmacokinetic and pharmacodynamic properties of a genome delivery or editing reagent, including durability of editing, bioavailability, bioactivity, cell/tissue specificity, and/or dose-prediction in clinical trials Potency assays to assess specificity and sensitivity measurements of the functionality and efficiency of genome editing product, including vector infectivity and identity, editor activity, and other parameters as appropriate Process development technologies for scale-up and cGMP manufacturing of genome editing products Bioanalytical methods for final product identity and potential contamination Technologies for tracking and monitoring of genome editing therapies in vivo, which may include amongst others, in utero therapeutic products Applications addressing the following topics will be deemed non-responsive and will not be reviewed: Exploratory research for new technology development that lack supporting unpublished and/or preliminary data Assays that are not applicable to genome editing INDs Discovery or development of new genome editing therapeutic products Assays/technologies for non-somatic cell editing Projects proposing clinical trials Technologies that can be broadly applicable to more than one genome editing therapeutic product and/or indication are encouraged Funds from the NIH will be made available through the U01 cooperative agreement award mechanism. Awards will be up to 3 years in duration and will include milestones to evaluate progress. During the initial two years of funding, it is expected that investigators will complete the necessary studies to establish an assay profile and performance criteria (Accuracy [Relative], Analytical Measurement Range, Parallelism, Precision, Selectivity, Specificity, and Stability, as applicable) of sufficient quality for the likely utilization of the technology or assay to support IND-submission of genome editing therapeutic products. As part of the NIH SCGE Consortium, Consortium-generated animal and/or human samples from genome-editing therapeutic studies are expected to become available, and applicants are encouraged to collaborate with other SCGE Consortium members to help evaluate the utility and performance of the assay(s). It is anticipated that in the remainder of the award period, projects will continue to perform assay optimization and further define the analytical parameters using relevant samples, including samples from other consortium members as scientifically appropriate. NIH's Interest in Diversity Every facet of the United States scientific research enterprise—from basic laboratory research to clinical and translational research to policy formation–requires superior intellect, creativity and a wide range of skill sets and viewpoints. NIH’s ability to help ensure that the nation remains a global leader in scientific discovery and innovation is dependent upon a pool of highly talented scientists from diverse backgrounds who will help to further NIH's mission. Research shows that diverse teams working together and capitalizing on innovative ideas and distinct perspectives outperform homogenous teams. Scientists and trainees from diverse backgrounds and life experiences bring different perspectives, creativity, and individual enterprise to address complex scientific problems. There are many benefits that flow from a diverse NIH-supported scientific workforce, including: fostering scientific innovation, enhancing global competitiveness, contributing to robust learning environments, improving the quality of the research, advancing the likelihood that underserved or health disparity populations participate in, and benefit from health research, and enhancing public trust. NIH encourages applicants to include a diverse group of scientists in their research programs, including individuals from underrepresented backgrounds (see NOT-OD-20-031, Notice of NIH’s Interest in Diversity and NOT-OD-22-019, Reminder: Notice of NIH’s Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities). See Section VIII. Other Information for award authorities and regulations.