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Bespoke Gene Therapy Consortium Publishes First 'Playbook' to Bring Rare Disease Programs to Clinic

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NEW YORK – A consortium of federal agencies and biotech companies this week released the first version of a "playbook" designed to shepherd developers of rare disease gene therapies through preclinical research and into first-in-human studies.

The Foundation for the National Institutes of Health (FNIH) on Tuesday published version 1.0 of a regulatory playbook developed by the public-private Bespoke Gene Therapy Consortium (BGTC), an effort backed by the US National Institutes of Health, US Food and Drug Administration, and multiple life science companies.

The playbook guides researchers through each stage of preclinical development — from the first preclinical study of a gene therapy candidate through submission of an investigational new drug (IND) application — and provides advice on how to prepare for key FDA meetings, best practices for manufacturing and preclinical testing, and considerations to keep in mind when proposing clinical trial designs. The playbook is intended to be a resource for smaller companies, academic researchers, and patient foundations that might be advancing gene therapies for the first time and lack the resources of traditional drugmakers.

This preliminary playbook is "really the first major deliverable of the Bespoke Gene Therapy Consortium," said Courtney Silverthorn, who oversees the consortium as associate VP of science partnerships at the nonprofit FNIH, the organization that manages the BGTC. "It provides a one-stop place that delineates a clear roadmap for how to navigate the FDA regulatory process toward an IND approval."

FNIH, which is independent from the NIH, was established by Congress in 1990 to create public-private partnerships that support the agency's mission.

The BGTC was convened by the Accelerating Medicines Partnership, another public-private group managed by FNIH, in 2021 to create tools and standardize practices for bringing gene therapies into clinical trials, specifically for adeno-associated virus (AAV) vector-based gene therapies targeting rare diseases. The consortium, which has received more than $100 million in financial and in-kind commitments from its member organizations, has previously conducted research into AAV vector production and preclinical and product testing processes. The BGTC's member organizations include 13 life science firms, 11 NIH centers, 10 patient foundations and other nonprofits, and the FDA.

The regulatory playbook released this week represents the BGTC's first publication. By providing a central resource for "family groups, nonprofits, patient foundations, academic research labs, small biotechs, but not necessarily large pharmaceutical companies" as they navigate through complex regulatory processes, the BGTC believes it can streamline time to market for such gene therapies, the consortium wrote in the playbook.

The BGTC's work focuses on rare diseases "that currently have no commercial interest," the consortium said. R&D funding in the rare disease space can be difficult to come by, given that treatments for rare diseases will only be adopted by a small segment of the population. It can also be challenging for developers to test investigational treatments in multiple phases of clinical trials, including gold standard randomized-controlled trials, that are often required for regulatory approval, since the total patient population for a rare disease can be miniscule.

Armed with the playbook, "we're hoping to … reduce the burdens of the process," Silverthorn said, enabling developers to cut down on potentially unnecessary work while ensuring critical information isn't omitted as they move gene therapies toward the clinic.

Now, as a next step, developers behind the eight preclinical gene therapies that the consortium selected last year to be part of the program will use the framework outlined in the playbook and other resources the BGTC is creating as they advance these agents toward human trials. In addition to manufacturing, preclinical testing, and regulatory best practices, the playbook also includes readiness checklists for key FDA meetings and templates for various agency interactions, such as for requesting meetings and designations.

Silverthorn said she expects that some of the developers of these eight gene therapies will submit INDs in late 2024 or early 2025. Each of the gene therapies are designed to treat a different rare disease: Charcot-Marie-Tooth disease type 4J, congenital hereditary endothelial dystrophy, Morquio A syndrome, multiple sulfatase deficiency, NPHP5-related retinal degeneration, PCCB-related propionic acidemia, retinitis pigmentosa 45, and spastic paraplegia 50.

The version of the playbook released Tuesday is just the first iteration, and the consortium will continue to update the playbook over time.

This first version is based on publicly accessible resources, such as existing regulatory guidance from the FDA, journal publications, and resources from patient groups, as well as insights from BGTC members. Future versions of the playbook will incorporate lessons from developing the eight gene therapies in the BGTC's clinical trial portfolio and from discussions with the FDA.

Silverthorn said she anticipates the BGTC will update the playbook two to three times over the next three years. Updated versions will include minimum requirements for manufacturing and preclinical testing that are expected to be sufficient to prove safety and efficacy, such as standard critical quality attributes and a minimum set of animal toxicology studies. 

The consortium is developing three preclinical testing protocols for intrathecally, intraocularly, and intravenously administered AAV gene therapies, and in the next version of the playbook, Silverthorn said she expects to have at least one of those protocols validated as preclinical gene therapy candidates move into human trials.

The BGTC plans to make substantial additions to each new version of the playbook it releases, rather than incremental updates, Silverthorn added. "Once we feel that we have a sufficient amount of information to make a valuable update to the playbook, we will do that in larger chunks, rather than bit by bit, as we go forward," she said.