NIH Project Aims to Make Gene Therapy 'Playbook' Public

As more families raise money for and partner with researchers to develop tailored, personalized treatments for rare diseases, some NIH agencies are trying to help by streamlining the process.

The PaVe-GT program aims not only to blaze a path forward in advancing gene therapy for four rare diseases, but to share its "playbook" for doing so publicly -- including often-proprietary information on manufacturing and FDA filings.

"We're hoping to pull the curtain back so people can actually see what goes into it ... and have an understanding of the complexity," said Elizabeth Ottinger, PhD, acting chief of the therapeutic development branch at the National Center for Advancing Translational Sciences (NCATS), which leads the program.

Indeed, the idea behind PaVe-GT -- which stands for Platform Vector Gene Therapy -- was so popular that a second initiative, the Bespoke Gene Therapy Consortium (BGTC), followed not long after to broaden the number of stakeholders involved and the number of diseases being treated.

PaVe-GT launched in 2019 as a pilot program to develop gene therapies for four conditions: two inherited metabolic disorders, and two neuromuscular junction disorders. The two metabolic disorders are specific types of propionic acidemia and methylmalonic acidemia, and the neuromuscular junction disorders are Dok7 deficiency and collagen Q deficiency. Thus, the project involves collaboration with the National Human Genome Research Institute (NHGRI) and the National Institute of Neurological Disorders and Stroke (NINDS), where those projects live, respectively.

"We're thinking about the patient groups that are trying to do this for a disease that's so rare that no biotech is going to be interested," said P.J. Brooks, PhD, acting director of the NCATS division of rare diseases research innovation. "We're aiming to make things easier for them, but ultimately it will benefit the whole field."

One key component to streamlining the development of gene therapy is to use a single adenoviral vector (AAV)-based platform for multiple diseases, Ottinger said. Another is to standardize manufacturing processes across those diseases. Ultimately, the program aims to minimize redundancies in preclinical development of gene therapies for these rare conditions, she said.

The NIH agencies plan to bring those therapies through the FDA's standard regulatory process and make public all of their communications with the agency. That includes sharing communications from meetings, as well as any investigational new drug (IND) applications -- something that would be considered proprietary to many drugmakers.

"We're not a drug company," Brooks said. "Our goal is to increase translation and the whole process of bringing more treatments to more people more quickly."

Yet the projects still earn the same valuable components that a drug company might prize. The therapy for one of the rare inherited metabolic disorders -- propionic acidemia caused by a specific mutation in the PCCA gene -- has earned both an orphan drug designation and a rare pediatric disease designation from the FDA, said project leader Charles Venditti, MD, PhD, head of the molecular medicine branch at NHGRI.

If that treatment is approved, the orphan drug designation conveys a certain period of exclusivity, as well as tax breaks, while the rare pediatric disease designation conveys a voucher that can be used for an expedited review of another product. These vouchers can also be sold, Ottinger said, noting that recently they have garnered around $100 million apiece.

Venditti's project is currently in the pre-IND phase. Ottinger said the teams have had an "interact" meeting with FDA, which she describes as a "pre-pre-IND" meeting, the "initial engagement to talk about the overall plan of the project."

The goal is to have a pre-IND meeting and submit an application by May or June, she added, so that the teams can get the therapy into the clinic by early 2024.

Carsten Bönnemann, MD, chief of the neuromuscular and neurogenetic disorders of childhood section at NINDS, who leads the neuromuscular junction gene therapy part of PaVe-GT, added that the program's transparency initiatives will also bolster the safety of gene therapy.

"Since every single trial has so few patients, if you put all of that information together, you have a powerful database on the immunological impact and safety," Bönnemann said. "Gene therapy not only becomes more affordable, but also safer, quicker."

Meanwhile, PaVe-GT's larger cousin, BGTC, will focus on standardizing and simplifying the development process for gene therapies. It's a public-private partnership run through the Foundation for the National Institutes of Health, which allows NIH experts to partner with industry in a way they otherwise couldn't, Brooks said. In addition to the NIH and the FDA's Center for Biologics Evaluation and Research, the project also involves 10 pharmaceutical companies and five non-profit organizations.

"It's like developing a community where everybody feels they know exactly what the expectations are, and how to move something forward for an AAV gene therapy," Ottinger said.

Although gene therapy had hit major hurdles by the early 2000s, including patient deaths, the field has refined its strategies and has started to show some successes.

One notable change has been the move from adenoviral vectors to adeno-associated viral vectors, which should improve safety, experts said. There's also more work being done in ex vivo gene therapy, which involves removing cells from the body, genetically modifying them, and returning them to the body.

The FDA has approved four directly administered gene therapies in recent years: voretigene neparvovec (Luxturna) for retinal disease, onasemnogene abeparvovec (Zolgensma) for spinal muscular atrophy, etranacogene dezaparvovec (Hemgenix) for hemophilia B, and nadofaragene firadenovec (Adstiladrin) for a type of bladder cancer.

The agency has also approved two ex vivo gene therapies, in which a patient's own stem cells are genetically altered and returned to the body to fight disease: betibeglogene autotemcel (beti-cel; Zynteglo) for transfusion-dependent beta-thalassemia and elivaldogene autotemcel (eli-cel; Skysona) for children with cerebral adrenoleukodystrophy.

In addition, some approved cancer treatments, known as chimeric antigen receptor (CAR) T-cell therapies, are also considered gene therapy, as they involve ex vivo editing of a patient's own T cells to make them target cancer cells.

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