New Path for a Gene Therapy Trial at NIH for a Rare Metabolic Disease

Nov. 19, 2024

When Selecta Biosciences decided not to pursue a clinical trial on a promising gene therapy for a rare metabolic disease in 2023, it could have been the end of the research, despite years of work. Instead, NCATS and NIH’s National Human Genome Research Institute (NHGRI) signed an agreement to collaborate and move the gene therapy forward. The clinical trial is expected to begin in fall 2025. In addition to giving new hope to people with the disease, the project could lay the groundwork for similar trials at NIH.

It was a surprising turn of events for a project begun in 2016 between the Watertown, Mass.–based biotech company and NHGRI researcher Charles Venditti, M.D., Ph.D. The goal was to develop a gene therapy for a form of methylmalonic acidemia (MMA) that has a faulty methylmalonyl-CoA mutase (MMUT) gene. Gene therapy delivers a working copy of a gene to take over for a faulty one. It’s a promising approach to treat many rare diseases caused by a change in a single gene. Venditti’s team has studied the disease within the NIH intramural research program since 2003. He and his colleagues also have led a 20-year MMA natural history study to chart the progress of the disease in patients.

MMA is a rare, often life-threatening genetic disorder that affects the liver. People with MMA cannot break down and use certain proteins and fats from food. As a result, acids and other substances build up in the blood, urine, and the brain and other organs. This buildup causes a range of symptoms, from lethargy and dehydration to kidney disease, brain fog and intellectual disabilities.

Venditti’s team and Selecta scientists carried out the necessary preclinical research studies. They showed the potential benefit of gene therapy and an immune system–modulating agent in a mouse model. The work resulted in a successful Investigational New Drug (IND) application with the U.S. Food and Drug Administration (FDA), which is needed before testing in people. Weeks before the first clinical trial participant was to receive the gene therapy at the NIH Clinical Center, the company halted the project for financial reasons.

The new NCATS-NHGRI collaboration made sure momentum wasn’t lost. NCATS is committing about $2.2 million over five years to the project through its Cures Acceleration Network. The new trial also was aided in large part by Selecta transferring regulatory documentation and donating two batches of the therapy to NHGRI. This trial will use a common gene therapy vector, adeno-associated virus 8 (AAV8), to deliver a healthy copy of the MMUT gene to a small number of people with the disease. The study is designed as a Phase 1/2 trial. Researchers want to see if the therapy is safe and shows some signs of treating the disease.

In addition to Venditti and NHGRI, several other groups in NIH also will work on the trial at the NIH Clinical Center. NCATS will provide overall project coordination and specific technical expertise on clinical product storage and stability testing. NCATS also will help with trial startup activities, especially for regulatory document preparation and review.

Other Institutes and Centers, such as the National Institute of Neurological Disorders and Stroke (NINDS) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the Clinical Center also will play roles. These will include clinical trial operations (NINDS), patient care and safety monitoring (NICHD and the Clinical Center’s Office of Research Support and Compliance, or ORSC), and regulatory filings and adverse event reporting (ORSC). NINDS also will set up a database to collect clinical trial information in a way that complies with standards and can make secure information sharing easier.

NCATS’ Roles in Gene-Targeted Therapy Trials

“NCATS is superbly positioned to help lead this trial, leveraging our expertise in gene therapy, preclinical development and regulatory support,” said NCATS Director Joni Rutter, Ph.D. “This collaboration reflects our commitment to providing new hope for people with rare diseases who have been waiting for a treatment. By driving this gene therapy trial forward, we’re not only addressing an urgent need for the MMA community, but also building a framework that could accelerate future rare disease trials at NIH.”

NCATS’ extensive experience in drug development has enabled 55 IND applications to move forward, so far resulting in three FDA-approved drugs and an FDA-European Medicines Agency–approved gene therapy. Intramural scientists carry out preclinical studies to improve drug chemistry, understand drug metabolism and effects on human biology, and more. Others at NCATS provide expertise in manufacturing, toxicology, and project and regulatory management.

NCATS also plays major roles in two related gene therapy clinical trial projects at NIH: the Platform Vector Gene Therapy (PaVe-GT) project and the Bespoke Gene Therapy Consortium (BGTC). PaVe-GT, an NIH intramural research project led by NCATS, aims to speed gene therapy clinical trials by using the same gene delivery and manufacturing systems to tackle multiple rare diseases. In addition to overall program management, NCATS has worked with PaVe-GT research teams at NHGRI and NINDS and with contract research organizations to develop more standardized gene vector manufacturing methods. It also continues to improve the regulatory path for gene therapies and accelerate progress by applying lessons learned in preclinical and clinical development to future products.

The BGTC, a public-private partnership managed by the Foundation for the National Institutes of Health, will use its eight gene therapy projects to make gene therapy more accessible. The BGTC aims to standardize manufacturing and preclinical development and streamlining navigation of the regulatory pathway. NCATS helps coordinate the BGTC and is the lead NIH member.

Future Gene Therapy Trials

MMA-101 could inform PaVe-GT and the BGTC, both of which have gene therapy clinical trial projects in development, and lead the way for more trials at the NIH Clinical Center.

“We hope that MMA-101 will help further establish a scientific and operational framework for gene therapy trials at NIH and provide an invaluable roadmap for others to follow,” said Elizabeth Ottinger, Ph.D., acting director of the NCATS Therapeutic Development Branch. “It can help provide a more centralized approach for rare disease clinical trial development at NIH.”

A bigger goal, Venditti noted, is to “democratize the use of gene therapy by lowering costs, increasing accessibility, and hopefully reducing barriers for commercialization.”