May 21, 2026

AI-generated image created by NCATS using ChatGPT. (OpenAI)

First-in-human clinical trial aims to address unmet need for patients with methylmalonic acidemia

On May 8, 2026, the U.S. Food and Drug Administration (FDA) cleared an Investigational New Drug (IND) application for MMA-101, an adeno-associated virus (AAV)-based gene therapy candidate for patients with methylmalonyl-CoA mutase (MMUT) methylmalonic acidemia (MMA), a rare pediatric metabolic disease with no approved treatments.

The IND clearance allows a first-in-human Phase I/II clinical trial to move forward at the NIH Clinical Center (CC).

Sponsored by the National Human Genome Research Institute (NHGRI) in collaboration with NCATS and several NIH partners, the program represents a unique effort to revive and develop a rare disease therapy after commercial development was discontinued.

“The MMA-101 program reflects the best of what NIH and NCATS can do for rare diseases: identify a promising opportunity, rigorously assess the path forward, and bring together the scientific, clinical, regulatory and translational expertise needed to move responsibly toward patients,” said Joni Rutter, Ph.D., director of NCATS. “For families living with MMA, this effort represents renewed hope. It also offers an opportunity to learn how we can build more collaborative and sustainable pathways for developing rare disease gene therapies when traditional commercial models are not enough.”

Reviving a promising therapy

In 2023, Selecta Biosciences (now Cartesian Therapeutics) discontinued its MMA gene therapy program because of commercial constraints and withdrew its IND application. Rather than allowing the work to end, the company donated manufactured drug product, key reagents and regulatory documentation to NIH.

NCATS conducted a feasibility and risk assessment to determine whether the program could continue and provided support through the Cures Acceleration Network. NIH collaborators then redesigned and relaunched the effort through a partnership involving NCATS, NHGRI, the National Institute of Neurological Disorders and Stroke, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the NIH CC Office of Research Support and Compliance.

To restart the program, the NCATS team resumed stability testing, reestablished bioanalytical assays, updated IND regulatory documentation and revised the clinical trial design. The new IND application was submitted to FDA on April 8, 2026.

“In 2017, our team partnered with Selecta to co-develop a gene therapy candidate for MMA, working together from early preclinical development through regulatory approvals and into patient screening,” said Charles Venditti, M.D., Ph.D., chief of the Metabolic Medicine Branch at NHGRI and principal investigator of the MMA-101 clinical trial. “When the trial was discontinued, the company donated the therapy to NIH because of our longstanding commitment to patients. Building on that foundation and with support from NCATS, we were able to revive the program and move it toward the clinic.”

Venditti added, “This IND marks an important transition from laboratory discovery to clinical investigation and reflects decades of collaborative work across NIH research and clinical teams.”

Addressing a significant unmet need

MMA is a life-threatening inherited metabolic disorder caused by deficiency of the MMUT enzyme. The condition affects multiple organs and is typically identified through newborn screening. Patients with severe disease can experience lethargy, vomiting, respiratory distress and dangerously elevated levels of ammonia, ketones and methylmalonic acid.

Current treatment options focus primarily on managing symptoms through strict dietary interventions. In severe cases, patients may undergo liver and kidney transplantation, although significant complications can still occur.

MMA-101 is designed to deliver a functional copy of the human MMUT gene to the liver using a serotype-8 AAV vector. Researchers hope the therapy will restore MMUT enzyme activity to levels closer to those seen in healthy individuals or liver transplant recipients, without the risks associated with transplantation and lifelong immunosuppression.

“We were given this experimental gene therapy — and with it, the hope that we could test a potential treatment for MMA,” said Rodica Stan, Ph.D., therapeutic development project lead for MMA-101 at NCATS. “To turn that hope into action, we brought together clinical, manufacturing, bioanalytical and regulatory experts to solve complex challenges and move this program into the clinic as quickly and responsibly as possible.”

Next steps

The upcoming Phase I/II clinical trial will evaluate the safety, tolerability and preliminary efficacy of a single intravenous dose of MMA-101 in adolescent and pediatric patients.

The study builds on NHGRI’s long-running natural history study of isolated MMA, which has helped researchers better understand disease progression and identify meaningful clinical endpoints for evaluating treatment response.

Researchers also expect lessons learned from the MMA-101 program to help inform future rare disease gene therapy efforts, including programs supported through NCATS’ Platform Vector Gene Therapy initiative and the Bespoke Gene Therapy Consortium.