New ARPA-H grant aims to advance genomic medicines for rare vascular diseases

Massachusetts General Hospital, a founding member of the Mass General Brigham healthcare system, has been awarded an Advanced Research Projects Agency for Health (ARPA-H) contract to develop advanced personalized genomic medicines to treat rare genetic vascular diseases. The award, up to $25.8 million, granted as part of the Treating Hereditary Rare Diseases with In Vivo Precision Genetic Medicine (THRIVE) program, will provide up to five years of funding to execute the Vascular mEdicineS using Scalable Editing pLatform (VESSEL) program. Incremental funding (Performer Cost Share) of $11.2 million is to be provided over this period: $10.2 million by ANGEA Biotherapeutics as an extension of previous funding support to bring this work to an advanced state and $1 million by a private donor. THRIVE is led by ARPA-H Program Manager Daria Fedyukina, Ph.D.

The VESSEL team includes researchers from Mass General Brigham's Gene and Cell Therapy Institute, Center for Genomic Medicine, Neuroscience Institute, and Heart & Vascular Institute.

VESSEL addresses a central and long-standing challenge in medicine: How to deliver durable effective therapies to the vasculature. The VESSEL initiative will focus specifically on rare genetic vasculopathies, serious and underserved subsets of vascular disease that cause stroke, aneurysms, and heart attacks in children for which no FDA-approved disease-modifying therapies currently exist to address the underlying genetic causes.

We have the privilege to bring together academic and industry experts to develop the technology and breakthroughs needed to revolutionize vascular medicines and, most importantly, improve the lives of all our patients, one patient at a time. This ARPA-H award will help accelerate the necessary shift from one-off therapies, or single drug products per genetic mutation, toward platform approaches for rare genetic diseases. Our program is unique in bringing genome editing approaches into the vascular domain."

Patricia Musolino, MD, PhD, lead and principal investigator, Center for Genomic Medicine, Gene and Cell Therapy Institute, and the Neuroscience Institute, Mass General Brigham

Although each individual disease is rare, more than 10,000 rare diseases exist that together affect more than 30 million Americans. The VESSEL team aims to address this challenge with a fundamentally different solution: a scalable, vessel-targeted gene editing platform that repairs disease-causing variants directly in the vascular cells that drive pathology (smooth muscle cells and endothelium), enabling durable, potentially one-time treatments that can be reused across multiple diseases cutting the time and cost of getting each new treatment to patients. VESSEL work is informed by patients, families, and advocacy groups.

The team's goal is to create a gene-editing platform to treat some of the most severe genetic vasculopathies like Multisystemic Smooth Muscle Dysfunction Syndrome (MSMDS), Generalized Arterial Calcification of Infancy (GACI) and Sturge-Weber syndrome, but, ultimately, rapidly adapt it to develop gene editing treatments for additional rare and common vascular diseases. By focusing on the scalability and reusability of the technology-which combines next-generation base editors with vascular-targeted delivery platforms-the team hopes to reduce development timelines and costs and to expand patient access to these therapies.

In addition to developing potential treatments, the program aims to establish clinical trial umbrella platforms and regulatory and stakeholder frameworks-including a Genetic Vascular Diseases Network-that could help accelerate future gene-editing therapies for rare vascular diseases.

The VESSEL team brings together various Mass General Brigham institutes, centers and departments as well as investigators from John Hopkins University, Kennedy Krieger Institute, University of Massachusetts, UCSF University of Alabama and Jackson Laboratories, to realize the ARPA-H proposal (which necessitated novel technology, trial design and regulatory frameworks).

Key contributors from Mass General Brigham include Mark Lindsay, MD, PhD, and Rajeev Malhotra, MD, experts in vascular disease; Benjamin Kleinstiver, PhD, an expert in enzyme engineering and genome editing; Natalie Artzi, PhD, and Alice Stanton, PhD, experts in nanoparticle development, and delivery guided by  Roger Hajjar, MD, Head of the Gene and Cell Therapy Institute, who brings translational, clinical and regulatory expertise.

"While it's critical for the gene therapy field to find ways to lessen the time and costs of moving from diagnosis to development to administering gene therapy, it's no easy feat," said Musolino. "It takes a collaboration across many areas of expertise to do this type of work and take on these types of scientific, manufacturing and medical challenges."