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Developing a Gene Therapy for an Extremely Rare Cerebrovascular Disease

In This Article

  • Atherosclerosis often takes decades to develop, but the process is greatly accelerated in rare cases caused by a specific genetic defect
  • Massachusetts General Hospital physician-scientist Patricia L. Musolino, MD, PhD, is studying these rare genetic disorders to develop approaches that may eventually lead to gene therapy treatments
  • She was key investigator in a recent clinical trial that led to the first FDA-approved gene therapy for a cerebral disease
  • Now, Dr. Musolino is leading a large preclinical and clinical research collaboration to bring promising advanced gene therapy technologies into the clinic

Cardiovascular disease is the number one cause of death worldwide, and 90% of these cases are due to defects in the vasculature. In the majority of patients, atherosclerosis takes decades to develop. But in a tiny handful of cases caused by a specific genetic defect, this process is greatly accelerated.

Massachusetts General Hospital physician-scientist Patricia L. Musolino, MD, PhD, is studying these rare conditions to develop treatments not only for the patients who have them but also to gain insight into the broader underlying causes of cardiovascular disease.

"We like to say that we are transforming drug development to bring life-changing treatments for those suffering from vascular diseases," she says. "We do this with the goal of helping one patient at a time, but with all patients in mind."

Dr. Musolino treats patients in the Neuroscience Intensive Care Unit and the Emergency Department at Mass General and is the co-director of the Pediatric Stroke and Cerebrovascular Service. One area of focus for her research is to translate discoveries about these rare genetic disorders into approaches that may eventually lead to gene therapy treatments. Leveraging her experience as a key investigator in the clinical trial that led to the first FDA-approved gene therapy for a cerebral disease, she is now leading a large preclinical and clinical research collaboration to bring promising advanced gene therapy technologies into the clinic.

Disease Leads to Strokes and Aortic Dissections at Very Young Age

Much of Dr. Musolino's research is dedicated to a cerebrovascular disease caused by the pathogenic variant ACTA2 arginine 179 (Arg179). The disease is called multisystemic smooth muscle dysfunction syndrome (MSMDS). This extremely rare condition, recognized only since 2010 and believed to affect about 10 patients per year, is caused by a single nucleotide change in the ACTA2 gene. Children born with this condition begin experiencing strokes between the ages of 1 and 10 and aortic dissections between the ages of 10 and 20. Most live only into their 20s or early 30s.

"This is a disease of the smooth muscle cells that line the arteries," Dr. Musolino explains. "Our therapeutic strategy is to normalize the function of these cells to restore vessel health and ultimately prevent tissue injury."

Developing Mouse Models of Human Disease

Dr. Musolino and collaborators have developed mouse models of the disease caused by the ACTA2 Arg179 variant. They confirmed that introducing the gene variant affects the smooth muscle cells in the vasculature, leading to dysfunction of their cytoskeletal apparatus and recapitulating the disease seen in humans.

"When we do an angiogram on a five-year-old child with MSMDS, their vessels are so narrow that their appearance would be uncommon even in an 80-year-old person," Dr. Musolino says. "What we see in these mice looks very similar."

The investigators also confirmed that, like the patients, the mice had decreased neurovascular coupling, leading to neurodegeneration and risk of stroke.

In addition to the mouse model, the investigators created a cell line, which has allowed them to optimize gene editing and study potential new approaches to correcting this condition.

Research on Gene Therapy Yields Promising Results

The focus is now on advancing a gene therapy to alleviate these effects. The therapy is delivered by adeno-associated virus (AAV) vectors and injected intravenously. The investigators developed a complementary assay to show that the therapy is precise and effective and causes no noxious off-target effects in the treated cells.

Research has shown that giving the therapy to perinatal mice increases the animals' survival four-fold. The treatment is still effective in juvenile mice, though less so, and higher doses were needed.

Examination of the vessels in the mouse models has shown that the therapy is acting as expected: The smooth muscle cells in the vasculature function normally, the vessels in the brain become contractile, and neurodegeneration is rescued.

The team is conducting more research to build up to an IND filing for clinical trials in patients. Studies are ongoing in mice, and the team plans to test the therapy in larger animals.

Developing New Technologies to Treat Vascular Disease

The leading work on ACTA2 has brought together a cutting-edge expert team that in record time has validated new CRISPR/Cas gene-editing tools and vehicles to deliver gene therapies to the vessels. The team has developed novel AAV vectors and nanoparticles that can target smooth muscle cells to increase the number of indications and types of gene therapy that can be used for vascular disorders. The new nanoparticles have already shown promising results in decreasing calcific atherosclerosis in mouse models of a rare genetic form of the disease that affects babies.

"Right now, there is a huge unmet need in developing treatments for these patients, and the severity of their disease justifies the risk of trying new technologies," Dr. Musolino says. "Developing these therapies will not only alleviate the suffering of these kids and families but also enable technologies never before used in humans to treat the most common forms of vascular disorders—the number one cause of death in the world. This justifies using as many resources as needed."

"Research on rare diseases like these," she adds, "is only possible by working together with patient families, and we are very grateful to those who are willing to share their lives with us."

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