Researchers at Mass General Brigham in Boston have designed a custom gene editing technique that corrected the mutation behind a rare blood vessel disease in mice, paving the way for further development of the approach to treat the deadly condition and other genetic vascular diseases.
At the eight-week mark, all the mice treated with the gene editor were still alive, while all the untreated mice had died. The results were published in Nature Biomedical Engineering on Sept. 11.
The researchers hope to test the potential therapy in people with multisystemic smooth muscle dysfunction syndrome (MSMDS) soon, Benjamin Kleinstiver, Ph.D., a genome engineer at Mass General Hospital and Harvard Medical School who co-led the study, told Fierce Biotech in an interview.
“We've had an INTERACT meeting where we discussed our initial plans with the FDA,” Kleinstiver said. “Then we had a pre-IND meeting where we really described what we would conceive of the drug product.”
The new approach is similar to the personalized CRISPR therapy used to treat KJ Muldoon, an infant born with a rare metabolic disease, earlier this year, said Kleinstiver, but it targets the smooth muscle with a viral vector instead of the liver with a lipid nanoparticle. Kleinstiver's team also contributed engineered gene editing enzymes to KJ’s treatment.
MSMDS is an extremely rare genetic disease most often caused by a single change, an adenine where a guanine should be, in the DNA of the ACTA2 gene. This disrupts an important structural protein in smooth muscle cells, which line blood vessels and organs like the bladder, eyes, uterus, intestines and lungs.
Without functional ACTA2 protein, these muscles can’t contract effectively, hindering the body’s ability to move blood and urine and to digest food, as well as dilate pupils. This leads to a litany of symptoms and complications, greatly increasing the chance of an aneurysm, stroke or aortic dissection. Most children born with the disease don’t survive to adulthood.
Developing a gene editing therapy to fix the ACTA2 mutation was a yearslong effort, Kleinstiver said. His lab is just down the hall from that of Patricia Musolino, M.D., Ph.D., a vascular neurologist who has long cared for patients with MSMDS.
His background in genome editing and her interest in developing a gene therapy for her patients “got us talking about this specific mutation and what the editing approaches might be to go and try and treat this disease,” Kleinstiver said.
“The story of this research truly began at the bedside,” Musolino said in a Sept. 11 release. “An infant in critical condition first brought together our team, which includes experts on the clinical, genetic, biological and therapeutic aspects of this disease. Now, we have a clear roadmap toward bringing an experimental drug back to the bedside.”
Musolino and cardiologist Mark Lindsay, M.D., Ph.D., another leader of the project, worked to create a mouse model of MSMDS while Kleinstiver’s group trialed different gene editing techniques. While many approaches didn’t work out, the team had a breakthrough when a new batch of base editors was released by the lab of David Liu, Ph.D., in 2020. When paired with a Cas9 enzyme, base editors are able to swap one letter of DNA to another without breaking the DNA strands apart first.
“That's when we started to really see big benefits in on-target efficiency,” Kleinstiver said.
In order to avoid these editors making changes where they weren’t supposed to, the team generated mutated versions of them until they found one that was highly specific for the correct location in the ACTA2 gene.
Earlier this year, another group of scientists led by Eric Olson, Ph.D., of the University of Texas Southwestern Medical Center, reported similar success using its own base editor and mouse model of MSDMS.
“Now we have two independent lines of evidence that base editing in an animal model of this disease can be efficacious and beneficial,” Kleinstiver said. “This has to be one of the first examples of customized gene editing for vascular disease.”