A customized gene editing approach has shown potential in treating a lethal vascular disease.
Researchers at Mass General Brigham (MA, USA) have developed a gene editing approach that successfully corrected the mutation behind Multisystemic Smooth Muscle Dysfunction Syndrome (MSMDS), a rare blood vessel disorder, in mice.
MSMDS is an extremely rare genetic condition typically caused by a single DNA letter mutation in the ACTA2 gene. This mutation disrupts a crucial structural protein in smooth muscle cells that line blood vessels and various organs.
Without properly functioning ACTA2 protein, these muscles cannot contract effectively, impairing blood circulation, digestion and other vital functions. The condition leads to severe complications including aneurysms, strokes and aortic dissections, with most affected children not surviving to adulthood.
To correct this mutation, the research team employed a base editor, comprised of CRISPR-Cas9 with DNA-modifying enzymes, guided by RNA to target specific genomic locations. However, they discovered that standard editing tools, while successful at correcting the MSMDS-causing mutation, simultaneously introduced unwanted changes to neighboring DNA sequences, effectively neutralizing the therapeutic benefits. This limitation highlighted the need for more precise editing technology that could make the necessary correction without disrupting surrounding genetic material.
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To overcome this challenge, the team designed and screened dozens of configurations of base editors with custom-made Cas9 proteins to improve the targeting. In doing so, they developed a highly precise version that could make the specific A-to-G correction, while minimizing the unwanted bystander edits that occurred with standard tools.
To deliver the therapy, the team engineered a specialized viral delivery vehicle designed to carry the gene-editing therapy directly to blood vessel smooth muscle tissue, the primary site affected in MSMDS. This innovation represents a breakthrough as the first CRISPR therapeutic specifically developed to target the vascular system, addressing the aggressive blood vessel deterioration characteristic in infants suffering from this condition.
When tested in a mouse model of MSMDS, a single dose of the therapy delivered via viral vector extended survival four-fold and significantly improved brain and aortic disease symptoms.
“The impact of this work extends beyond just one disease,” said Mark Lindsay, a pediatric cardiologist within the Mass General Brigham Heart and Vascular Institute. “Our team has created tools that have accelerated the field of genome-editing and precision therapeutics to levels that were unthinkable just two years ago. Cures are possible, but only if we continue to support biomedical research.”
The research team has already initiated discussions with the FDA and secured rare disease designations to accelerate development toward clinical trials.