Reviewed by Lexie CornerAug 23 2024
A groundbreaking study by researchers at the University of Pennsylvania and Moderna has shown that repeated mRNA therapy can significantly improve survival and reduce leucine levels in a mouse model of maple syrup urine disease (MSUD). This promising approach, which utilizes lipid nanoparticle-encapsulated mRNA, offers hope for patients with this rare genetic disorder. The study has been published in Human Gene Therapy.
When the researchers, headed by James Wilson, MD, Ph.D., of the University of Pennsylvania's Perelman School of Medicine, assessed a lipid nanoparticle-based treatment strategy, they considered all potential genetic mutations that can cause MSUD.
The investigators stated, “Repeated intravenous delivery of lipid nanoparticle-encapsulated mRNAs encoding hBCKDHA, hBCKDHB, and hDBT increased survival and body weight, and decreased serum leucine levels in a hypomorphic MSUD mouse model that survives until weaning without clinical intervention. Repeated administration of LNP-encapsulated mRNAs may represent a potential long-term universal treatment approach for MSUD.”
In another recent study from Dr. Wilson's lab, researchers discovered a novel family of adeno-associated virus (AAV) variants with favorable biodistribution properties. These variants may be useful for targeting tissues other than the liver, like the heart.
Capsid engineering efforts aim to reroute in vivo AAV biodistribution away from the liver toward disease-relevant peripheral organs to improve both the safety and cost of AAV gene therapy. When compared to wild-type AAV9 in mice, one recently discovered variant showed a ten-fold increase in cardiac RNA expression and a six-fold decrease in liver RNA expression.
The first of the two studies from the Wilson laboratory demonstrates correction of one of the classical inborn errors of metabolism, MSUD, a disease which can be caused by any of several different genes encoding the components of a multi-subunit enzyme complex responsible for degrading branched-chain amino acids.
Terence R. Flotte, Executive Deputy Chancellor, University of Massachusetts Medical School
Editor in Chief Terence R. Flotte, the Celia and Isaac Haidak Professor of Medical Education and Dean, Provost, added, “The other paper from the Wilson lab represents an important advance in AAV capsid engineering to deliver genes more selectively to the heart while decreasing exposure of the liver, thus making the vector safer.”
Journal Reference:
Greg, A. J., et al. (2024) Lipid Nanoparticle mRNA Therapy Improves Survival and Reduces Serum Branched-Chain Amino Acids in Mouse Models of Maple Syrup Urine Disease. Human Gene Therapy. doi.org/10.1089/hum.2024.047