Gene therapy could become a therapeutic, and possibly curative, option for patients with lysosomal acid lipase deficiency (LAL-D), according to a study recently published in Molecular Therapy Methods & Clinical Development.

“Intravenous injection of rscAAVrh74.miniCMV.LIPA largely corrected many of the phenotypes of LAL-D in a Lipa-/- mouse model, including hepatosplenomegaly, elevated serum transaminases, reduced lysosomal acid lipase activity, and cholesterol and triglyceride accumulation in organs, demonstrating that [adeno-associated virus (AAV)] gene therapy may be a viable approach to treating LAL-D,” the authors wrote.

This experimental study used a mouse model to determine the benefits of gene therapy for LAL-D and observed a marked decrease in the characteristic signs of the disease.

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Furthermore, young adult mice showcased a better response to treatment compared to newborns. This finding suggests that a single dose of rscAAVrh74.miniCMV.LIPA may be curative in adults and potentially teenagers, whereas newborns and infants may need repeated administration of this treatment as they age.

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The authors hypothesized that this phenomenon could be due to the particularly fast hepatocyte proliferation rate in the neonatal period along with the episomal location of the AAV genome, which prevents it from being transferred into dividing cells.

These results yield special promise for the cholesteryl ester storage disease subtype of LAL-D, a milder form that usually presents later in life. Meanwhile, patients with Wolman disease, the early-onset and more severe variation, could benefit from a second dose.

A treatment alternative with such a convenient administration would greatly benefit individuals with this enzymatic disease. Current therapeutic guidelines recommend enzyme replacement therapy infusions with sebelipase alfa, a human recombinant LAL enzyme that should be administered every 1 to 2 weeks.

“Additionally, expression into multiple tissue types through AAV-mediated gene therapy can help get LIPA expression into organs where enzyme replacement therapy would be less effective, for example in the brain,” Lam and colleagues explained.


Lam P, Ashbrook A, Zygmunt DA, Yan C, Du H, Martin PT. Therapeutic efficacy of rscAAVrh74.miniCMV.LIPA gene therapy in a mouse model of lysosomal acid lipase deficiency. Mol Ther Methods Clin Dev. Published online August 4, 2022. doi:10.1016/j.omtm.2022.08.001