Diet and gene therapy together may affect liver health in a rare muscle condition

Key study findings

• Liver health in XLMTM patients can be influenced by multiple factors, including nutrition, disease biology and gene therapy design
• A gene therapy delivery method using lipid nanoparticles avoided liver complications
• Preclinical studies used to prepare for gene therapy trials may not match real patient conditions

Findings support designing preclinical models that more closely consider a patient’s real-world unique biology and environment.

Children with X-linked myotubular myopathy (XLMTM) face complex medical challenges from birth. This rare neuromuscular condition, caused by changes in a gene called MTM1, primarily affects muscle and leads to severe weakness, but non-muscle complications are increasingly recognized as key drivers of illness and mortality. Affecting about 1 in 50,000 males, children with XLMTM often require support for breathing, movement and feeding, and there is currently no approved treatment.

A study led by The Hospital for Sick Children (SickKids), published on the cover of Science Translational Medicine, identifies factors that influence liver health in the context of XLMTM and gene therapy. The findings provide insight into why liver toxicity has emerged in some gene‑therapy approaches and how accounting for biological and environmental influences could support the development of safer, more personalized treatments.

“Traditional preclinical studies often rely on laboratory conditions that don’t reflect the complexity of real patients,” says Dr. Ashish Deshwar, co‑corresponding author and physician and Scientist in the Developmental Stem Cell & Cancer Biology program. “This study reinforces that the success and safety of a gene therapy depend on understanding the whole child, not just the disease.”

Dr. Emanuela Pannia, first author and post‑doctoral fellow in the Dowling Lab at SickKids adds: “We found that liver health in X‑linked myotubular myopathy may be influenced by several factors, including the underlying disease, the nutritional environment and how the liver responds to a gene therapy. Understanding these variables can shape how a gene therapy is tolerated, which is important to consider as genomic medicine reaches clinical trials.”

Exploring the environment and biology of XLMTM

XLMTM primarily affects muscles, but many children with the condition are tube fed and rely on specialized formula diets. Pannia, whose background is in nutritional sciences, questioned whether the unique nutritional environment of XLMTM patients could influence liver biology and contribute to this risk.

Using a mouse model with XLMTM, she and the research team confirmed previously unrecognized differences in liver function, which became pronounced under a more formula-like diet similar to that experienced by patients. In a subset of models, this nutritional environment triggered a type of liver injury called intrahepatic cholestasis, in which bile builds up in the liver and leads to toxic amounts of bile acids in the liver and blood. The researchers also found that the loss of MTM1 itself affected how liver cells are organized, resulting in structural changes that may explain why bile and bile acids accumulate.

The team then examined how these findings interacted with the gene therapy delivery method used in a past clinical trial. An adeno-associated virus (AAV) vector, which harnesses a virus’ natural ability to infect cells, was used to deliver a healthy copy of MTM1 specifically to muscle tissue. In this study, exposure to the AAV-based therapy was associated with increased liver injury in those already impacted by the disease and diet, and even in healthy mice fed the same diet.

Taken together, these biological and environmental factors interacted to place additional stress on the liver, helping explain why liver injury may have occurred.

Exploring gene-therapy delivery methods

To explore whether liver defects could be corrected, the team tested lipid nanoparticles (LNPs), which can deliver genetic material to cells without using a virus and naturally accumulate in the liver. As a proof-of-concept, the team engineered LNPs to deliver MTM1 and found that this approach could prevent liver issues observed by the diet.

“These findings give us new insight into how liver injury develops in children with XLMTM, pointing to opportunities to better predict and reduce unintended liver complications and further advance our understanding of gene therapy toxicity,” says Dr. James Dowling, study author, Adjunct Scientist at SickKids and now a Professor of Genetics and Neurology at the University of Pennsylvania and Director of the Penn Neurogenetics Therapy Center.

The findings underscore the importance of Precision Child Health (PCH), a SickKids movement to individualize care by considering each child’s unique biology, environment and lived experience. Translational Genomics is one of the pillars of PCH at SickKids, working to integrate genomic medicine into care and better understand how the unique characteristics of a child shape both disease and treatment response.

Deshwar, who co‑leads Translational Genomics and also serves as a Precision Child Health Scholar in Translational Genomics, notes: “Precision Child Health asks us to look beyond just genetics, to how environment can interact with our underlying biology. These findings show the value of that whole-child perspective and offer an important learning moment for improving how gene therapies are studied, tested, and ultimately designed.”

The researchers emphasize that further work is needed to understand influences on liver toxicity, and how more explicitly accounting for real‑world factors such as nutrition earlier in research could support the development of safer, more personalized gene therapies.

This study was funded by Astellas Gene Therapies, Canadian Institutes of Health Research (CIHR), Muscular Dystrophy Association (MDA), MDA Research Fellowship in collaboration with the Neuromuscular Disease Network for Canada, CIHR Postdoctoral Fellowship, and Myotubular Trust. The Precision Child Health Scholar in Translational Genomics position is funded by the Azrieli Foundation as part of the SickKids and CHU-Sainte Justine Precision Child Health Partnership.