Modeling Myopathy

Darabi Joins NIH-supported Collaboration on Stem Cell-based Disease Modeling for Lethal Neonatal Myopathy

Jan. 14 — When one thinks of human muscle, specific groups such as triceps, biceps and hamstrings often come to mind. However, approximately 40% of our total body weight is comprised of skeletal muscle, which includes the muscles in the face, neck and respiratory system that help us with breathing, chewing and swallowing.

Lurking behind variants in 14 different genes is nemaline myopathy (NM), a rare and lethal genetic skeletal muscle disorder which occurs in an estimated 1 in 50,000 live births and for which there is no cure. Characterized by muscle weakness, hypotonia (poor muscle tone), diminished reflexes and delays in reaching motor milestones like walking, NM can occur shortly after birth or may develop during childhood or even more uncommonly in adulthood.

University of Houston College of Pharmacy’s Radbod Darabi, M.D., Ph.D., associate professor of pharmacology, is taking on the most severe form of NM affecting infants and caused by mutations in the ACTA1 gene. According to the National Organization for Rare Disorders, ACTA1 gene mutations have been found to cause approximately 20-25% percent of all NM cases. Of these cases, about half are classified as severe NM. In the most severe form, some children with NM are so weak from birth that they are not able to breathe for themselves. Unfortunately, there is no cure for NM and even with intensive medical care, some of these children die in the first weeks or months of life.

With a five-year, $399,000 subaward as part of a $2 million grant from the National Institutes of Health’s National Institute of Arthritis and Musculoskeletal and Skin Diseases, Darabi will be working alongside Principal Investigator Callie Kwartler, Ph.D., assistant professor at McGovern Medical School at UTHealth Houston. To better understand the cellular and molecular mechanisms of this disease, Darabi and Kwartler will model this myopathy in reprogrammed stem cells by introducing gene mutations representing NM. They will then “direct” the NM stem cells to differentiate into skeletal muscle progenitor cells and will use them to identify pathogenic mechanisms of NM in the muscle cells.

“Considering the rarity of NM and difficulty obtaining enough patient samples, using reprogrammed stem cells to generate NM genetic models allows us to have abundant muscle cells with the disease genotype to identify disease mechanisms and hopefully discover new druggable therapeutic targets for this lethal myopathy,” Darabi said.

Additionally, Darabi will conduct sophisticated muscle contractile functional studies using NM murine models to determine muscle contractility defects in different muscle groups as well as identify any histopathologic features in the affected muscles, which will be helpful for identification of novel therapeutic targets in the future.