Dr. Hichem Tasfaout is an Assistant Professor in the UW Departments of Neurology and Bioengineering, and a faculty member in the Institute for Stem Cell and Regenerative Medicine (ISCRM). His lab is focused on new ways to package and deliver proteins to tissues impacted by muscle disorders caused by genetic mutations.
Several years ago, Tasfaout was presented with an opportunity by the RYR-1 Foundation, which funds research related to RYR-1-Related Diseases, inherited forms of muscle disease that cause muscle weakness, breathing difficulties, fatal reaction to certain types of anesthesia, and other symptoms.
The proposition was straightforward: If Tasfaout could generate preliminary data that a gene delivery method developed by his ISCRM collaborator Dr. Jeff Chamberlain could be used to treat RYR-1 diseases, the foundation would support further research into the viability of his lab’s approach to gene therapy.
Funding to gather the preliminary evidence came soon in the form of a 2024 grant from the John H. Tietze Foundation Trust, a program administered through ISCRM that helps fuel promising research led by early-career scientists. Within a year, Tasfaout received $120,000 from the RYR-1 Foundation to continue his efforts.
That grant, in turn, has led to an even bigger investment. Tasfaout is now part of a multi-institutional team that has received an NIH R01 grant that will allow the researchers to put Tasfaout’s gene therapy methods to the test and hopefully demonstrate that it can be used to safely treat human patients.
The primary investigator on the grant is Dr. Robert Dirksen, Chair of the Department of Pharmacology and Physiology at the University of Rochester School of Medicine and Dentistry. Dr. James Dowling, a professor of Genetics in the Department of Neurology at the University of Pennsylvania is also a key collaborator.
Patients with RYR-1 disorders are often born very sick, in some cases unable to move a finger. Many survive only with ventilation. The problem originates with a genetic mutation that blocks the expression of the RYR-1 protein, a malfunction that disrupts the travel of nerve signals through a calcium channel. When this happens, muscles cannot contract.
Researchers like Tasfaout are learning to deliver healthy versions of genetic material to sick parts of the body using AAV (adeno-associated virus) vectors. In this version of gene therapy, the replacement parts are loaded onto a modified virus, which carries the instructions into a cell. The hitch is that AAV vectors can only transport a small amount of DNA.
“The problem is similar to moving a very large piece of sectional furniture into your new house without a truck,” says Tasfaout. “If it won’t fit in one car, you can move it in separate vehicles in pieces, then put it back together once it’s been placed where you want it. Our technique, which we have used with other muscular dystrophies, is to divide the component proteins of the calcium channel, package them into four separate vectors, and send them all into the muscle, where they will naturally reassemble into a healthy calcium channel.”
Tasfaout will contribute to the joint effort by honing the delivery approach and validating it in mice – all part of the preclinical study, which will serve as a proof of concept for later stage testing.
Ultimately, Tasfaout says the researchers believe this gene replacement strategy can be used to fix the root cause of RYR-1 protein diseases. “Because patients with these kinds of congenital myopathies are not losing muscle tissue over time (unlike patients with muscular dystrophy), we should theoretically be able to inject once and see expression of the healthy protein for a long time.”
In the meantime, Tasfaout emphasizes the importance of the early seed funding that made the federal grant possible. “We started with $25,000, which opened the door to $120,000, and now our lab has close to $500,000 to push this exciting research forward. That’s not a bad return on a relatively modest, but very meaningful investment.”