Researchers at the University of Basel have developed a gene therapy that could potentially treat a rare and currently fatal muscle disease in children. The study shows in animal models that a single treatment is sufficient to stabilize muscles and nerves and to halt disease progression. The challenge now is to bring this promising therapy into the clinic.
Roughly once a year in Switzerland, a family receives the devastating diagnosis that their child is affected by a severe form of muscle weakness. This hereditary disease, known as LAMA2-related muscular dystrophy, is very rare and remains untreatable today. The most severely affected children are often identified shortly after birth due to a lack of muscle tone. They typically never learn to walk, and as they grow, their muscles become progressively weaker and lose strength. Many of them die in childhood or adolescence because their respiratory muscles eventually fail.
Gene therapy to treat congenital muscular dystrophy
Hope for affected families lies in a gene therapy that Prof. Markus Rüegg's team at the Biozentrum, University of Basel, has been developing for several years with its spin-off SEAL Therapeutics.
"With our first approach, we were able to restore muscle function and slow disease progression in a mouse model for LAMA2-related muscular dystrophy," says Rüegg. "We have since further optimized this approach. It now allows us not only to treat the diseased muscles and the muscle weakness itself successfully, but also the neuropathy associated with the condition."
Efficacy demonstrated in animal model
In the current study, published in the journal Molecular Therapy, the researchers report that their gene therapy approach is effective in diseased mice.
"When we treat the animals immediately after birth, they develop quite normally just like their healthy peers. They live long lives, and their muscles and nerves function almost normally," says lead investigator Dr. Judith Reinhard.
"Even when the gene therapy is administered at advanced disease stages, the mice benefit significantly. Their muscle strength improves, and the peripheral neuropathy – the damage to the peripheral nerves – is less severe than in untreated animals."
The team has advanced the gene therapy to a stage at which, following further safety testing, its effectiveness can be tested in human clinical trials. "We now have a therapy that is ready for the next translational steps," emphasizes Reinhard. "However, bringing it to clinics and patients – particularly given the extremely complex and costly production of the therapy – poses a major challenge."
Path to clinical application requires financial support
Despite the great potential medical benefits, bringing the gene therapy to market is economically unattractive to companies and investors. This is mainly due to the relatively small number of affected patients, the high production costs, and the fact that gene therapies still carry certain risks.
"In Switzerland, there are 19 affected families," says Reinhard. "When parents receive the diagnosis, they search the internet and find us. Many ask whether they could participate in a clinical trial – for many of them, we represent a great source of hope." Over the past few years, the researchers have built up a large network. They are in contact with affected families, patient organizations, pediatricians, and clinics. In principle, much of the groundwork to continue the study has already been laid, and the preclinical data is publicly available.
In 2019, Rüegg's team received financial support for the project from the Swiss Innovation Agency Innosuisse. "This Innosuisse project was a major scientific success," concludes Rüegg. "This, and the hope of being one day able to treat severely affected children, motivates us to keep going. Thanks to financial support from foundations and patient organizations, we were able to lay the basis to prepare this gene therapy for use in humans."
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How does the gene therapy work?
LAMA2-related muscular dystrophy (LAMA2 MD) is caused by mutations in the protein laminin-α2. This protein links the muscle fiber to the surrounding connective tissue, the so-called extracellular matrix. Laminin-α2 stabilizes muscle fibers and ensures the insulation of nerves that control muscles and movements. When laminin-α2 is defective or missing, as in LAMA2 MD, muscles progressively weaken and degenerate over time. In addition, nerve signal transduction is impaired.
The researchers developed a gene therapy that delivers the genetic instructions for specific "linker proteins" into muscle fibers and nerves. These linkers take over the function of laminin-α2 in the body. In animal models, a single treatment was sufficient to improve muscle and nerve function and significantly extend life expectancy.
