Finding FDA approved therapies that are effective at treating diseases they were not originally designed for is not only serendipitous, but it can also dramatically cut the time it takes to get drugs to patients in critical need—as these compounds have typically already undergone extensive safety testing which can take many years to compile. With that in mind, investigators at the University of Geneva (UNIGE), working in collaboration with the University of Strasbourg, France have identified that the long-used breast cancer drug tamoxifen not only greatly reduces the progression of myotubular myopathy—a severe genetic disease that leads to muscle paralysis from birth and results in death before two years of age—but also boosts life expectancy in animal models by a factor of seven.

Findings from the new study were released today in Nature Communications through an article titled “Tamoxifen prolongs survival and alleviates symptoms in mice with fatal X-linked myotubular myopathy.” Myotubular myopathy is a severe genetic disease that weakens all the skeletal muscles from birth. Ninety percent of affected babies do not live to two years of age.

“The disease affects the X chromosome in one in 50,000 male infants,” explains senior study investigator Leonardo Scapozza, Ph.D., a professor at the School of Pharmaceutical Sciences at UNIGE’s Faculty of Science. Only boys are struck by myotubular myopathy since the second X chromosome in girls generally compensates for the possible mutation of the first.”

Currently, no treatment exists for this genetic defect. However, valuable research in gene therapy is currently underway.

“But it will take years before we can come to a conclusion about how effective the clinical trials are,” adds co-senior study investigator Olivier Dorchies, Ph.D., a researcher in the UNIGE School of Pharmaceutical Sciences. “That’s why we turned to a molecule that is already authorized for other treatments in humans, in the hope of finding a quicker way to counter this life-threatening disease.”

Interestingly, the researchers focused on tamoxifen, which has been used for many years to treat breast cancer, because the molecule has several interesting properties for protecting muscle fibers: it is antioxidant, anti-fibrotic, and protects the mitochondria.

“In a previous study, we used tamoxifen against Duchenne muscular dystrophy, which is also an inherited muscular disease that affects one in 3,500 boys, where the life expectancy is 30 years,” notes lead study investigator Elinam Gayi, a doctoral candidate in UNIGE’s School of Pharmaceutical Sciences. “The results have been excellent, and a clinical trial is also in progress.”

This is why the scientists have been looking at the molecule in an attempt to combat myotubular myopathy, which—although it also leads to muscular paralysis—does not have the same mechanisms of action as Duchenne’s.

“Myotubular myopathy is caused by a lack of myotubularin, an enzyme that transforms the lipidic messengers. Without it, the protein known as dynamin 2 accumulates and brings on muscle atrophy,” continues Gayi. In the search for a cure, one of the avenues explored by several groups is to target dynamin 2, which is modulated by tamoxifen.

In the current study, the research team administered daily tamoxifen orally to sick mice with the same symptoms as affected babies, mixing it with their food. Three doses were tested: 0.03 mg/kg, 0.3 mg/kg, and 3 mg/kg. The highest dose matches that used for treating breast cancer in women if we consider the metabolic differences between mouse and human. The results obtained by the research team left no room for argument. An untreated sick mouse lived for 45 days on average. With the lowest dose, the average life expectancy was 80 days, rising to 120 days with the intermediate dose.

“But with the biggest dose, life expectancy went up to 290 days on average—seven times higher than for an untreated mouse. Some even survived for over 400 days!” Dr. Scapozza exclaims.

Also, the progress of the paralysis was slowed down enormously or even completely stopped. Muscular strength was tripled, and it was possible to recover 60% of the muscular deficit between a healthy mouse and a sick mouse. The scientists began the treatment when the mice developed the first symptoms, namely paralysis of the hind legs at about three weeks. However, they have not ruled out that administering the drug earlier might be more efficacious against muscle weakness.

“In parallel to our study, a team from the Children’s Hospital of Toronto tested the drug on even younger mice, and the disease did not develop,” states Dr. Dorchies. “The problem is that in humans, myotubular myopathy starts during fetal development, so it’s hard to know whether the total absence of paralysis might be achieved if this molecule is given after birth.”

Gayi concludes that “since tamoxifen is already authorized for use in humans, and a clinical trial is underway for Duchenne muscular dystrophy, we’re hopeful that a clinical trial will come online within a couple of years.” It is now up to clinicians to make the most of our research and put it into practice.

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