Antibiotic Rescues Muscle Cells in Collagen Myopathy Patients
Cyclosporin A holds promise for the treatment of the two obscure collagen VI myopathies, Bethlem myopathy and Ullrich congenital muscular dystrophy, according to a new study in the Proceedings of the National Academy of Science. Treatment in a small group of patients largely reversed the cellular abnormalities that cause the disease, and fostered muscle regeneration.
The findings show how the study of a rare disease can contribute information valuable for broader fields, experts said.
TARGETING A MITOCHONDRIAL PROTEIN
Over the past decade, studies in the mouse model for Bethlem myopathy led to the discovery that collagen gene mutations cause myopathy by inducing a defect in mitochondria within muscle cells. The defect affects the permeability transition pore (PTP), a protein complex embedded in the mitochondria's inner membrane. Normally, the PTP remains closed. But through an unknown mechanism, collagen mutations cause the PTP to open for prolonged periods of time, which causes ions to flow freely across the membrane, depolarizing it — decreasing the absolute value of a cell's membrane potential — and preventing production of cellular energy in the form of ATP. It also allows release of materials that lead to cell death through apoptosis.
Cyclosporin A (CsA) inhibits opening of the PTP, a discovery made almost two decades ago, before the connection between the PTP and myopathy was made. In a 2003 paper in Nature Genetics, researchers, including Paolo Bernardi, MD, of the University of Padua, Italy, reported that they developed a collagen-deficient mouse as a model of Bethlem myopathy, discovered the mitochondrial defect and the role of the PTP, and showed that treatment with CsA could mitigate its consequences both in mice and in isolated muscle cells from patients with Ullrich congenital muscular dystrophy (UCMD). This prompted Dr. Bernardi and colleagues to contemplate a small clinical trial.
Four of the patients in the study had UCMD and ranged in age from nine to 23 years, while the fifth, age 57, had Bethlem myopathy. All received 5 mg/kg oral CsA per day, a dose at the low end of that used for immunosuppression.
For this initial trial, Dr. Bernardi chose not to study clinical outcome measures, such as respiratory capacity or walking ability, because of possibly harmful immunosuppression during the prolonged treatment required to see a meaningful change. “Immunosuppression is a major concern,” he said, “especially since the patients often have pulmonary problems anyway.” Instead, he took muscle biopsies at baseline and after one month of CsA treatment.
Before treatment, mitochondria within the biopsied cells depolarized rapidly in response to oligomycin, an indication that the PTP was opening when it shouldn't. After treatment, though, abnormal PTP opening was reduced by 50 percent or more. Treatment substantially reduced the number of apoptotic nuclei within muscle cells, another feature of these diseases.
Most surprisingly for Dr. Bernardi, treatment also increased the number of regenerating cells within the muscle. “Usually you would expect maximal regeneration with maximal cell death,” he said. He speculated that the disease is probably causing regenerating cells to die as well as those showing degenerative changes, and treatment is rescuing these cells. “If that's true, we have a big hope for the children, because this would mean the new cells could repopulate the muscle.
“The results of this trial provide important proof of principle that hereditary muscle diseases can be cured with proper drugs that act downstream of the genetic lesion if the pathogenetic mechanisms are understood,” Dr. Bernardi said. But, he cautioned, “It's not yet a therapy. The clinical part of the story is still missing.”
LESS IMMUNOSUPPRESSIVE DRUG AVAILABLE
It would be a better trade-off if the price of successful treatment came at the expense of long-term immunosuppression and the many problems it can cause. But Dr. Bernardi noted that a derivative, named Debio 025 (developed by Debio Pharmaceuticals of Lausanne, Switzerland) may be an alternative. It is immunologically inactive, but retains the same ability to stabilize the PTP in both mice and cells isolated from patients. A clinical trial of this drug is planned.
“This is a hopeful and promising study,” said Carsten Bonnemann, MD, co-director of the Neuromuscular Program at Children's Hospital of Philadelphia, PA. While the drug appears to be working far downstream of the genetic defect, he said, that's not necessarily a bad feature, especially since the most upstream treatment for genetic diseases — gene transfer therapy — has proven unworkable in most cases.
Successfully interfering with apoptosis could also make the therapy an attractive option for other muscle diseases in which this features. “We always need to consider multiple lines of attack,” he said. Despite the promising results, some caution is still warranted in interpreting the findings, especially since clinical outcomes were not a part of the trial. He also noted that the PTP assay used was pioneered by the authors for this trial, and has not been validated as a surrogate marker for the disease.
More on Bethlem Myopathy and Ullrich Congenital Muscular Dystrophy
The two diseases are caused by mutations in genes encoding collagen VI. Both disorders are quite rare, with prevalence of each less than 1 in 100,000. Bethlem myopathy is an autosomal dominant disorder with onset from the neonatal period to adulthood. It causes slowly progressive weakness of the axial and proximal limb muscles, which may lead to the need for a walker to maintain mobility in older patients. Joint contractures are similar to those of Emery-Dreifuss muscular dystrophy but the heart is involved in EDMD and is spared in Bethlem myopathy.
Ullrich congenital muscular dystrophy (UCMD) is an autosomal recessive disorder, and is much more severe. Onset is usually at birth, and is characterized by hypotonia, muscle weakness, and progressive scoliosis. Most children never attain the ability to walk, and early and severe respiratory involvement leads to the need for respiratory aids within the first two decades.