DMD

Idebenone Slows Respiratory Decline in DMD

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Patients with Duchenne muscular dystrophy (DMD) who took the oral drug idebenone for 12 months showed significantly less decline in standard respiratory function measures including peak expiratory flow (PEF) in a placebo-controlled, 66-patient trial, researchers said.

PEF as a percentage of predicted normal fell by 3.05 points (95% CI -7.07 to 0.97) during the trial with idebenone, compared with a decrease of 9.01 points (95% CI -13.18 to -4.84,P=0.0001) in the placebo group, reported Gunnar M. Buyse, MD, of University Hospitals Leuven in Belgium, and colleagues.

The difference between groups in the modified intent-to-treat analysis was 5.96 points favoring idebenone (95% CI 0.16 to 11.76), the researchers wrote online in The Lancet. The study is also scheduled to be reported here at the American Academy of Neurology annual meeting.

“Idebenone also had a significant effect on PEF (L/min), weekly home-based PEF, FVC [forced vital capacity], and FEV1 [forced expiratory volume in 1 sec],” Buyse and colleagues added.

It’s the first phase III study to show a positive outcome in DMD, the investigators asserted, noting also that adverse effects that might be attributed to the drug were generally mild.

Progressive failure of respiration is a major factor in the overall downward slide of DMD patients, and is often the main cause of early death.

“The results are promising because of the favorable safety profile of idebenone,” wrote Eugenio Mercuri, MD, of Catholic University in Rome, and Francesco Muntoni, MD, of University College London, in an accompanying commentary.

But they pointed out that the trial’s outcome measures, while informative, may not be the most appropriate for the DMD population, and their predictive value for clinically significant outcomes such as time to ventilation and mortality is unclear.

Idebenone has antioxidant properties and inhibits lipid peroxidation, the study investigators indicated, leading to stimulation of mitochondrial activity and cellular energy production in lab studies.

The study, called DELOS, assigned 66 patients (all but two randomized) to receive either 300 mg idebenone or placebo three times daily for 52 weeks.

Patients were 10- to 18-years-old, with more than 90% confined to wheelchairs. PEF at baseline averaged 54% of predicted; FVC and FEV1 as percentage of predicted were almost the same. Absolute mean baseline values for FVC and FEV1 were 1.9 L and 1.6 L, respectively. Means in the two treatment arms for these parameters were similar.

Some other respiratory measures did not show an effect from idebenone, including peak cough flow and maximum inspiratory and expiratory pressures. There was also no difference between groups in arm strength or function.

Slightly more than half the patients had previously used glucocorticoids but there was no difference in idebenone’s apparent efficacy according to history of such use.

But Mercuri and Muntoni noted that the mean time since the last glucocorticoid use was shorter in the DMD group — 1.8 years versus 2.2 years in the placebo group — which might have influenced the results.

Other study limitations included the sample size and duration, Buyse and colleagues indicated.

The FDA has granted orphan drug and fast-track status to idebenone, according to the drug’s developer, Swiss-based Santhera Pharmaceuticals.

Umbilical-Cord Stem Cell Transplantation in Duchenne Muscular Dystrophy

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Without additional interventions that induce engraftment of donor cells in skeletal muscle, umbilical cord–derived hematopoietic stem cell transplantation does not appear to be an effective treatment.

Duchenne muscular dystrophy (DMD) is caused by a mutation in DMD, a gene encoding for dystrophin, a protein that stabilizes the sarcolemma. The absence of dystrophin leads to widespread myonecrosis; death typically results from cardiopulmonary complications. Despite our advanced understanding of DMD pathophysiology, treatment remains largely palliative. Stem cell transplantation has long been considered a potential treatment for DMD but has not been thoroughly investigated. Now, researchers report results of stem cell transplantation in a young boy with a diagnosis of chronic granulomatous disease (CGD) in infancy and, subsequently, a diagnosis of DMD. (Genes for each of these conditions are located on the X chromosome.)

Starting at age 16 months, the boy received two allogeneic stem cell transplantations from umbilical-cord donors, which cured him of CGD. At age 4 years he was diagnosed with DMD. To determine whether any donor dystrophin was being expressed in his cells, researchers examined his muscle tissue and DNA from skin fibroblasts, and they cultured myoblasts derived from his muscle tissue. The analyses revealed a large-scale deletion on the X chromosome that spanned the loci for both CGD and DMD. The absence of dystrophin led to muscle histology characteristic of DMD. Analysis of myofibers indicated no definite donor cell engraftment.

Comment: Regrettably, this case shows that umbilical cord–derived hematopoietic, allogeneic stem cell transplantation is not efficacious in treating DMD. Clearly, other strategies are needed to induce engraftment of donor cells in skeletal muscle. Even though transplanted cells can survive, improving muscle function remains elusive. Functional success will require highly efficient engraftment of transplanted cells.

The loss of pluripotentiality as the cells differentiate along specific cell lineages may account for lack of efficient engraftment of blood-derived stem cells in skeletal muscle in this case. As the authors note, certain stem cell subpopulations likely have better myogenic potential than others. Discovering novel, multipotent cell lineages that possess enhanced ability to engraft in muscle would markedly improve the efficacy of stem cell therapy in DMD. However, there are other hurdles to overcome, including the development of more-efficient delivery methods and management of immune-rejection events that can complicate any cell-based therapy.

Published in Journal Watch Neurology August 31, 2010