Developing Treatment for Hereditary Neuromuscular Disease

Air date: Wednesday, November 02, 2011, 3:00:00 PM
Time displayed is Eastern Time, Washington DC Local

Category: Wednesday Afternoon Lectures
Description: Several thousand human disease genes have been identified over the past 25 years. The challenge now is to convert what we know about the causes and mechanisms of hereditary diseases into safe and effective treatment. We are finally close to doing this for two pediatric neuromuscular diseases, Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA).

DMD is characterized by progressive weakness due to muscle degeneration. The disease is caused by mutations in the muscle protein dystrophin. Most of the mutations are partial gene deletions that shift the translational reading frame of the mRNA, leading to a truncated and unstable protein. Approaches to treatment include enhancing muscle regeneration and replacing or correcting the gene at the DNA or mRNA level. Myostatin inhibition and drugs that promote read-through of mutations have shown benefit in animals but not yet in clinical trials. Gene replacement has low efficiency and may induce an immune response to dystrophin. Oligonucleotide therapy to induce exon skipping may be the most promising approach at present. The oligonucleotides target specific mutations at the mRNA level. Recent clinical studies have shown partial restoration of muscle dystrophin with local and systemic delivery, and international trials are in progress.

SMA is the most common severe hereditary disease of infancy. It is characterized by weakness of the extremity and respiratory muscles due to motor neuron loss. SMA is caused by mutations that lead to reduced levels of the survival motor neuron (SMN) protein, which is an important factor in mRNA splicing. Motor neurons may be particularly vulnerable to SMN deficiency because of their unusual structure and function. A variety of cell and animal models are available to test potential SMA treatments. Histone deacetylase inhibitors are beneficial in mice, and this effect can be enhanced by improved nutrition. Clinical trials of drugs that increase SMN have had mixed results to date, and assays to screen for better drugs have been developed. Oligonucleotide and gene replacement therapy have recently shown great promise in animal studies, and clinical trials are planned. Meanwhile, there is evidence that better respiratory and nutritional support can be very helpful. Thus, the clinical outcome may be improved by optimizing currently available treatment.

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Author: Kenneth Fischbeck, M.D., National Institute of Neurological Disorders and Stroke, NIH
Runtime: 01:10:01

Permanent link: http://videocast.nih.gov/launch.asp?16943

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Science & Technology

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• wals110211

[kingplatoedwinkaku]

are they using a camera from the 70s?