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How advanced is the research on Steinert Disease?

The genetic anomaly responsible for Myotonic Dystrophy was identified in 1992 but we have only begun to understand how this anomaly produces the disease.

    Schematic representation of a muscle cell. In the nucleus you find DNA (green) that carries all the genetic information. There is a copy of the DNA inherited from our mother and a copy of the DNA inherited from our father. This means that each gene exists in double, one from the mother and one from the father. In a normal cell, the gene located on the DNA contains the information needed to produce a specific protein but DNA can only exit the nucleus to help in the production of proteins if it is located within the cell body. In order to transmit the information from the nucleus to the production site, the cell uses a transporter (red) that we call RNA. Once it arrives at the production site, RNA is read and a protein is produced.   

    In Myotonic Dystrophy, the genetic anomaly (blue star) is present on the DNA that has been transmitted by the parent who carries the disease. This DNA transmits information containing the genetic anomaly to the RNA. This RNA, which contains the genetic anomaly, cannot find its way out of the nucleus in order to go to the protein production site. It thus accumulates in the nucleus which has a toxic effect on the cell and ultimately produces the disease.

    The development of a treatment for this disease depends on the destruction of the abnormal transporter (RNA) which accumulates in the nucleus. The work we are doing in our laboratory has led to a gene medication that is able to destroy abnormal transporters (RNA) in the muscle cells of patients with Myotonic Dystrophy and to correct any muscular anomalies caused by the disease. We are currently testing the efficacy of this treatment in mice exhibiting symptoms of the disease. Initial results indicate that the treatment can reduce abnormal transporters in the muscle tissue after an intra-muscular injection of the gene medication. We must still determine if this destruction will restore normal muscle function. If the results are positive, a first Phase I trial on human subjects could start in 2008-2009. This trial’s objective would be to determine any toxicity or non efficacy of the gene medication after an intra-muscular injection. If the medication is not toxic, it will be possible to consider a Phase II trial to test the medication’s efficacy.

    Although our studies are very promising, there are many obstacles that still need to be tackled. First, in order for the gene medication to penetrate within the muscle tissue, we must use a transporter. The best known transporters are inactive viruses. There are currently no known transporters that are capable of introducing the gene medication into the entire muscle. It is thus necessary to consider multiple injections. Another obstacle is that it is impossible to have the gene medication express in all muscle groups so initial treatments will be limited to specific muscle groups (hands, feet). Recent research has demonstrated that certain inactive viruses seem to be able to express a protein throughout all muscle groups following an intravenous injection. Finally, one last obstacle is that we do not have enough information about the toxicity of inactive viruses in human subjects. All these problems need to be resolved before the start of any therapeutic trials involving human subjects.

    Another possibility for treatment rests upon restoring the level of the proteins that are sequestered on the genetic anomaly. Among these proteins the most interesting one is the muscle blind protein (MBNL). Recent studies by a U.S. team have demonstrated that overproduction of this protein could correct the maturation process of certain RNAs such as the ones coded for insulin receptors as well as for the muscle chlorine channel. This potential treatment could be used to improve certain symptoms of the disease such as myotonia and peripheral resistance to insulin. It is not yet known if this treatment could restore muscle strength.

Human genetic department

2705,  Laurier Boulevard. RC-9300. Quebec (Quebec) Canada. G1V 4G2. Phone: +1 (418) 654-2186. Fax: +1 (418) 654-2207.

E-mail: sec.genetique@crchul.ulaval.ca

Institut de Réadaptation en Déficience Physique de Québec

525, Hamel Boulevard . Quebec (Quebec) G1M 2S8

Phone : 418-529-9141

 

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