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Hamed S.A.,Assiut University | Hamed S.A.,Research Center for Genetic Medicine
Restorative Neurology and Neuroscience | Year: 2010

Cumulative evidences from experimental and clinical studies indicate that in some patients, not only prolonged but also repetitive brief seizures, may trigger series of damage promoting mechanisms which evolve over a period of time (up to years). They result in progressive degeneration and loss of function of several neuronal cell populations, thus rending the brain abnormal and resistant to antiepileptic medications (AEDs). This probably explains that in some patients, a) there is a delay from the onset of brain insult to the seizure onset, and b) suppression of seizures by AEDs is alone insufficient without clear prediction of disease progression. In this review, the analysis of information follows the assumption that epilepsy is a slowly progressive and a neurobiologically pleotropic disorder. Interaction between genes, neurotransmitters, ion channels, acid-base balance, mitochondria, calcium, glutamate and oxidative/antioxidants mechanisms, will determine the fate of the epilepsy process. The concept of neuroprotection aims not only to suppress seizures (anticonvulsant effect), but also to strengthen the auto-protective and repair mechanisms (antiepileptogenic and disease-modification effects) which prevent the development of spontaneous seizures, cognitive and behavioral problems later in life. This review is focusing on molecular evaluation of several models of epilepsy for the potential to follow disease modification and neuroprotection. Although AEDs of today possess multiple mechanisms of action, but mostly they are treating one part of the disease which is the seizures and do not offer high prospects of modification of the disease. This review is also discussing the prospects of novel drugs, molecular manipulations and cell therapy which address disease modification as approachs that will dominate the field of drug development and research on epilepsy in the future. © 2010-IOS Press and the authors. All rights reserved.

Hyldahl R.D.,Brigham Young University | Hubal M.J.,Research Center for Genetic Medicine
Muscle and Nerve | Year: 2014

The response of skeletal muscle to unaccustomed eccentric exercise has been studied widely, yet it is incompletely understood. This review is intended to provide an up-to-date overview of our understanding of how skeletal muscle responds to eccentric actions, with particular emphasis on the underlying molecular and cellular mechanisms of damage and recovery. This review begins by addressing the question of whether eccentric actions result in physical damage to muscle fibers and/or connective tissue. We next review the symptomatic manifestations of eccentric exercise (i.e., indirect damage markers, such as delayed onset muscle soreness), with emphasis on their relatively poorly understood molecular underpinnings. We then highlight factors that potentially modify the muscle damage response following eccentric exercise. Finally, we explore the utility of using eccentric training to improve muscle function in populations of healthy and aging individuals, as well as those living with neuromuscular disorders.© 2013 Wiley Periodicals, Inc.

Partridge T.A.,Research Center for Genetic Medicine
Current Opinion in Neurology | Year: 2011

Purpose of Review: As the first genetic disease for which the culpable gene was identified by positional cloning, Duchenne muscular dystrophy has served as a paradigm for therapeutic approaches to neuromuscular disease, in which role it has proved especially testing. The large mass and broad distribution of the target tissue, skeletal muscle, have stretched the patience and ingenuity of those seeking therapeutic delivery of the largest known gene. The most promising recent advances are summarized in this article. Recent Findings: The main obstacle to genetic therapies has been the development of vectors able to efficiently deliver large, potentially therapeutic, genetic constructs to the large and widely dispersed mass of body musculature. Recombinant viral vectors that efficiently transduce muscle are unable to carry the full-length construct. Myogenic cells that are able both to carry full-length genes and to repair muscles are technically challenging to produce in sufficient quantity. A recent promising approach is the use of agents that obviate the mutation. Summary: Although genetic and cell-mediated approaches are currently showing genuine promise in preclinical and clinical trials, there remains considerable interest in the development of agents that ameliorate the downstream pathology. One general challenge is the three-way tension between the interests of patients, regulators, and the biotechnology industry. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Lepper C.,Carnegie Institution for Science | Partridge T.A.,Research Center for Genetic Medicine | Fan C.-M.,Carnegie Institution for Science
Development | Year: 2011

Skeletal muscle tissue provides mechanical force for locomotion of all vertebrate animals. It is prone to damage from acute physical trauma and physiological stress. To cope with this, it possesses a tremendous capacity for rapid and effective repair that is widely held to be accomplished by the satellite cells lying between the muscle fiber plasmalemma and the basement membrane. Cell transplantation and lineage-tracing studies have demonstrated that Pax7-expressing (Pax7 +) satellite cells can repair damaged muscle tissue repeatedly after several bouts of acute injury. These findings provided evidence that Pax7 + cells are muscle stem cells. However, stem cells from a variety of other origins are also reported to contribute to myofibers upon engraftment into muscles, questioning whether satellite cells are the only stem cell source for muscle regeneration. Here, we have engineered genetic ablation of Pax7 + cells to test whether there is any significant contribution to muscle regeneration after acute injury from cells other than this source. We find that such elimination of Pax7 + cells completely blocks regenerative myogenesis either following injury to the tibialis anterior (TA) muscle or after transplantation of extensor digitorum longus (EDL) muscles into nude mice. As Pax7 is specifically expressed in satellite cells, we conclude that they are essential for acute injury-induced muscle regeneration. It remains to be established whether there is any significant role for stem cells of other origins. The implications of our results for muscle stem cell-based therapy are discussed. © 2011. Published by The Company of Biologists Ltd.

Yokota T.,Research Center for Genetic Medicine
Methods in molecular biology (Clifton, N.J.) | Year: 2011

Exon skipping is currently one of the most promising molecular therapies for Duchenne muscular -dystrophy (DMD). We have recently developed multiple exon skipping targeting exons 6 and 8 in -dystrophin mRNA of canine X-linked muscular dystrophy (CXMD), an animal model of DMD, which exhibits severe dystrophic phenotype in skeletal muscles and cardiac muscle. We have induced efficient exon skipping both in vitro and in vivo by using cocktail antisense 2'O-methyl oligonucleotides (2'OMePS) and cocktail phosphorodiamidate morpholino oligomers (morpholinos, or PMOs) and ameliorated phenotype of dystrophic dogs by systemic injections. The multiple exon skipping (double exon skipping) shown here provides the prospect of choosing deletions that optimize the functionality of the truncated dystrophin protein for DMD patients by using a common cocktail that could be validated as a single drug and also potentially applicable for more than 90% of DMD patients.

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