Abstract
IntroductionCongenital muscular dystrophy is a distinct group of diseases presenting with weakness in infancy or childhood and no current therapy. One form, MDC1A, is the result of laminin alpha-2 deficiency and results in significant weakness, respiratory insufficiency and early death. Modification of apoptosis is one potential pathway for therapy in these patients.Methodsdy2J mice were treated with vehicle, 0.1 mg/kg or 1 mg/kg of omigapil daily via oral gavage over 17.5 weeks. Untreated age matched BL6 mice were used as controls. Functional, behavioral and histological measurements were collected.Resultsdy2J mice treated with omigapil showed improved respiratory rates compared to vehicle treated dy2J mice (396 to 402 vs. 371 breaths per minute, p<0.03) and similar to control mice. There were no statistical differences in normalized forelimb grip strength between dy2J and controls at baseline or after 17.5 weeks and no significant differences seen among the dy2J treatment groups. At 30–33 weeks of age, dy2J mice treated with 0.1 mg/kg omigapil showed significantly more movement time and less rest time compared to vehicle treated. dy2J mice showed normal cardiac systolic function throughout the trial. dy2J mice had significantly lower hindlimb maximal (p<0.001) and specific force (p<0.002) compared to the control group at the end of the trial. There were no statistically significant differences in maximal or specific force among treatments. dy2J mice treated with 0.1 mg/kg/day omigapil showed decreased percent fibrosis in both gastrocnemius (p<0.03) and diaphragm (p<0.001) compared to vehicle, and in diaphragm (p<0.013) when compared to 1 mg/kg/day omigapil treated mice. Omigapil treated dy2J mice demonstrated decreased apoptosis.ConclusionOmigapil therapy (0.1 mg/kg) improved respiratory rate and decreased skeletal and respiratory muscle fibrosis in dy2J mice. These results support a putative role for the use of omigapil in laminin deficient congenital muscular dystrophy patients.
Highlights
Congenital muscular dystrophy is a distinct group of diseases presenting with weakness in infancy or childhood and no current therapy
[11] Omigapil (TCH346) was used previously in clinical trials for Parkinson disease and amyotrophic lateral sclerosis where apoptosis is considered a key pathogenic pathway based on animal models. [12,13] While neither trial demonstrated a clinical effect in these diseases, omigapil was well tolerated and may benefit patients with other neuromuscular diseases
A phenotypic analysis of preclinical outcomes measures was performed in the dy2J mouse model with truncated laminin a2 protein. These mice were treated with the antiapoptotic agent omigapil at two doses to assess effects on outcome measures. dy2J mice demonstrated functional and histological improvements and these results provide preclinical data for future putative clinical trials in congenital muscular dystrophies (CMDs) patients
Summary
Congenital muscular dystrophy is a distinct group of diseases presenting with weakness in infancy or childhood and no current therapy. One form, MDC1A, is the result of laminin alpha-2 deficiency and results in significant weakness, respiratory insufficiency and early death. The congenital muscular dystrophies (CMDs) are a group of heterogeneous pediatric neuromuscular diseases that present with hypotonia, progressive scoliosis, contractures and respiratory insufficiency. [4] There are two current mouse models of laminin mutations used for preclinical studies, dyW and dy2J. The dyW mouse model demonstrates a severe phenotype with poor growth and early death due to absence of the laminin a2 protein. Miyagoe et al (1997) described a LAMA2 deficient mouse model (dy3K) with increased TUNEL positive nuclei in degenerating skeletal muscles in LAMA2 knockout mice. [9] Most recently, Erb et al (2009) demonstrated a role for the GADPH-Siah1-CBP/p300 apoptosis pathway in dyW mice by demonstrating a beneficial effect on histology, locomotion, skeletal deformities, weight and survival in mice treated with omigapil. Miyagoe et al (1997) described a LAMA2 deficient mouse model (dy3K) with increased TUNEL positive nuclei in degenerating skeletal muscles in LAMA2 knockout mice. [7] Girgenrath et al (2004) showed improved survival and myofiber histology after applying anti-apoptotic breeding crosses. [8] Dominov et al (2005) demonstrated increased growth and survival in LAMA2 null dyW mice with over expression of the antiapoptotic protein BCL2. [9] Most recently, Erb et al (2009) demonstrated a role for the GADPH-Siah1-CBP/p300 apoptosis pathway in dyW mice by demonstrating a beneficial effect on histology, locomotion, skeletal deformities, weight and survival in mice treated with omigapil. [10] This drug was effective in a mouse model of progressive motor neuropathy. [11] Omigapil (TCH346) was used previously in clinical trials for Parkinson disease and amyotrophic lateral sclerosis where apoptosis is considered a key pathogenic pathway based on animal models. [12,13] While neither trial demonstrated a clinical effect in these diseases, omigapil was well tolerated and may benefit patients with other neuromuscular diseases
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