The Experts below are selected from a list of 24 Experts worldwide ranked by ideXlab platform
Kanneboyina Nagaraju - One of the best experts on this subject based on the ideXlab platform.
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Omigapil treatment decreases fibrosis and improves respiratory rate in dy2j mouse model of congenital muscular dystrophy
PLOS ONE, 2013Co-Authors: Qing Yu, Arpana Sali, Jack H Van Der Meulen, Brittany Creeden, Heather Gordishdressman, Anne Rutkowski, Sree Rayavarapu, Kitipong Uaesoontrachoon, Tony Huynh, Kanneboyina NagarajuAbstract:Introduction: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. Modification of apoptosis is one potential pathway for therapy in these patients.Methods:dy2J 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.Results:dy2J 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.Conclusion:Omigapil 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.
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Omigapil Treatment Decreases Fibrosis and Improves Respiratory Rate in dy2J Mouse Model of Congenital Muscular Dystrophy
PLOS ONE, 2013Co-Authors: Qing Yu, Arpana Sali, Jack H Van Der Meulen, Brittany Creeden, Anne Rutkowski, Sree Rayavarapu, Kitipong Uaesoontrachoon, Tony Huynh, Heather Gordish-dressman, Kanneboyina NagarajuAbstract:Introduction: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. Modification of apoptosis is one potential pathway for therapy in these patients.Methods:dy2J 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.Results:dy2J mice treated with Omigapil showed improved respiratory rates compared to vehicle treated dy2J mice (396 to 402 vs. 371 breaths per minute, p
Markus A Ruegg - One of the best experts on this subject based on the ideXlab platform.
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Apoptosis inhibitors and mini-agrin have additive benefits in congenital muscular dystrophy mice
Embo Molecular Medicine, 2011Co-Authors: Sarina Meinen, T Meier, Raphael Thurnherr, Markus A RueggAbstract:Mutations in LAMA2 cause a severe form of congenital muscular dystrophy, called MDC1A. Studies in mouse models have shown that transgenic expression of a designed, miniaturized form of the extracellular matrix molecule agrin (‘mini-agrin’) or apoptosis inhibition by either overexpression of Bcl2 or application of the pharmacological substance Omigapil can ameliorate the disease. Here, we tested whether mini-agrin and anti-apoptotic agents act on different pathways and thus exert additive benefits in MDC1A mouse models. By combining mini-agrin with either transgenic Bcl2 expression or oral Omigapil application, we show that the ameliorating effect of mini-agrin, which acts by restoring the mechanical stability of muscle fibres and, thereby, reduces muscle fibre breakdown and concomitant fibrosis, is complemented by apoptosis inhibitors, which prevent the loss of muscle fibres. Treatment of mice with both agents results in improved muscle regeneration and increased force. Our results show that the combination of mini-agrin and anti-apoptosis treatment has beneficial effects that are significantly bigger than the individual treatments and suggest that such a strategy might also be applicable to MDC1A patients.
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Omigapil ameliorates the pathology of muscle dystrophy caused by laminin α2 deficiency
Journal of Pharmacology and Experimental Therapeutics, 2009Co-Authors: Sarina Meinen, Patrizia Barzaghi, Markus A Ruegg, Lazar T Sumanovski, I Courdierfruh, T MeierAbstract:Laminin α2-deficient Congenital Muscular Dystrophy, called MDC1A, is a rare, devastating genetic disease characterized by severe neonatal hypotonia ("floppy infant syndrome"), peripheral neuropathy, inability to stand or walk, respiratory distress and premature death in early life. Transgenic overexpression of the apoptosis inhibitor protein BCL-2, or deletion of the pro-apoptotic Bax gene in a mouse model for MDC1A prolong survival and mitigate pathology, indicating that apoptotic events are involved in the pathology. Here we demonstrate that the pro-apoptotic glyceraldehyde 3-phosphate dehydrogenase (GAPDH)-Siah1-CBP/p300-p53 pathway is activated in a mouse model for MDC1A. Moreover, we show that Omigapil, which inhibits GAPDH-Siah1 mediated apoptosis, ameliorates several pathological hallmarks in the MDC1A mouse model. Specifically, we demonstrate that treatment with Omigapil inhibits apoptosis in muscle, reduces body weight loss and skeletal deformation, increases locomotive activity and protects from early mortality. These data qualify Omigapil, which is in late phase of clinical development for human use, as a drug candidate for the treatment of MDC1A.
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t o 2 Omigapil snt 317 prevents apoptosis and ameliorates the pathology of laminin alpha2 deficient muscle dystrophy
Neuromuscular Disorders, 2008Co-Authors: T Meier, Sarina Meinen, Patrizia Barzaghi, Markus A RueggAbstract:Mutations in LAMA2, the gene encoding the laminin-alpha2 chain of the extracellular matrix of muscle cells, cause a rare and severe form of congenital muscular dystrophy, called MDC1A. The disease is characterized by early onset, progressive muscle degeneration and impaired regeneration. As consequence, affected children are often never able to walk and, as there is no effective treatment available, frequently die in early childhood. Genetic evidence has shown that overexpression of the apoptosis inhibitor protein BCL-2 can protect from disease-relevant pathologies in the laminin-alpha2 deficient dyW/dyW mouse, a model for MDC1A. In addition, expression of a miniaturized form of the extracellular matrix molecule agrin (mini-agrin) has been shown to be an alternative way to ameliorate disease symptoms. The efficacy of Omigapil (N-(dibenz(b,f)oxepin-10-ylmethyl)-N-methyl-N-prop-2-ynylamine maleate; SNT-317, TCH346), a chemical derivative of selegiline, was tested in dyW/dyW mice by oral administration at a daily dose of 0.1 or 1 mg/kg starting at 3-weeks of age. Control animals were treated with vehicle. We show that Omigapil, a well characterized inhibitor of apoptosis that targets GAPDH, ameliorated key pathology hallmarks of the dyW/dyW mouse. Specifically, oral administration of Omigapil reduced apoptosis in muscle and preserved muscle histology, reduced body weight loss, mitigated skeletal deformation and improved locomotion. Moreover, Omigapil increased the 50% survival time from 35 days in vehicle treated dyW/dyWmice to 85 days and 105 days in dyW/dyW mice treated with 0.1 and 1 mg/kg Omigapil, respectively. In addition, we show that co-administration of mini-agrin had additive beneficial effects. The preclinical and clinical development of Omigapil is well advanced and Omigapil was proven to be safe in large clinical trials. Based on its efficacy in the dyW/dyW mouse, this orally bioavailable drug is well suited to be tested clinically as a potential therapy for MDC1A.
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T.O.2 Omigapil/SNT-317 prevents apoptosis and ameliorates the pathology of laminin-alpha2 deficient muscle dystrophy
Neuromuscular Disorders, 2008Co-Authors: T Meier, Sarina Meinen, Patrizia Barzaghi, Markus A RueggAbstract:Mutations in LAMA2, the gene encoding the laminin-alpha2 chain of the extracellular matrix of muscle cells, cause a rare and severe form of congenital muscular dystrophy, called MDC1A. The disease is characterized by early onset, progressive muscle degeneration and impaired regeneration. As consequence, affected children are often never able to walk and, as there is no effective treatment available, frequently die in early childhood. Genetic evidence has shown that overexpression of the apoptosis inhibitor protein BCL-2 can protect from disease-relevant pathologies in the laminin-alpha2 deficient dyW/dyW mouse, a model for MDC1A. In addition, expression of a miniaturized form of the extracellular matrix molecule agrin (mini-agrin) has been shown to be an alternative way to ameliorate disease symptoms. The efficacy of Omigapil (N-(dibenz(b,f)oxepin-10-ylmethyl)-N-methyl-N-prop-2-ynylamine maleate; SNT-317, TCH346), a chemical derivative of selegiline, was tested in dyW/dyW mice by oral administration at a daily dose of 0.1 or 1 mg/kg starting at 3-weeks of age. Control animals were treated with vehicle. We show that Omigapil, a well characterized inhibitor of apoptosis that targets GAPDH, ameliorated key pathology hallmarks of the dyW/dyW mouse. Specifically, oral administration of Omigapil reduced apoptosis in muscle and preserved muscle histology, reduced body weight loss, mitigated skeletal deformation and improved locomotion. Moreover, Omigapil increased the 50% survival time from 35 days in vehicle treated dyW/dyWmice to 85 days and 105 days in dyW/dyW mice treated with 0.1 and 1 mg/kg Omigapil, respectively. In addition, we show that co-administration of mini-agrin had additive beneficial effects. The preclinical and clinical development of Omigapil is well advanced and Omigapil was proven to be safe in large clinical trials. Based on its efficacy in the dyW/dyW mouse, this orally bioavailable drug is well suited to be tested clinically as a potential therapy for MDC1A.
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use of n dibenz b f oxepin 10 ilmetil n metil n prop 2 inylamine Omigapil for profilaxis and or muscular dystrophy treatment
2006Co-Authors: T Meier, Markus A RueggAbstract:Use of a compound of formula (I) ** Formula ** or a pharmaceutically acceptable addition salt thereof for the preparation of a medicament for the prophylaxis and / or treatment of muscular dystrophy.
T Meier - One of the best experts on this subject based on the ideXlab platform.
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Apoptosis inhibitors and mini-agrin have additive benefits in congenital muscular dystrophy mice
Embo Molecular Medicine, 2011Co-Authors: Sarina Meinen, T Meier, Raphael Thurnherr, Markus A RueggAbstract:Mutations in LAMA2 cause a severe form of congenital muscular dystrophy, called MDC1A. Studies in mouse models have shown that transgenic expression of a designed, miniaturized form of the extracellular matrix molecule agrin (‘mini-agrin’) or apoptosis inhibition by either overexpression of Bcl2 or application of the pharmacological substance Omigapil can ameliorate the disease. Here, we tested whether mini-agrin and anti-apoptotic agents act on different pathways and thus exert additive benefits in MDC1A mouse models. By combining mini-agrin with either transgenic Bcl2 expression or oral Omigapil application, we show that the ameliorating effect of mini-agrin, which acts by restoring the mechanical stability of muscle fibres and, thereby, reduces muscle fibre breakdown and concomitant fibrosis, is complemented by apoptosis inhibitors, which prevent the loss of muscle fibres. Treatment of mice with both agents results in improved muscle regeneration and increased force. Our results show that the combination of mini-agrin and anti-apoptosis treatment has beneficial effects that are significantly bigger than the individual treatments and suggest that such a strategy might also be applicable to MDC1A patients.
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Omigapil ameliorates the pathology of muscle dystrophy caused by laminin α2 deficiency
Journal of Pharmacology and Experimental Therapeutics, 2009Co-Authors: Sarina Meinen, Patrizia Barzaghi, Markus A Ruegg, Lazar T Sumanovski, I Courdierfruh, T MeierAbstract:Laminin α2-deficient Congenital Muscular Dystrophy, called MDC1A, is a rare, devastating genetic disease characterized by severe neonatal hypotonia ("floppy infant syndrome"), peripheral neuropathy, inability to stand or walk, respiratory distress and premature death in early life. Transgenic overexpression of the apoptosis inhibitor protein BCL-2, or deletion of the pro-apoptotic Bax gene in a mouse model for MDC1A prolong survival and mitigate pathology, indicating that apoptotic events are involved in the pathology. Here we demonstrate that the pro-apoptotic glyceraldehyde 3-phosphate dehydrogenase (GAPDH)-Siah1-CBP/p300-p53 pathway is activated in a mouse model for MDC1A. Moreover, we show that Omigapil, which inhibits GAPDH-Siah1 mediated apoptosis, ameliorates several pathological hallmarks in the MDC1A mouse model. Specifically, we demonstrate that treatment with Omigapil inhibits apoptosis in muscle, reduces body weight loss and skeletal deformation, increases locomotive activity and protects from early mortality. These data qualify Omigapil, which is in late phase of clinical development for human use, as a drug candidate for the treatment of MDC1A.
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t o 2 Omigapil snt 317 prevents apoptosis and ameliorates the pathology of laminin alpha2 deficient muscle dystrophy
Neuromuscular Disorders, 2008Co-Authors: T Meier, Sarina Meinen, Patrizia Barzaghi, Markus A RueggAbstract:Mutations in LAMA2, the gene encoding the laminin-alpha2 chain of the extracellular matrix of muscle cells, cause a rare and severe form of congenital muscular dystrophy, called MDC1A. The disease is characterized by early onset, progressive muscle degeneration and impaired regeneration. As consequence, affected children are often never able to walk and, as there is no effective treatment available, frequently die in early childhood. Genetic evidence has shown that overexpression of the apoptosis inhibitor protein BCL-2 can protect from disease-relevant pathologies in the laminin-alpha2 deficient dyW/dyW mouse, a model for MDC1A. In addition, expression of a miniaturized form of the extracellular matrix molecule agrin (mini-agrin) has been shown to be an alternative way to ameliorate disease symptoms. The efficacy of Omigapil (N-(dibenz(b,f)oxepin-10-ylmethyl)-N-methyl-N-prop-2-ynylamine maleate; SNT-317, TCH346), a chemical derivative of selegiline, was tested in dyW/dyW mice by oral administration at a daily dose of 0.1 or 1 mg/kg starting at 3-weeks of age. Control animals were treated with vehicle. We show that Omigapil, a well characterized inhibitor of apoptosis that targets GAPDH, ameliorated key pathology hallmarks of the dyW/dyW mouse. Specifically, oral administration of Omigapil reduced apoptosis in muscle and preserved muscle histology, reduced body weight loss, mitigated skeletal deformation and improved locomotion. Moreover, Omigapil increased the 50% survival time from 35 days in vehicle treated dyW/dyWmice to 85 days and 105 days in dyW/dyW mice treated with 0.1 and 1 mg/kg Omigapil, respectively. In addition, we show that co-administration of mini-agrin had additive beneficial effects. The preclinical and clinical development of Omigapil is well advanced and Omigapil was proven to be safe in large clinical trials. Based on its efficacy in the dyW/dyW mouse, this orally bioavailable drug is well suited to be tested clinically as a potential therapy for MDC1A.
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T.O.2 Omigapil/SNT-317 prevents apoptosis and ameliorates the pathology of laminin-alpha2 deficient muscle dystrophy
Neuromuscular Disorders, 2008Co-Authors: T Meier, Sarina Meinen, Patrizia Barzaghi, Markus A RueggAbstract:Mutations in LAMA2, the gene encoding the laminin-alpha2 chain of the extracellular matrix of muscle cells, cause a rare and severe form of congenital muscular dystrophy, called MDC1A. The disease is characterized by early onset, progressive muscle degeneration and impaired regeneration. As consequence, affected children are often never able to walk and, as there is no effective treatment available, frequently die in early childhood. Genetic evidence has shown that overexpression of the apoptosis inhibitor protein BCL-2 can protect from disease-relevant pathologies in the laminin-alpha2 deficient dyW/dyW mouse, a model for MDC1A. In addition, expression of a miniaturized form of the extracellular matrix molecule agrin (mini-agrin) has been shown to be an alternative way to ameliorate disease symptoms. The efficacy of Omigapil (N-(dibenz(b,f)oxepin-10-ylmethyl)-N-methyl-N-prop-2-ynylamine maleate; SNT-317, TCH346), a chemical derivative of selegiline, was tested in dyW/dyW mice by oral administration at a daily dose of 0.1 or 1 mg/kg starting at 3-weeks of age. Control animals were treated with vehicle. We show that Omigapil, a well characterized inhibitor of apoptosis that targets GAPDH, ameliorated key pathology hallmarks of the dyW/dyW mouse. Specifically, oral administration of Omigapil reduced apoptosis in muscle and preserved muscle histology, reduced body weight loss, mitigated skeletal deformation and improved locomotion. Moreover, Omigapil increased the 50% survival time from 35 days in vehicle treated dyW/dyWmice to 85 days and 105 days in dyW/dyW mice treated with 0.1 and 1 mg/kg Omigapil, respectively. In addition, we show that co-administration of mini-agrin had additive beneficial effects. The preclinical and clinical development of Omigapil is well advanced and Omigapil was proven to be safe in large clinical trials. Based on its efficacy in the dyW/dyW mouse, this orally bioavailable drug is well suited to be tested clinically as a potential therapy for MDC1A.
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use of n dibenz b f oxepin 10 ilmetil n metil n prop 2 inylamine Omigapil for profilaxis and or muscular dystrophy treatment
2006Co-Authors: T Meier, Markus A RueggAbstract:Use of a compound of formula (I) ** Formula ** or a pharmaceutically acceptable addition salt thereof for the preparation of a medicament for the prophylaxis and / or treatment of muscular dystrophy.
Qing Yu - One of the best experts on this subject based on the ideXlab platform.
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Omigapil treatment decreases fibrosis and improves respiratory rate in dy2j mouse model of congenital muscular dystrophy
PLOS ONE, 2013Co-Authors: Qing Yu, Arpana Sali, Jack H Van Der Meulen, Brittany Creeden, Heather Gordishdressman, Anne Rutkowski, Sree Rayavarapu, Kitipong Uaesoontrachoon, Tony Huynh, Kanneboyina NagarajuAbstract:Introduction: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. Modification of apoptosis is one potential pathway for therapy in these patients.Methods:dy2J 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.Results:dy2J 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.Conclusion:Omigapil 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.
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Omigapil Treatment Decreases Fibrosis and Improves Respiratory Rate in dy2J Mouse Model of Congenital Muscular Dystrophy
PLOS ONE, 2013Co-Authors: Qing Yu, Arpana Sali, Jack H Van Der Meulen, Brittany Creeden, Anne Rutkowski, Sree Rayavarapu, Kitipong Uaesoontrachoon, Tony Huynh, Heather Gordish-dressman, Kanneboyina NagarajuAbstract:Introduction: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. Modification of apoptosis is one potential pathway for therapy in these patients.Methods:dy2J 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.Results:dy2J mice treated with Omigapil showed improved respiratory rates compared to vehicle treated dy2J mice (396 to 402 vs. 371 breaths per minute, p
Sarina Meinen - One of the best experts on this subject based on the ideXlab platform.
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Apoptosis inhibitors and mini-agrin have additive benefits in congenital muscular dystrophy mice
Embo Molecular Medicine, 2011Co-Authors: Sarina Meinen, T Meier, Raphael Thurnherr, Markus A RueggAbstract:Mutations in LAMA2 cause a severe form of congenital muscular dystrophy, called MDC1A. Studies in mouse models have shown that transgenic expression of a designed, miniaturized form of the extracellular matrix molecule agrin (‘mini-agrin’) or apoptosis inhibition by either overexpression of Bcl2 or application of the pharmacological substance Omigapil can ameliorate the disease. Here, we tested whether mini-agrin and anti-apoptotic agents act on different pathways and thus exert additive benefits in MDC1A mouse models. By combining mini-agrin with either transgenic Bcl2 expression or oral Omigapil application, we show that the ameliorating effect of mini-agrin, which acts by restoring the mechanical stability of muscle fibres and, thereby, reduces muscle fibre breakdown and concomitant fibrosis, is complemented by apoptosis inhibitors, which prevent the loss of muscle fibres. Treatment of mice with both agents results in improved muscle regeneration and increased force. Our results show that the combination of mini-agrin and anti-apoptosis treatment has beneficial effects that are significantly bigger than the individual treatments and suggest that such a strategy might also be applicable to MDC1A patients.
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Omigapil ameliorates the pathology of muscle dystrophy caused by laminin α2 deficiency
Journal of Pharmacology and Experimental Therapeutics, 2009Co-Authors: Sarina Meinen, Patrizia Barzaghi, Markus A Ruegg, Lazar T Sumanovski, I Courdierfruh, T MeierAbstract:Laminin α2-deficient Congenital Muscular Dystrophy, called MDC1A, is a rare, devastating genetic disease characterized by severe neonatal hypotonia ("floppy infant syndrome"), peripheral neuropathy, inability to stand or walk, respiratory distress and premature death in early life. Transgenic overexpression of the apoptosis inhibitor protein BCL-2, or deletion of the pro-apoptotic Bax gene in a mouse model for MDC1A prolong survival and mitigate pathology, indicating that apoptotic events are involved in the pathology. Here we demonstrate that the pro-apoptotic glyceraldehyde 3-phosphate dehydrogenase (GAPDH)-Siah1-CBP/p300-p53 pathway is activated in a mouse model for MDC1A. Moreover, we show that Omigapil, which inhibits GAPDH-Siah1 mediated apoptosis, ameliorates several pathological hallmarks in the MDC1A mouse model. Specifically, we demonstrate that treatment with Omigapil inhibits apoptosis in muscle, reduces body weight loss and skeletal deformation, increases locomotive activity and protects from early mortality. These data qualify Omigapil, which is in late phase of clinical development for human use, as a drug candidate for the treatment of MDC1A.
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t o 2 Omigapil snt 317 prevents apoptosis and ameliorates the pathology of laminin alpha2 deficient muscle dystrophy
Neuromuscular Disorders, 2008Co-Authors: T Meier, Sarina Meinen, Patrizia Barzaghi, Markus A RueggAbstract:Mutations in LAMA2, the gene encoding the laminin-alpha2 chain of the extracellular matrix of muscle cells, cause a rare and severe form of congenital muscular dystrophy, called MDC1A. The disease is characterized by early onset, progressive muscle degeneration and impaired regeneration. As consequence, affected children are often never able to walk and, as there is no effective treatment available, frequently die in early childhood. Genetic evidence has shown that overexpression of the apoptosis inhibitor protein BCL-2 can protect from disease-relevant pathologies in the laminin-alpha2 deficient dyW/dyW mouse, a model for MDC1A. In addition, expression of a miniaturized form of the extracellular matrix molecule agrin (mini-agrin) has been shown to be an alternative way to ameliorate disease symptoms. The efficacy of Omigapil (N-(dibenz(b,f)oxepin-10-ylmethyl)-N-methyl-N-prop-2-ynylamine maleate; SNT-317, TCH346), a chemical derivative of selegiline, was tested in dyW/dyW mice by oral administration at a daily dose of 0.1 or 1 mg/kg starting at 3-weeks of age. Control animals were treated with vehicle. We show that Omigapil, a well characterized inhibitor of apoptosis that targets GAPDH, ameliorated key pathology hallmarks of the dyW/dyW mouse. Specifically, oral administration of Omigapil reduced apoptosis in muscle and preserved muscle histology, reduced body weight loss, mitigated skeletal deformation and improved locomotion. Moreover, Omigapil increased the 50% survival time from 35 days in vehicle treated dyW/dyWmice to 85 days and 105 days in dyW/dyW mice treated with 0.1 and 1 mg/kg Omigapil, respectively. In addition, we show that co-administration of mini-agrin had additive beneficial effects. The preclinical and clinical development of Omigapil is well advanced and Omigapil was proven to be safe in large clinical trials. Based on its efficacy in the dyW/dyW mouse, this orally bioavailable drug is well suited to be tested clinically as a potential therapy for MDC1A.
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T.O.2 Omigapil/SNT-317 prevents apoptosis and ameliorates the pathology of laminin-alpha2 deficient muscle dystrophy
Neuromuscular Disorders, 2008Co-Authors: T Meier, Sarina Meinen, Patrizia Barzaghi, Markus A RueggAbstract:Mutations in LAMA2, the gene encoding the laminin-alpha2 chain of the extracellular matrix of muscle cells, cause a rare and severe form of congenital muscular dystrophy, called MDC1A. The disease is characterized by early onset, progressive muscle degeneration and impaired regeneration. As consequence, affected children are often never able to walk and, as there is no effective treatment available, frequently die in early childhood. Genetic evidence has shown that overexpression of the apoptosis inhibitor protein BCL-2 can protect from disease-relevant pathologies in the laminin-alpha2 deficient dyW/dyW mouse, a model for MDC1A. In addition, expression of a miniaturized form of the extracellular matrix molecule agrin (mini-agrin) has been shown to be an alternative way to ameliorate disease symptoms. The efficacy of Omigapil (N-(dibenz(b,f)oxepin-10-ylmethyl)-N-methyl-N-prop-2-ynylamine maleate; SNT-317, TCH346), a chemical derivative of selegiline, was tested in dyW/dyW mice by oral administration at a daily dose of 0.1 or 1 mg/kg starting at 3-weeks of age. Control animals were treated with vehicle. We show that Omigapil, a well characterized inhibitor of apoptosis that targets GAPDH, ameliorated key pathology hallmarks of the dyW/dyW mouse. Specifically, oral administration of Omigapil reduced apoptosis in muscle and preserved muscle histology, reduced body weight loss, mitigated skeletal deformation and improved locomotion. Moreover, Omigapil increased the 50% survival time from 35 days in vehicle treated dyW/dyWmice to 85 days and 105 days in dyW/dyW mice treated with 0.1 and 1 mg/kg Omigapil, respectively. In addition, we show that co-administration of mini-agrin had additive beneficial effects. The preclinical and clinical development of Omigapil is well advanced and Omigapil was proven to be safe in large clinical trials. Based on its efficacy in the dyW/dyW mouse, this orally bioavailable drug is well suited to be tested clinically as a potential therapy for MDC1A.
