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Michael Sendtner - One of the best experts on this subject based on the ideXlab platform.
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Developmental regulation of SMN expression: pathophysiological implications and perspectives for Therapy Development in spinal muscular atrophy
Gene Therapy, 2017Co-Authors: S Jablonka, Michael SendtnerAbstract:Spinal muscular atrophy (SMA), the predominant form of motoneuron disease in children and young adults is caused by loss of function of the SMN protein. On the basis of a disrupted splice acceptor site in exon 7, transcripts from a second SMN gene in humans called SMN2 cannot give rise to SMN protein at sufficient levels for maintaining function of motoneurons and motor circuits. First clinical trials with Spinraza/Nusinersen, a drug that counteracts disrupted splicing of SMN2 transcripts, have shown that elevating SMN levels can successfully interfere with motoneuron dysfunction. This review summarizes current knowledge about the pathophysiological alterations in Smn-deficient motoneurons, which lead to defective neuromuscular transmission and altered spinal circuit formation. Both pathological mechanisms are important targets for therapeutic intervention. However, the Developmental time window when therapeutic interventions ideally should start is not known. Endogenous SMN expression both from SMN1 and SMN2 genes is high at early Developmental stages and declines progressively in humans and mice. Thus, therapeutic SMN upregulation should start just before SMN declines below a critical threshold, and before irreversible defects occur at neuromuscular junctions and in spinal circuits. Previous results indicate that loss of Smn function leads to synaptic dysfunction during a stage of neuromuscular Development when synaptic strength determines which synapses are maintained or not. This time window appears as an important target for Therapy, which possibly could be supported by additional strategies that strengthen synaptic transmission.
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Therapy Development in spinal muscular atrophy
Nature neuroscience, 2010Co-Authors: Michael SendtnerAbstract:Proximal spinal muscular atrophy (SMA) is the predominant form of motor neuron disease in children and young adults. In contrast to other neurodegenerative disorders, SMA is a genetically homozygous autosomal recessive disease that is caused by deficiency of the survival motor neuron (SMN) protein. This homogeneity should in principle facilitate Therapy Development. Previous Therapy approaches have focused on upregulation of SMN expression from a second SMN (SMN2) gene that gives rise to low amounts of functional SMN protein. Drug Development to target disease-specific mechanisms at cellular and physiological levels is in its early stages, as the pathophysiological processes that underlie the main disease symptoms are still not fully understood. Mouse models have helped to make conceptual progress in the disease mechanism, but their suitability in the search for therapeutic agents remains to be validated--an issue that is ubiquitous to the translational therapeutic research of other neurodegenerative diseases. Human induced pluripotent stem cell technology for generation of large numbers of human motor neurons could help to fill this gap and advance the power of drug screening. In parallel, advances in oligonucleotide technologies for engineering SMN2 pre-mRNA splicing are approaching their first clinical trials, whose success depends on improved technologies for drug delivery to motor neurons. If this obstacle can be overcome, this could boost Therapy Development, not only for SMA but also for other neurodegenerative disorders.
Henry L. Paulson - One of the best experts on this subject based on the ideXlab platform.
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Author Correction: Spinocerebellar ataxias: prospects and challenges for Therapy Development.
Nature reviews. Neurology, 2018Co-Authors: Tetsuo Ashizawa, Henry L. PaulsonAbstract:In Table 3 of this article as originally published, a sentence within the column “Comments” in the row “SCA6” contains an error. The text incorrectly reads “Needs rigorous preclinical studies in SCA3 animal models”. This sentence has been corrected to “Needs rigorous preclinical studies in SCA6 animal models” in the PDF and HTML versions of the article.
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Spinocerebellar ataxias: prospects and challenges for Therapy Development
Nature Reviews Neurology, 2018Co-Authors: Tetsuo Ashizawa, Gülin Öz, Henry L. PaulsonAbstract:Advances in our understanding of the pathogenic mechanisms of spinocerebellar ataxias (SCAs) have resulted in the Development of promising therapeutic strategies for these inherited neurodegenerative disorders. Here, Ashizawa and colleagues review the current progress and future challenges facing clinical trials of new therapies for the SCAs. Spinocerebellar ataxias (SCAs) are a group of dominantly inherited degenerative disorders that principally involve the cerebellum and its connections. Insights into the pathogenic mechanisms of many SCAs have suggested promising routes to symptomatic and disease-modifying Therapy. Clinical research consortia for SCAs have started international collaborations to share and analyse natural history data. The Scale for Assessment and Rating of Ataxia is the best validated clinical outcome assessment measure, but additional measures should be developed with improved responsiveness to changes that are directly relevant to patients’ lives. MRI and magnetic resonance spectroscopy have emerged as potentially powerful biomarkers for disease activities and progression, but target engagement biomarkers, especially molecular biomarkers in biofluids, are yet to be developed. Collective efforts in SCA clinical research within the past few years have improved the prospects for eventual successful therapeutic Development for the SCAs. The spinocerebellar ataxias (SCAs) comprise more than 40 autosomal dominant neurodegenerative disorders that present principally with progressive ataxia. Within the past few years, studies of pathogenic mechanisms in the SCAs have led to the Development of promising therapeutic strategies, especially for SCAs caused by polyglutamine-coding CAG repeats. Nucleotide-based gene-silencing approaches that target the first steps in the pathogenic cascade are one promising approach not only for polyglutamine SCAs but also for the many other SCAs caused by toxic mutant proteins or RNA. For these and other emerging therapeutic strategies, well-coordinated preparation is needed for fruitful clinical trials. To accomplish this goal, investigators from the United States and Europe are now collaborating to share data from their respective SCA cohorts. Increased knowledge of the natural history of SCAs, including of the premanifest and early symptomatic stages of disease, will improve the prospects for success in clinical trials of disease-modifying drugs. In addition, investigators are seeking validated clinical outcome measures that demonstrate responsiveness to changes in SCA populations. Findings suggest that MRI and magnetic resonance spectroscopy biomarkers will provide objective biological readouts of disease activity and progression, but more work is needed to establish disease-specific biomarkers that track target engagement in therapeutic trials. Together, these efforts suggest that the Development of successful therapies for one or more SCAs is not far away.
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Spinocerebellar ataxias: prospects and challenges for Therapy Development
Nature reviews. Neurology, 2018Co-Authors: Tetsuo Ashizawa, Henry L. PaulsonAbstract:The spinocerebellar ataxias (SCAs) comprise more than 40 autosomal dominant neurodegenerative disorders that present principally with progressive ataxia. Within the past few years, studies of pathogenic mechanisms in the SCAs have led to the Development of promising therapeutic strategies, especially for SCAs caused by polyglutamine-coding CAG repeats. Nucleotide-based gene-silencing approaches that target the first steps in the pathogenic cascade are one promising approach not only for polyglutamine SCAs but also for the many other SCAs caused by toxic mutant proteins or RNA. For these and other emerging therapeutic strategies, well-coordinated preparation is needed for fruitful clinical trials. To accomplish this goal, investigators from the United States and Europe are now collaborating to share data from their respective SCA cohorts. Increased knowledge of the natural history of SCAs, including of the premanifest and early symptomatic stages of disease, will improve the prospects for success in clinical trials of disease-modifying drugs. In addition, investigators are seeking validated clinical outcome measures that demonstrate responsiveness to changes in SCA populations. Findings suggest that MRI and magnetic resonance spectroscopy biomarkers will provide objective biological readouts of disease activity and progression, but more work is needed to establish disease-specific biomarkers that track target engagement in therapeutic trials. Together, these efforts suggest that the Development of successful therapies for one or more SCAs is not far away.
Tetsuo Ashizawa - One of the best experts on this subject based on the ideXlab platform.
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Author Correction: Spinocerebellar ataxias: prospects and challenges for Therapy Development.
Nature reviews. Neurology, 2018Co-Authors: Tetsuo Ashizawa, Henry L. PaulsonAbstract:In Table 3 of this article as originally published, a sentence within the column “Comments” in the row “SCA6” contains an error. The text incorrectly reads “Needs rigorous preclinical studies in SCA3 animal models”. This sentence has been corrected to “Needs rigorous preclinical studies in SCA6 animal models” in the PDF and HTML versions of the article.
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Spinocerebellar ataxias: prospects and challenges for Therapy Development
Nature Reviews Neurology, 2018Co-Authors: Tetsuo Ashizawa, Gülin Öz, Henry L. PaulsonAbstract:Advances in our understanding of the pathogenic mechanisms of spinocerebellar ataxias (SCAs) have resulted in the Development of promising therapeutic strategies for these inherited neurodegenerative disorders. Here, Ashizawa and colleagues review the current progress and future challenges facing clinical trials of new therapies for the SCAs. Spinocerebellar ataxias (SCAs) are a group of dominantly inherited degenerative disorders that principally involve the cerebellum and its connections. Insights into the pathogenic mechanisms of many SCAs have suggested promising routes to symptomatic and disease-modifying Therapy. Clinical research consortia for SCAs have started international collaborations to share and analyse natural history data. The Scale for Assessment and Rating of Ataxia is the best validated clinical outcome assessment measure, but additional measures should be developed with improved responsiveness to changes that are directly relevant to patients’ lives. MRI and magnetic resonance spectroscopy have emerged as potentially powerful biomarkers for disease activities and progression, but target engagement biomarkers, especially molecular biomarkers in biofluids, are yet to be developed. Collective efforts in SCA clinical research within the past few years have improved the prospects for eventual successful therapeutic Development for the SCAs. The spinocerebellar ataxias (SCAs) comprise more than 40 autosomal dominant neurodegenerative disorders that present principally with progressive ataxia. Within the past few years, studies of pathogenic mechanisms in the SCAs have led to the Development of promising therapeutic strategies, especially for SCAs caused by polyglutamine-coding CAG repeats. Nucleotide-based gene-silencing approaches that target the first steps in the pathogenic cascade are one promising approach not only for polyglutamine SCAs but also for the many other SCAs caused by toxic mutant proteins or RNA. For these and other emerging therapeutic strategies, well-coordinated preparation is needed for fruitful clinical trials. To accomplish this goal, investigators from the United States and Europe are now collaborating to share data from their respective SCA cohorts. Increased knowledge of the natural history of SCAs, including of the premanifest and early symptomatic stages of disease, will improve the prospects for success in clinical trials of disease-modifying drugs. In addition, investigators are seeking validated clinical outcome measures that demonstrate responsiveness to changes in SCA populations. Findings suggest that MRI and magnetic resonance spectroscopy biomarkers will provide objective biological readouts of disease activity and progression, but more work is needed to establish disease-specific biomarkers that track target engagement in therapeutic trials. Together, these efforts suggest that the Development of successful therapies for one or more SCAs is not far away.
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Spinocerebellar ataxias: prospects and challenges for Therapy Development
Nature reviews. Neurology, 2018Co-Authors: Tetsuo Ashizawa, Henry L. PaulsonAbstract:The spinocerebellar ataxias (SCAs) comprise more than 40 autosomal dominant neurodegenerative disorders that present principally with progressive ataxia. Within the past few years, studies of pathogenic mechanisms in the SCAs have led to the Development of promising therapeutic strategies, especially for SCAs caused by polyglutamine-coding CAG repeats. Nucleotide-based gene-silencing approaches that target the first steps in the pathogenic cascade are one promising approach not only for polyglutamine SCAs but also for the many other SCAs caused by toxic mutant proteins or RNA. For these and other emerging therapeutic strategies, well-coordinated preparation is needed for fruitful clinical trials. To accomplish this goal, investigators from the United States and Europe are now collaborating to share data from their respective SCA cohorts. Increased knowledge of the natural history of SCAs, including of the premanifest and early symptomatic stages of disease, will improve the prospects for success in clinical trials of disease-modifying drugs. In addition, investigators are seeking validated clinical outcome measures that demonstrate responsiveness to changes in SCA populations. Findings suggest that MRI and magnetic resonance spectroscopy biomarkers will provide objective biological readouts of disease activity and progression, but more work is needed to establish disease-specific biomarkers that track target engagement in therapeutic trials. Together, these efforts suggest that the Development of successful therapies for one or more SCAs is not far away.
Li-kai Tsai - One of the best experts on this subject based on the ideXlab platform.
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Therapy Development for Spinal Muscular Atrophy in SMN Independent Targets
Neural plasticity, 2012Co-Authors: Li-kai TsaiAbstract:Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder, leading to progressive muscle weakness, atrophy, and sometimes premature death. SMA is caused by mutation or deletion of the survival motor neuron-1 (SMN1) gene. An effective treatment does not presently exist. Since the severity of the SMA phenotype is inversely correlated with expression levels of SMN, the SMN-encoded protein, SMN is the most important therapeutic target for Development of an effective treatment for SMA. In recent years, numerous SMN independent targets and therapeutic strategies have been demonstrated to have potential roles in SMA treatment. For example, some neurotrophic, antiapoptotic, and myotrophic factors are able to promote survival of motor neurons or improve muscle strength shown in SMA mouse models or clinical trials. Plastin-3, cpg15, and a Rho-kinase inhibitor regulate axonal dynamics and might reduce the influences of SMN depletion in disarrangement of neuromuscular junction. Stem cell transplantation in SMA model mice resulted in improvement of motor behaviors and extension of survival, likely from trophic support. Although most therapies are still under investigation, these nonclassical treatments might provide an adjunctive method for future SMA Therapy.
Annemieke Aartsma-rus - One of the best experts on this subject based on the ideXlab platform.
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226th ENMC International Workshop:: Towards validated and qualified biomarkers for Therapy Development for Duchenne muscular dystrophy 20-22 January 2017, Heemskerk, The Netherlands.
Neuromuscular disorders : NMD, 2017Co-Authors: Annemieke Aartsma-rus, Alessandra Ferlini, Elizabeth M. Mcnally, Pietro Spitali, H.l. SweeneyAbstract:Twenty-three participants from 6 countries (England; Germany; Italy; Sweden, The Netherlands; USA) attended the 226th ENMC workshop on Duchenne biomarkers “Towards validated and qualified biomarkers for Therapy Development for Duchenne Muscular Dystrophy.” The meeting was a follow-up of the 204th ENMC workshop on Duchenne muscular dystrophy biomarkers. The workshop was organized with the support of Parent Project Muscular Dystrophy (PPMD) and Marathon Pharmaceuticals, which provided travel support for participants from the US via an unrestricted grant to PPMD in addition to ENMC support. It was attended by representatives of academic institutions, industry working in the Duchenne muscular dystrophy field and patient representatives. 1.1. Background to the workshop 1.1.1. Biomarkers Biomarkers are defined as biological, measurable and quantifiable indicators of underlying biological processes. Different types of biomarkers can be distinguished: diagnostic biomarkers indicate the presence of disease, prognostic biomarkers correlate with predicted disease course, and therapeutic biomarkers are designed to predict or measure response to treatment [1]. Therapeutic biomarkers can indicate whether a Therapy is having an effect. This type of biomarker is called a pharmacodynamics biomarker and can be used to e.g. show that a missing protein is restored after a Therapy. Safety biomarkers assess likelihood, presence, or extent of toxicity as an adverse effect, e.g. through monitoring blood markers indicative of liver or kidney damage. Sometimes biomarkers can also be used as primary endpoints in clinical trials instead of functional outcome measures, and these are termed “surrogate endpoints”. In Europe [2,3] biomarkers can only be used as surrogate endpoints after going through a rigorous regulatory process to officially qualify them for this purpose. Similar pathways exist in the US, where the Food and Drug Administration (FDA) also supplies a process for qualification of biomarkers for other contexts of use.
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Stakeholder collaboration for spinal muscular atrophy Therapy Development.
The Lancet. Neurology, 2017Co-Authors: Annemieke Aartsma-rus, Pavel Balabanov, Luca Binetti, Manuel Haas, Marion Haberkamp, Joanna Mitchell, Mário M. Rosa, Francesco Muntoni, Richard S. Finkel, Eugenio MercuriAbstract:N/
