Molecular and Clinical Manifestations of Matrix and Aggregate Myopathies

基质和聚集性肌病的分子和临床表现

• 批准号: 10930561
• 负责人: Carsten Bönnemann
• 金额: $ 392.01万
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10930561
• 关键词: Address; Adolescent; Affect; Afferent Neurons; Animal Model; Antisense Oligonucleotide Therapy; Atrophic; Biological Markers; Biopsy; Breathing; COL6A1; COL6A2; Case Study; Cell model; Centronuclear myopathy; Child; Childhood; Clinic; Clinical; Clinical Trials; Clinical assessments; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Cohort Studies; Collaborations; Collagen Type VI; Compensation; Congenital Myasthenic Syndromes; Dedications; Development; Disease; Disease model; Dominant-Negative Mutation; Dose; Drug Kinetics; Engineering; Etiology; Evaluation; Extracellular Matrix; FHL1 gene; FXR1 gene; Gait; Gene Transfer; Gene therapy trial; Genes; Genetic; Genomic approach; Genomics; Goals; Growth Factor; Human; Image; Imaging Device; Infrastructure; International; Joints; Laboratories; Magnetic Resonance Imaging; Mediating; Modality; Molecular; Muscle; Mutation; Myopathy; National Center for Advancing Translational Sciences; Natural History; Natural regeneration; Neuromuscular Diseases; Neuromuscular Junction Diseases; Outcome Measure; Outcome Study; Pain; Pathway interactions; Patients; Pharmacologic Substance; Phase; Phenotype; Piezo 2 ion channel; Positioning Attribute; Proprioception; Protocols documentation; RNA Interference; RNA Splicing; Rare Diseases; Research; Respiratory Muscles; Sensory; Signal Transduction; Syndrome; Technology; Testing; Therapeutic; Tissue Model; Touch sensation; Transcript; Translating; Translations; United States National Institutes of Health; Validation; Visualization; Work; X-linked myotubular myopathy; base editing; causal variant; clinical outcome measures; clinical translation; cohort; congenital muscular dystrophy; congenital myopathy; early onset; exome; exosuit; falls; first-in-human; gene therapy; genome sequencing; genomic data; giant axonal neuropathy; humanized mouse; immunoregulation; improved; induced pluripotent stem cell; loss of function; member; mouse model; neurogenetics; neuromuscular; next generation; next generation sequencing; novel; phenotypic data; precision medicine; preservation; programs; receptor; safety assessment; sensory prosthesis; therapeutic gene; tool; transcriptome sequencing; trial design; whole genome

The Neuromuscular and Neurogenetic Disorders of Childhood Section (NNDCS) is dedicated to elucidating the genetic and pathophysiologic basis of early-onset neuromuscular disorders, to exploring therapeutic approaches to these conditions and to bringing first clinical trials to patients affected by these disorders. To accomplish these goals, we are using next generation genomic technology, tissue, cellular and animal models in the laboratory, while in the clinic we are using outcome measures and biomarker research, the development of phenotyping tools and novel trial designs to enable first clinical trials in patients. A particular focus in the section is on early onset muscle disorders caused by mutations in genes coding for components of the muscle extracellular matrix and its receptors (often falling within the group of Congenital Muscular Dystrophies, CMD) and on reducing body myopathy, a severe early onset myopathy with aggregate formation. For the matrix myopathies we are studying the mechanisms of muscle involvement in mouse models, in particular as they relate to atrophy, failing regeneration and abnormal growth factor signaling in the muscle. A pathway-independent approach directed at the causative mutation is under development for dominant negative mutations in collagen VI. We also discovered a novel deep intronic mutation in COL6A1 causing inclusion of a dominant negative pseudo-exon and are developing a therapeutic approach to this mutation in a specially created humanized mouse model. In a clinical cohort of patients with the most common of the matrix CMDs (COL6 and LAMA2), we have completed a phase I pharmacokinetics study under sponsorship of Santhera pharmaceutical (Congenital Muscular Dystrophy Ascending Multiple Dose Cohort Study Analyzing Pharmacokinetics at Three Dose Levels In Children and Adolescents With Assessment of Safety and Tolerability of Omigapil (CALLISTO, NCT01805024)). This trial was based on our careful natural history and clinical outcomes study. We are also adding novel clinical outcome measures such as dynamic breathing MRI to directly visualize the involvement of respiratory muscles as well as those for younger patients. We are using and developing new next generation sequencing technology to identify new genes in our cohort of undiagnosed patients in collaboration with the as a member of the Center of Mendelian Genomics at MGH/Broad, continuously identifying novel disease genes, including a new form of childhood ALS (SPTLC1) as well as several new muscle disorders (TAMM41, HNRNPA2B1, FXR1). We are continuing the evaluation of all the diverse manifestations of the PIEZO2 deficiency, and in collaboration with the engineers in the NIH Gait Lab are working on developing a sensory exo-suit to help compensate for the deficiency of proprioception. Finally, in collaboration with Dr. Steven Gray at UTSW, we are performing a first trial of intrathecal gene transfer in giant axonal neuropathy, using scAAV9/JeT-GAN (Intrathecal Administration of scAAV9/JeT-GAN for the Treatment of Giant Axonal Neuropathy, NCT02362438), which continues with dose escalation and protocol refinements. We are also participating in a study to define natural history and outcome measures in the congenital myopathy myotubular myopathy (A Clinical Assessment Study in X-Linked Myotubular Myopathy (XLMTM) Subjects (INCEPTUS, NCT02704273)) and are participating in a gene transfer study in this condition (ASPIRO), under the sponsorship of Astellas Gene Therapies. Finally we are also working with NCATS to develop a platform gene therapy approach to ultrarare disorders of the neuromuscular junction (PaveGT).

儿童期（NNDC）的神经肌肉和神经遗传疾病致力于阐明早期发作的神经肌肉疾病的遗传和病理生理基础，以探索针对这些疾病的治疗方法，并将这些疾病影响的患者带给这些疾病患者。为了实现这些目标，我们在实验室中使用下一代基因组技术，组织，细胞和动物模型，而在诊所中，我们正在使用结果指标和生物标志物研究，开发表型工具和新颖的试验设计来实现患者的首次临床试验。本节中的一个特别重点是由编码肌肉外基质组成部分的基因突变引起的早期发作肌肉疾病及其受体（通常落在先天性肌肉营养不良的肌营养不良症中）和减少体内肌病，严重的早期肌病与聚集的肌病。对于基质肌病，我们正在研究肌肉参与小鼠模型的机制，尤其是与萎缩相关，肌肉中的再生和异常生长因子信号传导。胶原蛋白VI中主要的阴性突变的主要依赖性方法正在发展。我们还发现了一种新型的COL6A1中内含子突变，导致纳入了主导的阴性伪外激素，并正在为特殊创建的人源性小鼠模型开发一种治疗方法来进行这种突变。 In a clinical cohort of patients with the most common of the matrix CMDs (COL6 and LAMA2), we have completed a phase I pharmacokinetics study under sponsorship of Santhera pharmaceutical (Congenital Muscular Dystrophy Ascending Multiple Dose Cohort Study Analyzing Pharmacokinetics at Three Dose Levels In Children and Adolescents With Assessment of Safety and Tolerability of Omigapil (CALLISTO, NCT01805024）。该试验基于我们仔细的自然史和临床结果研究。我们还添加了新的临床结局指标，例如动态呼吸MRI，以直接可视化呼吸肌肉以及年轻患者的参与。我们正在使用并开发新的下一代测序技术来鉴定我们在未诊断的患者队列中与MGH/Broad的Mendelian基因组学中心合作，不断识别新型疾病基因的成员，包括一种新形式的儿童ALS ALS ALS（SPTLC1）（SPTLC1）（SPTLC1），以及几种新肌肉性肌肉折磨（TAMM4111，TAMM41，HNR1），FXB1，FxR1，FxR1，FXR1，FXR1，FX2。我们正在继续评估压电2缺乏的所有不同表现，并与NIH步态实验室中的工程师合作，正在努力开发一种感官外观西装，以帮助弥补本体缺乏。最后，通过使用SCAAV9/JET-GAN（SCAAV9/SCAAV9/JET-GAN治疗巨型轴突神经病治疗巨型轴突神经病治疗，NCT02362438）的治疗，我们正在与巨型轴突神经病中的肠内基因转移进行首次试验，以供应和剂量调整。我们还参与了一项研究，以定义先天性肌病肌管肌病（一项临床评估研究）（X链接肌管肌病（XLMTM）受试者（Inceptus，NCT02704273））中的一项临床评估研究（NCT02704273）），并参与了基因转移的基因（Asperso）（Asperso）（Asprestos）（Asperso）。最后，我们还与NCAT合作开发了一种平台基因治疗方法，用于神经肌肉结（PaveGT）的超男性疾病。

项目成果

An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy.

• DOI: 10.1093/brain/awaa420
• 发表时间: 2021-03-03
• 期刊: Brain : a journal of neurology
• 作者: Pagnamenta AT;Kaiyrzhanov R;Zou Y;Da'as SI;Maroofian R;Donkervoort S;Dominik N;Lauffer M;Ferla MP;Orioli A;Giess A;Tucci A;Beetz C;Sedghi M;Ansari B;Barresi R;Basiri K;Cortese A;Elgar G;Fernandez-Garcia MA;Yip J;Foley AR;Gutowski N;Jungbluth H;Lassche S;Lavin T;Marcelis C;Marks P;Marini-Bettolo C;Medne L;Moslemi AR;Sarkozy A;Reilly MM;Muntoni F;Millan F;Muraresku CC;Need AC;Nemeth AH;Neuhaus SB;Norwood F;O'Donnell M;O'Driscoll M;Rankin J;Yum SW;Zolkipli-Cunningham Z;Brusius I;Wunderlich G;Genomics England Research Consortium;Karakaya M;Wirth B;Fakhro KA;Tajsharghi H;Bönnemann CG;Taylor JC;Houlden H
• 通讯作者: Houlden H

Clinical spectrum and genetic variations of LMNA-related muscular dystrophies in a large cohort of Chinese patients.

• DOI: 10.1136/jmedgenet-2019-106671
• 发表时间: 2021-05
• 期刊: Journal of medical genetics
• 影响因子: 4
• 作者: Fan Y;Tan D;Song D;Zhang X;Chang X;Wang Z;Zhang C;Chan SH;Wu Q;Wu L;Wang S;Yan H;Ge L;Yang H;Mao B;Bönnemann C;Liu J;Wang S;Yuan Y;Wu X;Zhang H;Xiong H
• 通讯作者: Xiong H

Electrophysiological Characterization of a MYH7 Variant with Tremor Phenotype.

具有震颤表型的 MYH7 变体的电生理学特征。

• DOI: 10.1002/mdc3.13664
• 发表时间: 2023
• 期刊: Movement disorders clinical practice
• 影响因子: 4
• 作者: Vial,Felipe;McGurrin,Patrick;Osterholt,Thomas;Ehrlich,DebraJ;Iannacone,SusanT;Donkervoort,Sandra;Neuhaus,SarahB;Chao,KatherineC;Bönnemann,CarstenG;Haubenberger,Dietrich;Hallett,Mark
• 通讯作者: Hallett,Mark

Myogenic tremor - a novel tremor entity.

肌源性震颤 - 一种新的震颤实体。

• DOI: 10.1097/wco.0000000000000976
• 发表时间: 2021
• 期刊: Current opinion in neurology
• 影响因子: 4.8
• 作者: Schaefer,Jochen;Saak,Annika;Bönnemann,CarstenG;Jackson,Sandra
• 通讯作者: Jackson,Sandra

A novel variant in the COL6A1 gene causing Ullrich congenital muscular dystrophy in a consanguineous family: a case report.

• DOI: 10.1186/s12883-021-02134-7
• 发表时间: 2021-03-09
• 期刊: BMC neurology
• 影响因子: 2.6
• 作者: Sirisena ND;Samaranayake UMJE;Neto OLA;Foley AR;Pathirana BAPS;Neththikumara N;Paththinige CS;Rathnayake P;Donkervoort S;Bönnemann CG;Dissanayake VHW
• 通讯作者: Dissanayake VHW