更新于：2024-11-01

Muscular Dystrophy, Congenital, Lmna-Related

先天性肌营养不良症，Lmna相关

更新于：2024-11-01

基本信息

别名

Congenital muscular dystrophy due to LMNA (lamin A/C) mutation、Congenital muscular dystrophy due to LMNA mutation、Congenital muscular dystrophy due to lamin A/C mutation

+ [10]

简介

An autosomal recessive muscular dystrophy caused by mutation(s) in the LMNA gene, encoding prelamin-A/C. Limb-girdle muscular dystrophy type 1B and Emery-Dreifuss muscular dystrophy-2 are allelic disorders with overlapping phenotypes.

关联

项与先天性肌营养不良症，Lmna相关相关的药物

Emprumapimod

靶点

p38 MAPK

作用机制

p38 MAPK抑制剂

在研机构-

原研机构

Array BioPharma, Inc.

在研适应症-

非在研适应症

强直性脊柱炎 [+4]

最高研发阶段终止

首次获批国家/地区-

首次获批日期1800-01-20

项与先天性肌营养不良症，Lmna相关相关的临床试验

NCT06503367 / Not yet recruitingN/AIIT

Establishing Clinical Trial Readiness in Patients Age 0-5 Years With LAMA2-related Congenital Muscular Dystrophy (READY CMD LAMA2)

The goal of this observational study is to understand how young children with LAMA2-related dystrophy move and change over time. We will also learn about how this condition impacts other body systems.
Participants will undergo:
* Neuromuscular assessments
* Blood collections
* Swallowing and breathing assessments
* Questionnaires

开始日期2024-09-01

申办/合作机构

Nationwide Children's Hospital

[+11]

NCT05743140 / RecruitingN/AIIT

A Clinical Study of Fundus Optical Coherence Tomography Angiography for the Identification of Coronary Microvascular Diseases

Coronary microvascular dysfunction (CMD) carries an increased risk of adverse cardiovascular clinical outcomes. The association between fundus microcirculation changes and coronary microcirculation is not well understood. Optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA) is a new type of optical diagnostic imaging technology for non-invasive detection, which can perform multi-dimensional quantitative assessment of fundus microcirculation. In this study, investigators intend to use the coronary angiography-derived index of microvascular resistance (caIMR) to screen patients with CMD, explore the relationship between relevant parameters based on OCT and OCTA measurements and caIMR, and evaluate the feasibility and clinical value of non-invasive identification of CMD through fundus OCT and OCTA.

开始日期2023-03-01

申办/合作机构

北京大学第一医院

NCT05394506 / RecruitingN/AIIT

Identification of Genetic Modifying Factors in Striated Muscle Laminopathies

Mutations in the LMNA gene, which codes for lamins A and C, proteins of the nuclear lamina, are responsible for a wide spectrum of pathologies, including a group specifically affecting striated skeletal and cardiac muscles, with cardiac involvement being life-threatening. At the skeletal muscle level, a wide phenotypic spectrum has been described, ranging from severe forms of congenital muscular dystrophy to less severe forms of limb-girdle muscular dystrophy. The great clinical variability of striated muscle laminopathies, both inter- and intra-familial, can be observed in the age of onset, severity of signs and progression of muscle and heart involvement. To date, more than 400 LMNA mutations have been associated with striated muscle laminopathies (www.umd.be/LMNA/), highlighting strong clinical and genetic heterogeneity. A few recurrent mutations linked to a difference in severity have been identified. However, these genotype-phenotype relationships and the rare cases of digenism reported do not explain all the clinical variability of laminopathies. Therefore, there are probably other factors of severity than the causative mutation, called "modifier genes".
Identification of such modifier genes has been initiated by studying a large family with significant clinical variability in the age of onset of muscle signs. A segregation analysis within this family identified 2 potential modifier loci. High-throughput sequencing restricted to these 2 regions according to phenotypic subgroups did not led to meaningful results so far. In addition, an international retrospective study of the natural history of early muscle laminopathies has allowed the investigators to highlight a strong inter-family clinical variability in patients carrying recurrent mutations. The investigators thus have strong preliminary data that could allow them to identify modifying genetic factors in a cohort of patients carrying a mutation in the LMNA gene.
In order to identify these factors that modulate the clinical severity of laminopathies, the investigators wish to collect biological material (muscle and/or skin biopsies) from patients carrying a mutation in the LMNA gene. The study of this biological material using multi OMICs technics will allow the investigators to identify and functionally validate the action of these modifying genes.
OMIICs is a set of techniques for characterising biological molecules using high-throughput approaches such as DNA sequencing, RNA sequencing and/or chromatin conformation (ATACseq...), proteins.

开始日期2022-09-08

申办/合作机构

Institut National de la Santé et de la Recherche Médicale

100 项与先天性肌营养不良症，Lmna相关相关的临床结果

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100 项与先天性肌营养不良症，Lmna相关相关的转化医学

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0 项与先天性肌营养不良症，Lmna相关相关的专利（医药）

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216

项与先天性肌营养不良症，Lmna相关相关的文献（医药）

2024-10-01·Journal of Genetics and Genomics

Lama1 upregulation prolongs the lifespan of the dyH/dyH mouse model of LAMA2-related congenital muscular dystrophy

Article

作者: Tan, Dandan ; Guo, Yuxuan ; Luo, Huaxia ; Xu, Luzheng ; Ge, Lin ; Yang, Shiqi ; Xiong, Hui ; Zhang, Hong ; Shen, Qiang ; Ma, Kaiyue ; Luo, Jihang ; Mao, Jingping ; Liu, Yidan

LAMA2-related congenital muscular dystrophy (LAMA2-CMD), characterized by laminin-α2 deficiency, is debilitating and ultimately fatal. To date, no effective therapy has been clinically available. Laminin-α1, which shares significant similarities with laminin-α2, has been proven as a viable compensatory modifier. To evaluate its clinical applicability, we establish a Lama2 exon-3-deletion mouse model (dy^H/dy^H). The dy^H/dy^H mice exhibit early lethality and typical LAMA2-CMD phenotypes, allowing the evaluation of various endpoints. In dy^H/dy^H mice treated with synergistic activation mediator-based CRISPRa-mediated Lama1 upregulation, a nearly doubled median survival is observed, as well as improvements in weight and grip. Significant therapeutical effects are revealed by MRI, serum biochemical indices, and muscle pathology studies. Treating LAMA2-CMD with LAMA1 upregulation is feasible, and early intervention can alleviate symptoms and extend lifespan. Additionally, we reveal the limitations of LAMA1 upregulation, including high-dose mortality and non-sustained expression, which require further optimization in future studies.

2024-09-06·Medicine

Transformed follicular lymphoma with laryngeal edema requiring tracheal intubation after tisagenlecleucel treatment: A case report.

Article

作者: Kaneda, Yuto ; Ikoma, Yoshikazu ; Goto, Takayuki ; Shimazu, Ryoma ; Kanemura, Nobuhiro ; Matsumoto, Takuro ; Shimizu, Masahito ; Nakamura, Nobuhiko ; Nakamura, Hiroshi

RATIONALECytokine release syndrome (CRS) is a common adverse event of chimeric antigen receptor T (CAR-T) cell therapy. CRS is generally a systemic inflammatory reaction, but in rare cases, it can occur in specific body areas and is referred to as "local CRS (L-CRS)." A case of laryngeal edema due to L-CRS that required tracheal intubation because of the lack of response to tocilizumab (TCZ) and dexamethasone (DEX) is reported.PATIENT CONCERNSA 67-year-old woman with relapsed transformed follicular lymphoma was treated with CAR-T cell therapy. Although she had been given TCZ and DEX for CRS, neck swelling appeared on day 4 after infusion.DIAGNOSESLaryngoscopy showed severe laryngeal edema, which was presumed to be due to L-CRS, since there were no other apparent triggers based on history, physical examination, and computed tomography.INTERVENTIONSTracheal intubation was performed because of the risk of upper airway obstruction. Ultimately, 4 doses of tocilizumab (8 mg/kg) and 6 doses of dexamethasone (10 mg/body) were required to improve the L-CRS.OUTCOMESOn day 7, laryngeal edema improved, and the patient could be extubated.LESSONSThe lessons from this case are, first, that CAR-T cell therapy may induce laryngeal edema in L-CRS. Second, TCZ alone may be ineffective in cervical L-CRS. Third, TCZ, as well as DEX, may be inadequate. In such cases, we should recognize L-CRS and manage it early because it may eventually progress to laryngeal edema that requires securing the airway.

2024-09-03·Journal of Neuromuscular Diseases

Clinical and Genetic Heterogeneity of Nuclear Envelopathy Related Muscular Dystrophies in an Indian Cohort

Article

作者: Vengalil, Seena ; Arunachal, Gautham ; Girija, Manu Santhappan ; Nalini, Atchayaram ; Polavarapu, Kiran ; Nandeesh, Bevinahalli Nanjegowda ; Preethish-Kumar, Veeramani ; Menon, Deepak ; Baskar, Dipti ; Ganaraja, Valakunja Harikrishna ; Nashi, Saraswati

Introduction: Nuclear envelopathies occur due to structural and/or functional defects in various nuclear envelope proteins such as lamin A/C and lamin related proteins. This study is the first report on the phenotype-genotype patterns of nuclear envelopathy-related muscular dystrophies from India. Methods: In this retrospective study, we have described patients with genetically confirmed muscular dystrophy associated with nuclear envelopathy. Data on clinical, laboratory findings and muscle MRI were collected. Results: Sixteen patients were included with median age at onset of 3 years (range: 1 month – 17 years). Three genes were involved: LMNA (11, 68.75%), EMD (4, 25%) and SYNE1 (1, 6.25%). The 11 patients with LMNA variants were Congenital muscular dystrophy (MDCL)=4, Limb Girdle Muscular Dystrophy (LGMD1B)=4 and Emery-Dreifuss Muscular Dystrophy (EDMD2)=3. On muscle biopsy, one patient from each laminopathy phenotype (n = 3) revealed focal perivascular inflammatory infiltrate. Other notable features were ophthalmoparesis in one and facial weakness in one. None had cardiac involvement. Patients with EDMD1 had both upper (UL) and lower limb (LL) proximo-distal weakness. Cardiac rhythm disturbances such as sick sinus syndrome and atrial arrhythmias were noted in two patients with EDMD1. Only one patient with variant c.654_658dup (EMD) lost ambulation in the 3rd decade, 18 years after disease onset. Two had finger contractures with EMD and SYNE1 variants respectively. All patients with LMNA and SYNE1 variants were ambulant at the time of evaluation. Mean duration of illness (years) was 11.6±13 (MDCL), 3.2±1.0 (EDMD2), 10.4±12.8 (LGMD1B), 11.8±8.4 (EDMD1) and 3 (EDMD4). One patient had a novel SYNE1 mutation (c.22472dupA, exon 123) and presented with UL phenotype and prominent finger and wrist contractures. Conclusion: The salient features included ophthalmoparesis and facial weakness in LMNA, prominent finger contractures in EMD and SYNE1 and upper limb phenotype with the novel pathogenic variant in SYNE1.

项与先天性肌营养不良症，Lmna相关相关的新闻（医药）

2021-06-18

·BioSpace

Nuevocor closes US$24M Series A Financing to Advance Novel Gene Therapies for Cardiomyopathies

SINGAPORE, June 18, 2021 /PRNewswire/ -- Nuevocor, a preclinical-stage biotech company specializing in gene therapy for cardiomyopathies, has announced the completion of an oversubscribed $24 million Series A financing round. The round was co-led by EVX Ventures and Boehringer Ingelheim Venture Fund (BIVF), with EDBI, Xora Innovation, SEEDS Capital and other investors joining the syndicate. The funds will be used to accelerate the preclinical development of its lead programme, an adeno-associated virus (AAV) – based gene therapy for patients suffering from dilated cardiomyopathy (DCM) due to mutations in the lamin A/C (LMNA) gene. The company also plans to address other untreatable cardiomyopathies using their novel target discovery platform. Nuevocor's founding CEO, Dr Yann Chong Tan stated: "We are delighted to have this strong group of investors join us in developing gene therapy-based treatments that have the potential to restore cardiac function in diseased hearts. The current standard of care for dilated cardiomyopathy only serves to delay disease progression, and the only cure is to have a heart transplant. At Nuevocor, we hope to give patients a new lease of life through our technology." XQ Lin, Chairman of EVX Ventures, commented, "We are thrilled to co-lead Nuevocor's Series A round alongside other top tier investors. Nuevocor is the latest company to emerge from our venture creation ecosystem. We look forward to supporting Nuevocor's path towards the clinic and bringing new medicines to patients in need." "Nuevocor is trying to apply a very innovative and challenging approach using gene therapy for the treatment of genetically-driven, dilated cardiomyopathies. We are excited to see that the company is exploiting the potential of genetic suppressors to change the course of these diseases and hopefully to significantly extend the life span and improve the life quality of DCM patients," said Dr. Weiyi Zhang, Managing Director of BIVF Asia. Headquartered in Singapore, Nuevocor is a privately held preclinical-stage biopharmaceutical company focused on developing AAV gene therapy for the treatment of genetically defined cardiac diseases with high unmet need. Nuevocor's lead program, lamin A/C dilated cardiomyopathy (LMNA DCM) gene therapy is based on decades of research into fundamental mechanisms underlying LMNA-associated disease enabled by development of novel technologies on the part of scientific co-founders Colin Stewart and Brian Burke of the Agency for Science, Technology and Research (A*STAR). Together with AAV gene therapy and cardiac disease modelling expertise of scientific co-founders Mark Kay from Stanford University and Jianming Jiang from the National University of Singapore respectively, Nuevocor is well-positioned to treat LMNA and other genetic cardiomyopathies, amongst other cardiac diseases. "Singapore has made long-term R&D investments to drive health outcomes and economic growth, and to build the local biotech ecosystem. A*STAR is proud to have supported our spin-off Nuevocor in translating excellent science from bench to bedside so they can develop more effective gene therapies for hard-to-treat cardiac diseases, for better patient outcomes," said Professor Ng Huck Hui, Assistant Chief Executive, Biomedical Research Council, A*STAR. About LMNA dilated cardiomyopathy LMNA mutations are the #2 cause of familial DCM, affecting approximately 60,000 people in the US and EU alone. The mutation confers amongst the worst prognosis of all DCM, with increased risk of arrhythmogenic DCM and sudden cardiac death. Being an autosomal dominant disease characterized by gain-of-function of the mutant Lmna protein, conventional gene replacement therapies would be ineffective for LMNA DCM. Nuevocor's innovative approach to gene therapy circumvents this roadblock. About EVX Ventures EVX Ventures is a global VC that builds, incubates, and invests in biotech companies. With a focus on disruptive therapeutics platform technologies and novel therapeutic modalities, they invest in global technologies to redefine the therapeutics of tomorrow. Learn more at About Boehringer Ingelheim Venture Fund Created in 2010, the Boehringer Ingelheim Venture Fund GmbH (BIVF) invests in groundbreaking therapeutics-focused biotechnology companies to drive innovation in biomedical research. BIVF is searching for significant enhancements in patient care through pioneering science and its clinical translation by building long-term relationships with scientists and entrepreneurs. BIVF's focus is to target unprecedented therapeutic concepts addressing high medical needs in immuno-oncology, regenerative medicine, infectious diseases and digital health. For more information, visit . Contact: info@nuevocor.com

基因疗法