更新于：2024-05-01

Muscular Dystrophy, Congenital, Lmna-Related

先天性肌营养不良症，Lmna相关

更新于：2024-05-01

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

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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相关相关的临床试验

NCT05743140 / RecruitingN/A

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

NCT05723315 / Not yet recruitingN/AIIT

Effect of rhBNP on Coronary Microcirculation in Patients With Acute ST-segment Elevation Myocardial Infarction After Primary PCI

The target population of this interventional study was STEMI patients. Primary discussion: Early rhBNP reduces microcirculation obstruction in STEMI patients undergoing primary PCI

开始日期2023-02-20

申办/合作机构-

NCT05394506 / RecruitingN/A

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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178

项与先天性肌营养不良症，Lmna相关相关的文献（医药）

2024-02-08·Arteriosclerosis, thrombosis, and vascular biology

p53 Acetylation Exerts Critical Roles in Pressure Overload-Induced Coronary Microvascular Dysfunction and Heart Failure in Mice.

Article

作者: Xiaochen He ; Aubrey C Cantrell ; Quinesha A Williams ; Wei Gu ; Yingjie Chen ; Jian-Xiong Chen ; Heng Zeng

BACKGROUND:

Coronary microvascular dysfunction (CMD) has been shown to contribute to cardiac hypertrophy and heart failure (HF) with preserved ejection fraction. At this point, there are no proven treatments for CMD.

METHODS:

We have shown that histone acetylation may play a critical role in the regulation of CMD. By using a mouse model that replaces lysine with arginine at residues K98, K117, K161, and K162R of p53 (p53^4KR), preventing acetylation at these sites, we test the hypothesis that acetylation-deficient p53^4KR could improve CMD and prevent the progression of hypertensive cardiac hypertrophy and HF. Wild-type and p53^4KR mice were subjected to pressure overload by transverse aortic constriction to induce cardiac hypertrophy and HF.

RESULTS:

Echocardiography measurements revealed improved cardiac function together with a reduction of apoptosis and fibrosis in p53^4KR mice. Importantly, myocardial capillary density and coronary flow reserve were significantly improved in p53^4KR mice. Moreover, p53^4KR upregulated the expression of cardiac glycolytic enzymes and Gluts (glucose transporters), as well as the level of fructose-2,6-biphosphate; increased PFK-1 (phosphofructokinase 1) activity; and attenuated cardiac hypertrophy. These changes were accompanied by increased expression of HIF-1α (hypoxia-inducible factor-1α) and proangiogenic growth factors. Additionally, the levels of SERCA-2 were significantly upregulated in sham p53^4KR mice, as well as in p53^4KR mice after transverse aortic constriction. In vitro, p53^4KR significantly improved endothelial cell glycolytic function and mitochondrial respiration and enhanced endothelial cell proliferation and angiogenesis. Similarly, acetylation-deficient p53^4KR significantly improved coronary flow reserve and rescued cardiac dysfunction in SIRT3 (sirtuin 3) knockout mice.

CONCLUSIONS:

Our data reveal the importance of p53 acetylation in coronary microvascular function, cardiac function, and remodeling and may provide a promising approach to improve hypertension-induced CMD and to prevent the transition of cardiac hypertrophy to HF.

2023-11-09·Biochimica et biophysica acta. Molecular basis of disease

LMNA-related muscular dystrophy involving myoblast proliferation and apoptosis through the FOXO1/GADD45A pathway.

Article

作者: Yue Wu ; Xintong Zhu ; Wen Jiang ; Jia Li ; Hongyan Li ; Kun Zhang ; Yixuan Yang ; Song Qu ; Xingying Guan ; Yun Bai ; Hong Guo ; Limeng Dai

LMNA-related muscular dystrophy is a major disease phenotype causing mortality and morbidity in laminopathies, but its pathogenesis is still unclear. To explore the molecular pathogenesis, a knock-in mouse harbouring the Lmna-W520R mutation was modelled. Morphological and motor functional analyses showed that homozygous mutant mice revealed severe muscular atrophy, profound motor dysfunction, and shortened lifespan, while heterozygotes showed a variant arrangement of muscle bundles and mildly reduced motor capacity. Mechanistically, the FOXO1/GADD45A pathway involving muscle atrophy processes was found to be altered in vitro and in vivo assays. The expression levels of FOXO1 and its downstream regulatory molecule GADD45A significantly increased in atrophic muscle tissue. The elevated expression of FOXO1 was associated with decreased H3K27me3 in its gene promotor region. Overexpression of GADD45A induced apoptosis and cell cycle arrest of myoblasts in vitro, and it could be partially restored by the FOXO1 inhibitor AS1842856, which also slowed the muscle atrophy process with improved motor function and prolonged survival time of homozygous mutant mice in vivo. Notably, the inhibitor also partly rescued the apoptosis and cell cycle arrest of hiPSC-derived myoblasts harbouring the LMNA-W520R mutation. Together, these data suggest that the activation of the FOXO1/GADD45A pathway contributes to the pathogenesis of LMNA-related muscle atrophy, and it might serve as a potential therapeutic target for laminopathies.

2023-10-01·Quantitative imaging in medicine and surgery

Evaluation of left ventricular diastolic function in patients with coronary microvascular dysfunction via cardiovascular magnetic resonance feature tracking.

Article

作者: Huihui Kong ; Jiaxin Cao ; Jinfan Tian ; Jingwen Yong ; Jing An ; Lijun Zhang ; Xiantao Song ; Yi He

Background:

Coronary microvascular dysfunction (CMD) has been suggested to be one of the pathologic mechanisms contributing to heart failure with preserved left ventricular ejection fraction (LVEF) and left ventricular (LV) diastolic dysfunction. We therefore aimed to evaluate LV diastolic function in patients with CMD using cardiovascular magnetic resonance feature tracking (CMR-FT).

Methods:

We prospectively enrolled 115 patients referred to cardiology clinics for chest pain assessment who subsequently underwent coronary computed tomography angiogram and stress perfusion CMR. CMD was defined as the presence of subendocardial inducible ischemia detected through visual assessment. LV diastolic function was evaluated using CMR-derived volume-time curves and CMR-FT parameters. The former included early peak filling rate (PFR) and time to PFR; the latter included LV global/regional peak longitudinal diastolic strain rate (LDSR), circumferential diastolic strain rate (CDSR), and radial diastolic strain rate (RDSR).

Results:

A total of 92 patients with 1,312 segments were eventually included. Of these, 19 patients were classified as non-CMD (48.8±11.2 years; 63.2% male) and 73 as with CMD (52.3±11.9 years; 54.8% male). The LVEFs were similar and preserved in both groups (P=0.266). At the per-patient level, no differences were observed in PFR, time to PFR, or LV global diastolic strain rates between the two groups. At the per-segment level, 51% (665/1,312) of the myocardial segments were classified as CMD, whereas 49% (647/1,312) were classified as non-CMD. CMD segments showed significantly lower regional CDSR (P=0.019) and RDSR (P=0.006) compared with non-CMD segments.

Conclusions:

Despite normal LV ejection fraction in CMD patients, decreased LV diastolic function in CMD myocardial segments indicates early diastolic impairment.

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