Therapeutic genetics and disease modeling in LAMA2-CMD
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PROVIDER: PRJNA951468 | ENA |
REPOSITORIES: ENA
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Project description:Therapeutic genetics and disease modeling in LAMA2-CMD
| PRJNA951467 | ENA
Project description:Adeno-associated virus (AAV)-mediated gene replacement holds promise for treating genetic diseases but faces challenges due to AAV’s limited packaging capacity and potential immune responses to transgene products, especially in patients lacking endogenous protein. LAMA2-related muscular dystrophy (LAMA2 MD), a severe congenital disorder caused by loss of laminin-α2, presents both hurdles: the LAMA2 gene exceeds AAV capacity, and severely affected patients do not produce the native protein. Here, we developed an AAV-based therapy using two engineered linker proteins derived from endogenously expressed components. These linker proteins restore laminin receptor binding and polymerization, enabling reassembly of a functional basement membrane. Dual AAV delivery of the linkers in a severe LAMA2 MD mouse model resulted in robust expression and significant improvements in muscle histology and function. Employing myotropic capsids enabled therapeutic efficacy at lower vector doses. However, muscle-specific targeting unmasked a LAMA2-related peripheral neuropathy. To address this, we expressed one linker under a muscle-specific promoter and the other under a ubiquitous promoter, delivered via AAV9 or AAV8. This approach achieved near-complete phenotypic restoration when administered neonatally and provided significant benefit when given at progressed disease stages. Our strategy offers a mutation-independent, size-compatible, and potentially immune-tolerable treatment for LAMA2 MD with broad clinical potential.
2026-02-03 | GSE312724 | GEO
Project description:LAMA2-deficient congenital muscular dystrophy (LAMA2-CMD) is a severe neuromuscular disorder caused by LAMA2 mutations, leading to muscle degeneration, chronic inflammation, and fibrosis. Histopathological assessment of muscle biopsies from LAMA2-CMD patients and mouse models show clear evidence of inflammation, which oftentimes are regarded as one of the typical dystrophic hallmarks. However, the composition of immune cells in the laminin-deficient muscles remain understood. Consequently, targeted pharmacological intervention to reduce inflammation has never been tested. In this study, we characterized the immune landscape in dyW mouse model of LAMA2-CMD using RNA sequencing and flow cytometry. Transcriptomic analysis of dyW quadriceps identified 2,143 differentially expressed genes, with most of the upregulated genes belong to immune-related pathways. Lgals3 (Galectin-3) was significantly upregulated (log₂FC = 4.27, FDR p-value= 9.21x10-88) and identified as a key upstream regulator of the immune-related pathways. In parallel, flow cytometry analysis revealed elevated leukocyte (CD45⁺) infiltration, with macrophages as the predominant cell population. Pro-inflammatory (M1) macrophages were increased, whereas anti-inflammatory (M2) macrophages remained low, indicating persistent inflammation and impaired resolution. Interestingly, Galectin-3+ macrophages were significantly enriched, which strongly suggest that Galectin-3 drives inflammation in LAMA2-CMD. Treatment of dyW mice with TD-139, a Galectin-3 inhibitor, reduced leukocyte infiltration, decreased Galectin-3+ macrophages, and shifted macrophage polarization toward an M2 anti-inflammatory profile. In addition, RNA sequencing of TD-139-treated dyW muscles showed upregulation of muscle repair pathways and downregulation of fibrosis-related genes. These findings establish Galectin-3-expressing macrophages as an important player in LAMA2-CMD pathophysiology. Importantly, it warrants further investigation on the therapeutic potential of TD-139-mediated inhibition of Galectin-3, including long-term preclinical study, in LAMA2-CMD and potentially other dystrophic conditions driven by chronic immune activation.
2025-03-25 | GSE292894 | GEO
Project description:Alzheimer's Disease Genetics Consortium
| PRJNA155369 | ENA
Project description:Tissue-Engineered Disease Modeling of Lymphangioleiomyomatosis Exposes a Therapeutic Vulnerability to HDAC Inhibition
| PRJNA742011 | ENA
Project description:Genetics of Inherited Muscle Disease
| PRJNA215657 | ENA
Project description:The extracellular matrix protein laminin-α2 is essential for preserving the integrity of skeletal muscle fibers during contraction. Its importance is reflected by the severe, congenital LAMA2-related muscular dystrophy (LAMA2 MD) caused by loss-of-function mutations in the LAMA2 gene. While laminin-α2 has an established role in structurally supporting muscle fibers, it remains unclear whether it exerts additional functions that contribute to the maintenance of skeletal muscle integrity. Submitted transcriptomic data represents gene expression profile of control and LAMA2-deficient human myogenic precursor cells derived from induced pluripotent stem cells which was analyzed to better understand the role of laminin-α2 in human cells.
2025-09-14 | GSE307443 | GEO
Project description:Lymphangioleiomyomatosis (LAM) is a rare disease involving cystic lung destruction by invasive LAM cells. These cells harbor loss-of-function mutations in TSC2, conferring hyperactive mTORC1 signaling. Here, tissue engineering tools are employed to model LAM and identify new therapeutic candidates. Biomimetic hydrogel culture of LAM cells is found to recapitulate the molecular and phenotypic characteristics of human disease more faithfully than culture on plastic. A 3D drug screen is conducted, identifying histone deacetylase (HDAC) inhibitors as anti-invasive agents that are also selectively cytotoxic toward TSC2−/− cells. The anti-invasive effects of HDAC inhibitors are independent of genotype, while selective cell death is mTORC1-dependent and mediated by apoptosis. Genotype-selective cytotoxicity is seen exclusively in hydrogel culture due to potentiated differential mTORC1 signaling, a feature that is abrogated in cell culture on plastic. Importantly, HDAC inhibitors block invasion and selectively eradicate LAM cells in vivo in zebrafish xenografts. These findings demonstrate that tissue-engineered disease modeling exposes a physiologically relevant therapeutic vulnerability that would be otherwise missed by conventional culture on plastic. This work substantiates HDAC inhibitors as possible therapeutic candidates for the treatment of patients with LAM and requires further study.
2023-07-06 | GSE179044 | GEO
Project description:Genetics of Charcot-Marie-Tooth Disease
| PRJNA382008 | ENA
Project description:CIDR: Genetics of Graft-vs-Host Disease
| PRJNA671477 | ENA