Therapeutic genetics and disease modeling in LAMA2-CMD
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PROVIDER: PRJNA951467 | ENA |
REPOSITORIES: ENA
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Project description:Therapeutic genetics and disease modeling in LAMA2-CMD
| PRJNA951468 | ENA
Project description:Epigenome editing technology holds great promise for treating diverse genetic disorders. Here we demonstrate epigenetic activation of the LAMA1 gene for the treatment of LAMA2-CMD, a severe congenital muscular dystrophy (CMD) caused by biallelic mutations in the LAMA2 gene. LAMA1 is a sister homologue that is known to compensate for the function of LAMA2. However, supplementing LAMA1 or LAMA2 gene via viral platform is not feasible due to the large size of their coding sequences. Through a single administration of our Adeno-associated virus (AAV) vector encoding all the necessary elements for epigenetic activation, we observed significant LAMA1 gene upregulation and phenotype improvements in mouse disease models. The muscle-tropic AAV capsid exhibited desired vector biodistribution and promising pharmacodynamics with good safety profiles in 2-year-old juvenile non-human primates (NHPs). Moreover, administration to 8-month-old infant NHPs demonstrated superior pharmacodynamics compared to juveniles, even at half the dose. Our approach holds broad applicability for a range of loss-of-function genetic disorders and could offer a therapeutic breakthrough where active epigenome offers clinical benefit.
2026-06-01 | GSE299372 | 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:Efficient LAMA1 gene activation by epigenome editing as a therapeutic 2 approach for LAMA2-CMD
| PRJNA1273989 | ENA
Project description:Congenital muscular dystrophy type-1A (Lama2-CMD) and Duchenne Muscular dystrophy (DMD) result from deficiencies of laminin-α2 and dystrophin proteins, respectively. Although both proteins strengthen the sarcolemma, they are implicated in clinically distinct phenotypes. We used RNA-deep sequencing (RNA-Seq) of dy2J/dy2J, Lama2-CMD mouse model, skeletal muscle at 8 weeks of age to elucidate disease pathophysiology. This study is the first report of dy2J/dy2J model whole transcriptome profile. RNA-Seq of the mdx mouse model of DMD and WT mouse was carried as well in order to enable a novel comparison of dy2J/dy2J to mdx. A large group of shared differentially expressed genes (DEG) were found in dy2J/dy2J and mdx models (1,834 common DEG, (FDR) < 0.05). Enrichment pathway analysis using Ingenuity Pathway Analysis (IPA) showed enrichment of inflammation, fibrosis, cellular movement, migration and proliferation of cells, apoptosis and necrosis in both mouse models (p-values 3E-10 – 9E-37). Via Canonical pathway analysis; Actin cytoskeleton, Integrin, ILK, NF-kB, Renin-angiotensin, calcium signaling were also enriched and upregulated in both models (FDR<0.05). Interestingly, significant downregulation of Pax7 was detected in dy2J/dy2J compared to upregulation of this key regeneration gene in mdx mice. Pax3 and Mamstr genes were also downregulated in dy2J/dy2J compared to WT mice. These results may explain the distinct disease course and severity in these models. While the mdx model at that stage shows massive regeneration, the dy2J/dy2J shows progressive dystrophic process. Our data deepen our understanding of the molecular pathophysiology and suggest new targets for additional therapies to upregulate regeneration in Lama2-CMD.
2020-04-14 | GSE126416 | GEO
Project description:LAMA2-congenital muscular dystrophy (LAMA2-CMD) is the most common congenital muscular dystrophy and is triggered by mutations in LAMA2, coding for laminin α2 chain. Several phenotypes have been associated with LAMA2-CMD, including inflammation, fibrosis and increased oxidative stress. However, it is not yet known what mechanisms are faulty, right at disease onset, which in the mouse model of LAMA2-CMD dyW/dyW has been previously established to occur between embryonic days (E) 17.5 and E18.5. This transcriptomic analysis of fetal muscle fibers perfomed at E17.5 provides critical information regarding the genes and pathways that are altered in LAMA2-CMD right at the onset of the disease.
2024-09-23 | GSE253680 | GEO
Project description:Genetic variation underlies much of human diversity, including differences in disease severity, progression, and response to therapy. Yet, most mouse models used to study genetic diseases and evaluate therapeutic interventions are maintained on a single genetic background, limiting their ability to reflect the genetic heterogeneity observed in patients. This limitation extends even to Mendelian disorders such as LAMA2-deficient congenital muscular dystrophy (LAMA2-CMD), where individuals with the same pathogenic mutation in LAMA2 gene often exhibit variable clinical presentations. Current preclinical mouse models of LAMA2-CMD, constrained by their genetic uniformity, fail to capture this variability. Goal: In this study, we aimed to develop genetically diverse mouse models that better recapitulate the spectrum of disease phenotypes seen in LAMA2-CMD. We leveraged the BXD recombinant inbred panels, which are unique families of advanced intercrosses between C57BL/6J and DBA/2J mice with well-documented SNP profiles and phenotypes, to assess the impact of genetic background on disease expressivity. Methods: We generated LAMA2-CMD mouse models carrying the same Lama2. c.271+1 G>A mutation on C57BL/6J, DBA/2J, BXD67, and BXD87 backgrounds, referred to as CMD-B6, CMD-D2, CMD-67, and CMD-87 mice, respectively. We performed longitudinal assessments of body weight, forelimb grip strength, locomotor activity, and analyzed tibialis anterior (TA) muscle contractile force, muscle histology and transcriptomic profiles across all genotypes. Results: All CMD mice exhibited failure to thrive and reduced forelimb grip strength at 8 and 25 weeks. In contrast, reductions in locomotor activity and TA muscle force were observed only in select strains. Histological analyses revealed smaller muscle fiber diameter in CMD-B6 and CMD-87 compared to their WT littermates, while CMD-67 showed no difference relative to controls. Transcriptomic profiling revealed consistent upregulation of immune-related genes and leukocyte-associated pathways across all CMD strains. Notably, CMD-67 mice uniquely exhibited concurrent enrichment of both immune- and muscle developmental pathways. In contrast, downregulated pathways were largely strain-specific and included changes in developmental and metabolic processes. Conclusion: These findings demonstrate that while body weight and forelimb weakness are consistent across genetic backgrounds, other traits such as mobility, muscle force, and muscle growth, are strongly influenced by genetic backgrounds. Moreover, strain-dependent transcriptomic signatures highlight how genetic background can influence the molecular interpretation of disease. Overall, this work establishes a novel LAMA2-CMD mouse panel as a valuable resource for future studies, including identification of disease modifiers and evaluation of therapeutic responses, and provides evidence that preclinical models incorporating genetic diversity may better translate to human disease.
2026-01-31 | GSE316106 | GEO
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:RNA-deep sequencing (RNA-Seq) analysis of dy2J/dy2J (Lama2-CMD mouse model), mdx (DMD mouse model) and Wild-type skeletal muscles
| PRJNA521797 | 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