RARE DISEASE
Laminin subunit alpha 2-related congenital muscular dystrophy
Laminin subunit alpha 2-related congenital muscular dystrophy
Laminin subunit alpha 2-related congenital muscular dystrophy
Synonyms: CMD1A, Congenital muscular dystrophy due to laminin alpha2 deficiency, Congenital muscular dystrophy type 1A, MDC1A, Merosin-negative congenital muscular dystrophy
Synonyms: CMD1A, Congenital muscular dystrophy due to laminin alpha2 deficiency, Congenital muscular dystrophy type 1A, MDC1A, Merosin-negative congenital muscular dystrophy
Synonyms: CMD1A, Congenital muscular dystrophy due to laminin alpha2 deficiency, Congenital muscular dystrophy type 1A, MDC1A, Merosin-negative congenital muscular dystrophy
Drug discovery
3
drugs
With orphan designations
Overview
Laminin subunit alpha 2-related congenital muscular dystrophy (LAMA2-CMD) is an autosomal recessive disorder caused by mutations in the LAMA2 gene, leading to partial or complete deficiency of laminin-α2 (merosin). Clinical features range from severe congenital hypotonia, joint contractures, and respiratory insufficiency (MDC1A) to milder limb-girdle muscular dystrophy with late-onset proximal weakness. Central nervous system involvement includes white matter abnormalities on MRI, while serum creatine kinase (CK) levels typically exceed 1,000 IU/L [1][9][14].
Burden
Severe forms: 30% mortality in the first decade due to respiratory failure [14][17].
Progressive disability: Contractures, scoliosis, cardiac involvement (dilated cardiomyopathy), and epilepsy in 30% of cases [4][14][15].
High caregiving demands: Multidisciplinary management and lifelong assistance required [17][18].
Therapies
Supportive care: Respiratory support, physiotherapy, and scoliosis management [1][17].
Experimental approaches: Gene therapy, laminin-111 protein replacement, and anti-apoptotic small molecules (e.g., omigapil in phase 1 trials) [3][7][19].
Preclinical research: CRISPR/Cas9-mediated exon skipping and artificial linker proteins to stabilize muscle membranes [7][20].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
192 drug discovery papers about Laminin subunit alpha 2-related congenital muscular dystrophy, with 3 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
192 drug discovery papers about Laminin subunit alpha 2-related congenital muscular dystrophy, with 3 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
gene therapies
2026-05-26 | Unexplained multiorgan fat embolism syndrome in a 10-year-old child with LAMA2-related congenital muscular dystrophy
A 10-year-old cachectic boy who was delivered at 29 weeks' gestation following an uneventful first pregnancy was diagnosed with laminin subunit alpha-2 (LAMA2)-related (merosin deficient) congenital muscular dystrophy at the age of 5 years. A week before his last hospitalization, he was treated with antibiotics for respiratory infection. A day before his death, he vomited and was visibly irritable. He collapsed during rehabilitation treatment and became unresponsive. He did not sustain any injuries. The patient presented to the hospital with tachycardia, elevated cardiac enzymes, and respiratory insufficiency. Computed tomography of the brain revealed irregular hypodense areas in the supratentorial region and the lungs showed ground glass opacity. He required mechanical ventilation and high doses of vasopressors. The patient died 12 h after admission due to circulatory collapse. Postmortem histologic examination revealed skeletal muscle and myocardial degeneration, and multiorgan fat embolism involving the lungs, heart, kidneys and brain. Death was attributed to cardiovascular collapse due to heart failure associated with a genetically determined muscle disease with unexplained fat embolism syndrome.
2026-03-02 | Expanding the phenotypic spectrum of LAMA2-related disorders: Axonal neuropathy in the absence of muscular dystrophy.
The LAMA2 gene encodes the alpha-2 chain of laminin-2, a key component of the basement membrane that maintains muscle fiber stability and integrity. Mutations in this gene are linked with LAMA2-related muscular dystrophies, which includes congenital muscular dystrophy type 1 A (MDC1A) and limb-girdle muscular dystrophy autosomal recessive 23 (LGMDR23). Here, we present two siblings from one of 200 unrelated Iranian Charcot-Marie-Tooth (CMT) families, exhibiting axonal sensorimotor polyneuropathy, without any clinical signs of muscular dystrophy, carrying a homozygous variant in the LAMA2 gene. Following clinical and paraclinical assessments of the patients, genomic DNA was extracted from peripheral blood samples. Whole-exome sequencing (WES) was employed to identify potential genetic variants, and Sanger sequencing was subsequently used to confirm the detected variant. In silico prediction tools were further applied to evaluate the potential pathogenicity and functional impact of the identified variant. A homozygous missense variant in the LAMA2 gene, c.2916 T > G; p.Phe972Leu, was identified and co-segregated with the disease status within the family, whose neurological assessments confirmed axonal sensorimotor polyneuropathy. So far, only two studies have reported LAMA2 variants in patients only manifesting a neuropathy phenotype. None of these studies reported the detailed clinical data of their cases. However, our study provides further evidence of the association between LAMA2 mutations and neuropathy, and includes comprehensive clinical and paraclinical characterization of the affected individuals. Our findings underscore the importance of comprehensive genomic testing in diagnosing neuromuscular disorders and expand the phenotypic spectrum associated with LAMA2 mutations.
2026-02-04 | Dual AAV gene therapy using laminin-linking proteins ameliorates muscle and nerve defects in LAMA2-related muscular dystrophy.
Adeno-associated virus (AAV)-mediated gene replacement holds promise for treating genetic diseases but faces challenges due to the 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.
2026-01-22 | LAMA2 variants associated with muscular dystrophy, brain structural abnormalities, and epilepsy: a genotype-phenotype study.
LAMA2-related congenital muscular dystrophy (LAMA2-MD) is a genetically heterogeneous disorder defined by progressive muscle weakness, brain structural abnormalities, epilepsy, and multisystem involvement. The primary goal of this study was to characterize the clinical features, temporal progression, and genotype-phenotype correlations of LAMA2-MD. Medical records of patients with genetically confirmed LAMA2-MD were extracted from a clinical data repository and analyzed retrospectively. Clinical manifestations, laboratory findings, and neuroimaging features were systematically reviewed and compared across different age groups. Variant data were retrieved from public databases to perform comprehensive genetic analyses. A total of five patients (two males and three females) were enrolled, delayed motor milestones and varying degrees of ankle contractures and persistent motor impairment in all patients were the initial presenting symptom at diagnosis in all cases, and two patients also exhibited cognitive delays. Laboratory analysis of muscle enzymes showed varying degrees of abnormalities, with creatine kinase (CK) levels displaying the most significant elevation. Cranial magnetic resonance imaging (MRI) revealed symmetrical white matter abnormalities in four patients. Seizures were documented in three school-aged patients. All patients carried compound heterozygous variants in the LAMA2 gene. A literature review indicated that the most common variant types were stop-gain and missense variants: stop-gain variants were predominantly associated with complete merosin deficiency (MDC1A), whereas missense variants typically correlated with late-onset limb-girdle muscular dystrophy. LAMA2-MD exhibits a broad phenotypic spectrum and a progressive disease course. Early manifestations include muscle weakness, delayed achievement of developmental milestones, joint contractures, seizures and characteristic intracranial abnormalities.
2025-12-24 | Efficient LAMA1 Gene Activation by Epigenome Editing as a Therapeutic Approach for LAMA2-CMD.
Epigenome editing technology holds great promise for treating diverse genetic disorders. In this study, we demonstrate epigenetic activation of the LAMA1 gene for the treatment of LAMA2-CMD, a severe congenital muscle dystrophy (CMD) caused by biallelic mutations in the LAMA2 gene. LAMA1 is a sister homolog 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 nonhuman primates (NHPs). Moreover, administration to 8-month-old infant NHPs demonstrated superior pharmacodynamics compared with 2-year-old 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.
proteins
2023-12-21 | Identification of a short, single site matriglycan that maintains neuromuscular function in the mouse
Matriglycan (-1,3-β-glucuronic acid-1,3-α-xylose-) is a polysaccharide that is synthesized on α-dystroglycan, where it functions as a high-affinity glycan receptor for extracellular proteins, such as laminin, perlecan and agrin, thus anchoring the plasma membrane to the extracellular matrix. This biological activity is closely associated with the size of matriglycan. Using high-resolution mass spectrometry and site-specific mutant mice, we show for the first time that matriglycan on the T317/T319 and T379 sites of α-dystroglycan are not identical. T379-linked matriglycan is shorter than the previously characterized T317/T319-linked matriglycan, although it maintains its laminin binding capacity. Transgenic mice with only the shorter T379-linked matriglycan exhibited mild embryonic lethality, but those that survived were healthy. The shorter T379-linked matriglycan exists in multiple tissues and maintains neuromuscular function in adult mice. In addition, the genetic transfer of α-dystroglycan carrying just the short matriglycan restored grip strength and protected skeletal muscle from eccentric contraction-induced damage in muscle-specific dystroglycan knock-out mice. Due to the effects that matriglycan imparts on the extracellular proteome and its ability to modulate cell-matrix interactions, our work suggests that differential regulation of matriglycan length in various tissues optimizes the extracellular environment for unique cell types.
2022-07-11 | Amelioration of muscle and nerve pathology of Lama2-related dystrophy by AAV9-laminin-αLN linker protein.
LAMA2 deficiency, resulting from a defective or absent laminin α2 subunit, is a common cause of congenital muscular dystrophy. It is characterized by muscle weakness from myofiber degeneration and neuropathy from Schwann cell amyelination. Previously it was shown that transgenic muscle-specific expression of αLNNd, a laminin γ1-binding linker protein that enables polymerization in defective laminins, selectively ameliorates the muscle abnormality in mouse disease models. Here, adeno-associated virus was used to deliver linker mini-genes to dystrophic dy2J/dy2J mice for expression of αLNNd in muscle, or αLNNdΔG2', a shortened linker, in muscle, nerve, and other tissues. Linker and laminin α2 levels were higher in αLNNdΔG2'-treated mice. Both αLNNd- and αLNNdΔG2'-treated mice exhibited increased forelimb grip strength. Further, αLNNdΔG2'-treated mice achieved hind limb and all-limb grip strength levels approaching those of WT mice as well as ablation of hind limb paresis and contractures. This was accompanied by restoration of sciatic nerve axonal envelopment and myelination. Improvement of muscle histology was evident in the muscle-specific αLNNd-expressing mice but more extensive in the αLNNdΔG2'-expressing mice. The results reveal that an αLN linker mini-gene, driven by a ubiquitous promoter, is superior to muscle-specific delivery because of its higher expression that extends to the peripheral nerve. These studies support a potentially novel approach of somatic gene therapy.
2022-05-20 | Nerve pathology is prevented by linker proteins in mouse models for LAMA2-related muscular dystrophy
ABSTRACT LAMA2 -related muscular dystrophy (LAMA2 MD or MDC1A) is caused by mutations in the LAMA2 gene encoding laminin-α2, the long chain of several heterotrimeric laminins. Laminins are essential components of the extracellular matrix that interface with underlying cells. The pathology of LAMA2 MD patients is dominated by the severe muscular dystrophy but also involves other tissues. In the dy W / dy W mouse model for LAMA2 MD, amelioration of muscle function by skeletal muscle-specific expression of the two linker proteins, mini-agrin and αLNNd, is sufficient to greatly increase survival. In such survivors, the phenotype is dominated by the hindlimb paralysis. We now show that ubiquitous expression of the two linker proteins in dy W / dy W mice improves muscle function and prevents hindlimb paralysis. The same ameliorating effect of the linker proteins was seen in dy 3K / dy 3K mice, which represent the most severe mouse model of LAMA2 MD. In summary, these data show that the two linker proteins can compensate the loss of laminin-α2 in many, if not all tissues affected in LAMA2 MD.
2020-05-20 | Human Laminin-111 and Laminin-211 protein therapy prevents muscle disease progression in an immune deficient mouse model of LAMA2-CMD
Abstract Background Laminin-α2 related Congenital Muscular dystrophy (LAMA2-CMD) is a devastating genetic disease caused by mutations in the LAMA2 gene. These mutations result in progressive muscle wasting and inflammation leading to delayed milestones, and reduced lifespan in affected patients. There is currently no cure or treatment for LAMA2-CMD. Preclinical studies have demonstrated that mouse Laminin-111 can serve as an effective protein replacement therapy in a mouse model of LAMA2-CMD. Methods In this study, we generated a novel immunocompromised dy W mouse model of LAMA2-CMD to study the role the immune system plays in muscle disease progression. We used this immune deficient dy W mouse model to test the therapeutic benefits of recombinant human laminin-111 and laminin-211 protein therapy on Laminin-α2 deficient muscle disease progression. Results We show that immune deficient Laminin-α2 null mice demonstrate subtle differences in muscle regeneration compared to immune competent animals during early disease stages, but overall exhibit a comparable muscle disease progression. We found human laminin-111 and laminin-211 could serve as effective protein replacement strategies with mice showing improvements in muscle pathology and function. We observed that human laminin-111 and laminin-211 exhibit differences on satellite and myoblast cell populations and differentially affect muscle repair. Conclusions This study describes the generation of a novel immune deficient mouse model that allows investigation of the role the immune system plays in LAMA2-CMD. This model can be used to assess the therapeutic potential of heterologous therapies that would illicit an immune response. Using this model, we show that recombinant human Laminin-111 can serve as effective protein replacement therapy for the treatment of LAMA2-CMD.
2019-12-13 | Linker Protein Repair of LAMA2 Dystrophic Neuromuscular Basement Membranes
An understanding of basement membrane (BM) assembly at a molecular level provides a foundation with which to develop repair strategies for diseases with defects of BM structure. As currently understood, laminins become anchored to cell surfaces through receptor-mediated interactions and polymerize. This provisional matrix binds to proteoglycans, nidogens and type IV collagen to form a mature BM. Identification of BM binding domains and their binding targets has enabled investigators to engineer proteins that link BM components to modify and improve their functions. This approach is illustrated by the development of two linker proteins to repair the LAMA2-deficient muscular dystrophy (LAMA2-MD). Dystrophy-causing mutations of the LAMA2 gene product (Lm alpha2) disrupt the BM molecular architecture, destabilizing it. In a mild ambulatory type of the dystrophy, Alpha2LN mutations in laminin-211 prevents polymerization. In the more common and severe non-ambulatory type (MDC1A), an absent Lm2 subunit is re-placed by the naturally-occurring Lm alpha4 subunit that is normally largely confined to the micro-vasculature. The compensatory laminin, however, is a poor substitute because it neither polymerizes nor binds adequately to the anchoring receptor -dystroglycan. A chimeric laminin-binding protein called alphaLNNd enables laminins with defective or absent LN domains to polymerize while another engineered protein, miniagrin (mag), promotes efficient alpha-dystroglycan receptor-binding in otherwise weakly adhesive laminins. Alone, LNNd enables Lm211 with a self-assembly defect to polymerize and was used to ameliorate a mouse model of the ambulatory dystrophy. Together, these linker proteins alter Lm411 such that it both polymerizes and binds DG such that it properly assembles. This combination was used to ameliorate a mouse model of the non-ambulatory dystrophy in which Lm411 replaced Lm211 as seen in the human disease. Collectively, these studies pave the way for the development of somatic gene delivery of repair proteins for treatment of LAMA2-MD. The studies further suggest a more general approach of linker-protein mediated repair in which a variety of existing BM protein domains can be combined together to stabilize BMs in other diseases.
oligonucleotides
2025-07-28 | Exon-Skipping Using Antisense Oligonucleotides for Laminin-Alpha2-Deficient Muscular Dystrophy.
Phosphorodiamidate morpholino oligomer (PMO)-mediated exon-skipping is among the more promising approaches available for the treatment of several neuromuscular disorders, including Duchenne muscular dystrophy. The main weakness of this treatment arises from the low efficiency and sporadic nature of the delivery of neutrally charged PMOs into muscle fibres, the mechanism of which is unknown. Recently, using wild-type and dystrophic mdx52 mice, we showed that muscle fibres took up PMOs more efficiently during myotube formation. Interestingly, we detected PMO mainly in embryonic myosin heavy chain-positive regenerating fibres through in situ hybridisation. Next, we tested the therapeutic potential of PMOs in laminin-alpha2 (laminin-α2) chain-null dy3K/dy3K mice, a model of merosin-deficient congenital muscular dystrophy 1A (MDC1A or LAMA2-related muscular dystrophy: LAMA2-MD) with active muscle regeneration. We confirmed the recovery of the laminin-α2 chain following the skipping of the mutated exon 4 in dy3K/dy3K mice, which prolonged the lifespan of the animals slightly. These findings support the theory that PMO entry into fibres is dependent on the developmental stage in myogenesis rather than on dystrophin-deficient muscle membranes, and recommend a platform for the future development of PMO-mediated therapies for a variety of muscular disorders, such as LAMA2-MD, that involve active muscle regeneration. Herein, we describe the methods for PMO transfection/injection and the evaluation of the efficacy of exon-skipping in the laminin-α2-deficient dy3K/dy3K mouse model both in vitro and in vivo.
2025-07-28 | An Overview of Recent Advances and Clinical Applications of Exon Skipping and Splice Modulation for Muscular Dystrophy and Various Genetic Diseases.
Exon skipping and splice modulation using synthetic antisense oligonucleotides (AONs) are therapeutic approaches to delay or arrest the progression of genetic diseases. AON-mediated exon skipping modifies pre-mRNA splicing to correct the reading frame of genes responsible for disease and modulate a protein structure, providing therapeutic benefits. Studied for over two decades, exon skipping AONs have received conditional marketing authorization for Duchenne muscular dystrophy (DMD). The US Food and Drug Administration (FDA) has granted accelerated approval for four AONs to skip a single DMD exon for treating patients with DMD: eteplirsen for exon 51 skipping, golodirsen and viltolarsen for exon 53 skipping, and casimersen for exon 45 skipping. Various preclinical and clinical trials are underway with AONs targeting other exons and ones loading bioconjugates, such as cell-penetrating peptides and antibodies to enhance the exon skipping ability. Besides AONs targeting pre-mRNA, genomic DNA target exon skipping using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) technology, which holds promise in current preclinical trials for DMD. In hopes of achieving clinical success parallel to DMD, exon skipping and splice modulation are studied in other muscular dystrophies, such as Fukuyama congenital muscular dystrophy (FCMD), dysferlinopathy including limb-girdle muscular dystrophy type 2B (LGMD2B), Miyoshi myopathy (MM), and distal anterior compartment myopathy (DMAT), myotonic dystrophy, and merosin-deficient congenital muscular dystrophy type 1A (MDC1A). Splice-modulating AONs have also been extensively tested in other inherited diseases, such as Usher syndrome, dystrophic epidermolysis bullosa (DEB), fibrodysplasia ossificans progressiva (FOP), and allergic diseases. This chapter will introduce the developmental status of exon skipping and splice-modulating therapies for genetic diseases.
2022-06-01 | Skeletal muscle-specific overexpression of miR-486 limits mammary tumor-induced skeletal muscle functional limitations
miR-486 is a myogenic microRNA, and its reduced skeletal muscle expression is observed in muscular dystrophy. Transgenic overexpression of miR-486 using muscle creatine kinase promoter (MCK-miR-486) partially rescues muscular dystrophy phenotype. We had previously demonstrated reduced circulating and skeletal muscle miR-486 levels with accompanying skeletal muscle defects in mammary tumor models. To determine whether skeletal muscle miR-486 is functionally similar in dystrophies and cancer, we performed functional limitations and biochemical studies of skeletal muscles of MMTV-Neu mice that mimic HER2+ breast cancer and MMTV-PyMT mice that mimic luminal subtype B breast cancer and these mice crossed to MCK-miR-486 mice. miR-486 significantly prevented tumor-induced reduction in muscle contraction force, grip strength, and rotarod performance in MMTV-Neu mice. In this model, miR-486 reversed cancer-induced skeletal muscle changes, including loss of p53, phospho-AKT, and phospho-laminin alpha 2 (LAMA2) and gain of hnRNPA0 and SRSF10 phosphorylation. LAMA2 is a part of the dystrophin-associated glycoprotein complex, and its loss of function causes congenital muscular dystrophy. Complementing these beneficial effects on muscle, miR-486 indirectly reduced tumor growth and improved survival, which is likely due to systemic effects of miR-486 on production of pro-inflammatory cytokines such as IL-6. Thus, similar to dystrophy, miR-486 has the potential to reverse skeletal muscle defects and cancer burden.
2020-05-18 | Recent advancements in exon-skipping therapies using antisense oligonucleotides and genome editing for the treatment of various muscular dystrophies.
Muscular dystrophy is a group of genetic disorders characterised by degeneration of muscles. Different forms of muscular dystrophy can show varying phenotypes with a wide range of age, severity and location of muscle deterioration. Many palliative care options are available for muscular dystrophy patients, but no curative treatment is available. Exon-skipping therapy aims to induce skipping of exons with disease-causing mutations and/or nearby exons to restore the reading frame, which results in an internally truncated, partially functional protein. In antisense-mediated exon-skipping synthetic antisense oligonucleotide binds to pre-mRNA to induce exon skipping. Recent advances in exon skipping have yielded promising results; the US Food and Drug Administration (FDA) approved eteplirsen (Exondys51) as the first exon-skipping drug for the treatment of Duchenne muscular dystrophy, and in vivo exon skipping has been demonstrated in animal models of dysferlinopathy, limb-girdle muscular dystrophy type 2C and congenital muscular dystrophy type 1A. Novel methods that induce exon skipping utilizing Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) are also being developed where splice site mutations are created within the genome to induce exon skipping. Challenges remain as exon-skipping agents can have deleterious non-specific effects and different in-frame deletions show phenotypic variance. This article reviews the state of the art of exon skipping for treating muscular dystrophy and discusses challenges and future prospects.
2018-08-31 | Tips to Design Effective Splice-Switching Antisense Oligonucleotides for Exon Skipping and Exon Inclusion
Antisense-mediated exon skipping and exon inclusion have proven to be powerful tools for treating neuromuscular diseases. The approval of Exondys 51 (eteplirsen) and Spinraza (nusinersen) for the treatment of patients with Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA) was the most noteworthy accomplishment in 2016. Exon skipping uses short DNA-like molecules called antisense oligonucleotides (AONs) to correct the disrupted reading frame, allowing the production of functional quasi-dystrophin proteins, and ameliorate the progression of the disease. Exon inclusion for SMA employs an AON targeting an intronic splice silencer site to include an exon which is otherwise spliced out. Recently, these strategies have also been explored in many other genetic disorders, including dysferlin-deficient muscular dystrophy (e.g., Miyoshi myopathy; MM, limb-girdle muscular dystrophy type 2B; LGMD2B, and distal myopathy with anterior tibial onset; DMAT), laminin α2 chain (merosin)-deficient congenital muscular dystrophy (MDC1A), sarcoglycanopathy (e.g., limb-girdle muscular dystrophy type 2C; LGMD2C), and Fukuyama congenital muscular dystrophy (FCMD). A major challenge in exon skipping and exon inclusion is the difficulty in designing effective AONs. The mechanism of mRNA splicing is highly complex, and the efficacy of AONs is often unpredictable. We will discuss the design of effective AONs for exon skipping and exon inclusion in this chapter.
small molecules
2023-10-19 | Artificial intelligence and the analysis of cryo-EM data provide structural insight into the molecular mechanisms underlying LN-lamininopathies
Laminins (Lm) are major components of basement membranes (BM), which polymerize to form a planar lattice on cell surface. Genetic alternations of Lm affect their oligomerization patterns and lead to failures in BM assembly manifesting in a group of human disorders collectively defined as Lm N-terminal domain lamininopathies (LN-lamininopathies). We have employed a recently determined cryo-EM structure of the Lm polymer node, the basic repeating unit of the Lm lattice, along with structure prediction and modeling to systematically analyze structures of twenty-three pathogenic Lm polymer nodes implicated in human disease. Our analysis provides the detailed mechanistic explanation how Lm mutations lead to failures in Lm polymerization underlining LN-lamininopathies. We propose the new categorization scheme of LN-lamininopathies based on the insight gained from the structural analysis. Our results can help to facilitate rational drug design aiming in the treatment of Lm deficiencies.
2023-05-11 | Vemurafenib improves muscle histopathology in a mouse model of LAMA2-related congenital muscular dystrophy.
Laminin-α2-related congenital muscular dystrophy (LAMA2-CMD) is a neuromuscular disease affecting around 1-9 in 1,000,000 children. LAMA2-CMD is caused by mutations in the LAMA2 gene resulting in the loss of laminin-211/221 heterotrimers in skeletal muscle. LAMA2-CMD patients exhibit severe hypotonia and progressive muscle weakness. Currently, there is no effective treatment for LAMA2-CMD and patients die prematurely. The loss of laminin-α2 results in muscle degeneration, defective muscle repair and dysregulation of multiple signaling pathways. Signaling pathways that regulate muscle metabolism, survival and fibrosis have been shown to be dysregulated in LAMA2-CMD. As vemurafenib is a US Food and Drug Administration (FDA)-approved serine/threonine kinase inhibitor, we investigated whether vemurafenib could restore some of the serine/threonine kinase-related signaling pathways and prevent disease progression in the dyW-/- mouse model of LAMA2-CMD. Our results show that vemurafenib reduced muscle fibrosis, increased myofiber size and reduced the percentage of fibers with centrally located nuclei in dyW-/- mouse hindlimbs. These studies show that treatment with vemurafenib restored the TGF-β/SMAD3 and mTORC1/p70S6K signaling pathways in skeletal muscle. Together, our results indicate that vemurafenib partially improves histopathology but does not improve muscle function in a mouse model of LAMA2-CMD.
2020-02-04 | Fibrogenesis in LAMA2-Related Muscular Dystrophy Is a Central Tenet of Disease Etiology
LAMA2-related congenital muscular dystrophy, also known as MDC1A, is caused by loss-of- function mutations in the alpha2 chain of Laminin-211. Loss of this protein interupts the connection between the muscle cell and its extracellular environment and results in an aggressive, congenital-onset muscular dystrophy characterized by severe hypotonia, lack of independent ambulation, and early mortality driven by respiratory complications and/or failure to thrive. Of the pathomechanisms of MDC1A, the earliest and most prominent is widespread and rampant fibrosis. Here, we will discuss some of the key drivers of fibrosis including TGF-beta and Renin-Angiotensin System signaling,consequences of these pathways including myofibroblast transdifferentiation and matrix remodeling. We will also highlight some of the differences in fibrogenesis in Congenital Muscular Dystrophy (CMD) with that seen in more classical Duchenne Muscular Dystrophy (DMD). Finally, we will connect the key signaling pathawys in the pathogenesis of MDC1A to the current status of the therapeutic approaches that have been tested in the preclinical models of MDC1A to treat fibrosis.
2018-11-02 | Effects of metformin on congenital muscular dystrophy type 1A disease progression in mice: a gender impact study
Congenital muscular dystrophy with laminin α2 chain-deficiency (LAMA2-CMD) is a severe muscle disorder with complex underlying pathogenesis. We have previously employed profiling techniques to elucidate molecular patterns and demonstrated significant metabolic impairment in skeletal muscle from LAMA2-CMD patients and mouse models. Thus, we hypothesize that skeletal muscle metabolism may be a promising pharmacological target to improve muscle function in LAMA2-CMD. Here, we have investigated whether the multifunctional medication metformin could be used to reduce disease in the dy2J/dy2J mouse model of LAMA2-CMD. First, we show gender disparity for several pathological hallmarks of LAMA2-CMD. Second, we demonstrate that metformin treatment significantly increases weight gain and energy efficiency, enhances muscle function and improves skeletal muscle histology in female dy2J/dy2J mice (and to a lesser extent in dy2J/dy2J males). Thus, our current data suggest that metformin may be a potential future supportive treatment that improves many of the pathological characteristics of LAMA2-CMD.
2018-08-27 | Ribitol restores functionally glycosylated α-dystroglycan and improves muscle function in dystrophic FKRP-mutant mice
Abstract O -mannosylated α-dystroglycan (α-DG) serves as receptors for cell–cell and cell–extracellular matrix adhesion and signaling. Hypoglycosylation of α-DG is involved in cancer progression and underlies dystroglycanopathy with aberrant neuronal development. Here we report that ribitol, a pentose alcohol with previously unknown function in mammalian cells, partially restores functional O -mannosylation of α-DG (F-α-DG) in the dystroglycanopathy model containing a P448L mutation in fukutin-related protein ( FKRP ) gene, which is clinically associated with severe congenital muscular dystrophy. Oral administration of ribitol increases levels of ribitol-5-phosphate and CDP-ribitol and restores therapeutic levels of F-α-DG in skeletal and cardiac muscles. Furthermore, ribitol, given before and after the onset of disease phenotype, reduces skeletal muscle pathology, significantly decreases cardiac fibrosis and improves skeletal and respiratory functions in the FKRP mutant mice. Ribitol treatment presents a new class, low risk, and easy to administer experimental therapy to restore F-α-DG in FKRP-related muscular dystrophy.
other
2026-05-13 | Anti-Receptor Activator of Nuclear Factor-κB Ligand Improves Muscle Dysfunction and Strengthens Bone in Laminin-α2-Deficient dy2J/dy2J Dystrophic Mice.
Congenital muscular dystrophy type 1A (CMD1A) is a severe genetic neuromuscular disorder caused by mutations in the LAMA2 gene, which encodes the laminin-α2 subunit, an essential structural protein for maintaining muscle integrity during contraction. Affected children experience progressive muscle damage, hypotonia, delayed motor development, and respiratory tract insufficiency. CMD1A muscles undergo repeated cycles of degeneration and regeneration accompanied by chronic inflammation. Beyond its established role in bone remodeling, the receptor activator of nuclear factor-κB/receptor activator of nuclear factor-κB ligand (RANKL)/osteoprotegerin signaling axis has also been implicated in muscle pathophysiology. A 10-day treatment with full-length osteoprotegerin fused to an Fc fragment was previously shown to restore muscle function in a Duchenne muscular dystrophy mouse model. In this study, anti-RANKL therapy was evaluated in a more severe mouse model, specifically 4-week-old male dy2J/dy2J mice, which recapitulate key CMD1A features. A 1-month anti-RANKL treatment significantly improved specific muscle strength, increased myofiber cross-sectional area, and reduced edema and immune cell infiltration. It also enhanced bone strength and microarchitecture. However, absolute muscle force and global motor performance remained unchanged. Overall, anti-RANKL treatment improved muscle intrinsic properties and bone parameters in dy2J/dy2J dystrophic mice, but these improvements were insufficient to enhance absolute muscle force or global motor performance.
2024-12-02 | Systemic inhibition of bone morphogenetic protein 1.3 as a possible treatment for laminin-related congenital muscular dystrophy.
Congenital muscular dystrophy (CMD) is a group of rare neuromuscular disorders typically characterized by the onset of symptoms at birth or within the first two years of life. CMDs are relatively rare, but extremely severe pathological conditions currently without a safe and effective therapeutic solution. Merosin-deficient congenital muscular dystrophy type 1A (MDC1A) is among the most frequent CMDs and it is caused by mutations in the LAMA2 gene that encodes for the α2 chain of laminin-211 (merosin). Laminin-211 is a crucial constituent of the basement membrane that provides muscle fibre stability and signal transduction. Bone morphogenetic protein 1.3 (BMP1.3) is evolutionarily conserved and structurally related to mammalian Tolloid-like metalloproteinase (mTld) that is involved in the processing of procollagens, non-collagenous extracellular matrix proteins, and growth factor-related proteins. Recently, it has been shown that BMP1.3 is present in circulation and its levels are elevated in patients with chronic kidney failure, hepatic fibrosis, and acute myocardial infarction. It has been demonstrated that administering the BMP1.3 antibody ameliorated kidney, liver, and heart function in animal disease models. Furthermore, we observed highly enhanced BMP1.3 gene expression in the skeletal muscles of mice with congenital muscular dystrophy. Therefore, we hypothesize that BMP1.3 inhibition represents a novel therapeutic strategy for reversing the progression of CMD. The development of an anti-BMP1.3 therapy might lead to groundbreaking changes in CMD treatment and provide relief to numerous patients suffering from this disabling disease.
2017-10-01 | Immunoglobulin therapy modulates the severe inflammatory progression of neuromuscular disorders
The lack of dystrophin in muscle tissue of Duchenne muscular dystrophy (DMD) patients induces a release of DAMPs, CPK and mRNAs in the extracellular environment which interact with toll-like receptors, triggering an innate immune response, with recruitment of inflammasomes and activation of the NF-kB signaling pathway. In addition, muscle antigens are processed and can be presented to T-effector cells, mainly TCD4+ and TCD8+, activating an adaptive immune response characterized by an intensive secretion of pro-inflammatory cytokines and tissue necrosis. Immunoglobulin G (IG) modulates the inflammatory response by several mechanisms and has been widely used as a therapy in autoimmune diseases. It was recently shown that IG administration improves the clinical phenotype of mdx mice. Here we evaluated IG clinical effect in two severely affected mice models: the double mutant 2KO mdx/utr- and LAMA2dy/2j (MDC1A), both comparable to human patients' phenotype. Mice were divided in two groups: the IG treated group received 2 mg/kg of human polyclonal IG monthly and the control group received equivalent volume of standard saline solution. Comparative analysis included physical evaluation, muscle histology and survival. For both mice models, IG increased motor ability and decreased inflammatory clusters infiltrates in gastrocnemius and quadriceps muscles, maintaining tissue integrity. Moreover, in mdx/utr- mice, it significantly increased lifespan and dampened splenic inflammation. In DMD models, IG appears to have a modulating role both in innate and adaptive immunity, with a decrease in DCs activation (less expression of MHC, CD86, CD40 and FcgRI) and also in proinflammatory cytokines TNF-a, IL-1b, IFN-g and IL-2 in IG-treated mice. The results of the present study may open new perspectives for the treatment of these disorders, decreasing the progression of the dystrophic process and increasing life expectancy with less side effects than the currently used glucocorticoids.
2017-03-10 | Potent pro-inflammatory and pro-fibrotic molecules, osteopontin and galectin-3, are not major disease modulators of laminin α2 chain-deficient muscular dystrophy
A large number of human diseases are caused by chronic tissue injury with fibrosis potentially leading to organ failure. There is a need for more effective anti-fibrotic therapies. Congenital muscular dystrophy type 1A (MDC1A) is a devastating form of muscular dystrophy caused by laminin α2 chain-deficiency. It is characterized with early inflammation and build-up of fibrotic lesions, both in patients and MDC1A mouse models (e.g. dy3K/dy3K). Despite the enormous impact of inflammation on tissue remodelling in disease, the inflammatory response in MDC1A has been poorly described. Consequently, a comprehensive understanding of secondary mechanisms (impaired regeneration, enhanced fibrosis) leading to deterioration of muscle phenotype in MDC1A is missing. We have monitored inflammatory processes in dy3K/dy3K muscle and created mice deficient in laminin α2 chain and osteopontin or galectin-3, two pro-inflammatory and pro-fibrotic molecules drastically increased in dystrophic muscle. Surprisingly, deletion of osteopontin worsened the phenotype of dy3K/dy3K mice and loss of galectin-3 did not reduce muscle pathology. Our results indicate that osteopontin could even be a beneficial immunomodulator in MDC1A. This knowledge is essential for the design of future therapeutic interventions for muscular dystrophies that aim at targeting inflammation, especially that osteopontin inhibition has been suggested for Duchenne muscular dystrophy therapy.
gene therapies
2026-05-26 | Unexplained multiorgan fat embolism syndrome in a 10-year-old child with LAMA2-related congenital muscular dystrophy
A 10-year-old cachectic boy who was delivered at 29 weeks' gestation following an uneventful first pregnancy was diagnosed with laminin subunit alpha-2 (LAMA2)-related (merosin deficient) congenital muscular dystrophy at the age of 5 years. A week before his last hospitalization, he was treated with antibiotics for respiratory infection. A day before his death, he vomited and was visibly irritable. He collapsed during rehabilitation treatment and became unresponsive. He did not sustain any injuries. The patient presented to the hospital with tachycardia, elevated cardiac enzymes, and respiratory insufficiency. Computed tomography of the brain revealed irregular hypodense areas in the supratentorial region and the lungs showed ground glass opacity. He required mechanical ventilation and high doses of vasopressors. The patient died 12 h after admission due to circulatory collapse. Postmortem histologic examination revealed skeletal muscle and myocardial degeneration, and multiorgan fat embolism involving the lungs, heart, kidneys and brain. Death was attributed to cardiovascular collapse due to heart failure associated with a genetically determined muscle disease with unexplained fat embolism syndrome.
2026-03-02 | Expanding the phenotypic spectrum of LAMA2-related disorders: Axonal neuropathy in the absence of muscular dystrophy.
The LAMA2 gene encodes the alpha-2 chain of laminin-2, a key component of the basement membrane that maintains muscle fiber stability and integrity. Mutations in this gene are linked with LAMA2-related muscular dystrophies, which includes congenital muscular dystrophy type 1 A (MDC1A) and limb-girdle muscular dystrophy autosomal recessive 23 (LGMDR23). Here, we present two siblings from one of 200 unrelated Iranian Charcot-Marie-Tooth (CMT) families, exhibiting axonal sensorimotor polyneuropathy, without any clinical signs of muscular dystrophy, carrying a homozygous variant in the LAMA2 gene. Following clinical and paraclinical assessments of the patients, genomic DNA was extracted from peripheral blood samples. Whole-exome sequencing (WES) was employed to identify potential genetic variants, and Sanger sequencing was subsequently used to confirm the detected variant. In silico prediction tools were further applied to evaluate the potential pathogenicity and functional impact of the identified variant. A homozygous missense variant in the LAMA2 gene, c.2916 T > G; p.Phe972Leu, was identified and co-segregated with the disease status within the family, whose neurological assessments confirmed axonal sensorimotor polyneuropathy. So far, only two studies have reported LAMA2 variants in patients only manifesting a neuropathy phenotype. None of these studies reported the detailed clinical data of their cases. However, our study provides further evidence of the association between LAMA2 mutations and neuropathy, and includes comprehensive clinical and paraclinical characterization of the affected individuals. Our findings underscore the importance of comprehensive genomic testing in diagnosing neuromuscular disorders and expand the phenotypic spectrum associated with LAMA2 mutations.
2026-02-04 | Dual AAV gene therapy using laminin-linking proteins ameliorates muscle and nerve defects in LAMA2-related muscular dystrophy.
Adeno-associated virus (AAV)-mediated gene replacement holds promise for treating genetic diseases but faces challenges due to the 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.
2026-01-22 | LAMA2 variants associated with muscular dystrophy, brain structural abnormalities, and epilepsy: a genotype-phenotype study.
LAMA2-related congenital muscular dystrophy (LAMA2-MD) is a genetically heterogeneous disorder defined by progressive muscle weakness, brain structural abnormalities, epilepsy, and multisystem involvement. The primary goal of this study was to characterize the clinical features, temporal progression, and genotype-phenotype correlations of LAMA2-MD. Medical records of patients with genetically confirmed LAMA2-MD were extracted from a clinical data repository and analyzed retrospectively. Clinical manifestations, laboratory findings, and neuroimaging features were systematically reviewed and compared across different age groups. Variant data were retrieved from public databases to perform comprehensive genetic analyses. A total of five patients (two males and three females) were enrolled, delayed motor milestones and varying degrees of ankle contractures and persistent motor impairment in all patients were the initial presenting symptom at diagnosis in all cases, and two patients also exhibited cognitive delays. Laboratory analysis of muscle enzymes showed varying degrees of abnormalities, with creatine kinase (CK) levels displaying the most significant elevation. Cranial magnetic resonance imaging (MRI) revealed symmetrical white matter abnormalities in four patients. Seizures were documented in three school-aged patients. All patients carried compound heterozygous variants in the LAMA2 gene. A literature review indicated that the most common variant types were stop-gain and missense variants: stop-gain variants were predominantly associated with complete merosin deficiency (MDC1A), whereas missense variants typically correlated with late-onset limb-girdle muscular dystrophy. LAMA2-MD exhibits a broad phenotypic spectrum and a progressive disease course. Early manifestations include muscle weakness, delayed achievement of developmental milestones, joint contractures, seizures and characteristic intracranial abnormalities.
2025-12-24 | Efficient LAMA1 Gene Activation by Epigenome Editing as a Therapeutic Approach for LAMA2-CMD.
Epigenome editing technology holds great promise for treating diverse genetic disorders. In this study, we demonstrate epigenetic activation of the LAMA1 gene for the treatment of LAMA2-CMD, a severe congenital muscle dystrophy (CMD) caused by biallelic mutations in the LAMA2 gene. LAMA1 is a sister homolog 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 nonhuman primates (NHPs). Moreover, administration to 8-month-old infant NHPs demonstrated superior pharmacodynamics compared with 2-year-old 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.
proteins
2023-12-21 | Identification of a short, single site matriglycan that maintains neuromuscular function in the mouse
Matriglycan (-1,3-β-glucuronic acid-1,3-α-xylose-) is a polysaccharide that is synthesized on α-dystroglycan, where it functions as a high-affinity glycan receptor for extracellular proteins, such as laminin, perlecan and agrin, thus anchoring the plasma membrane to the extracellular matrix. This biological activity is closely associated with the size of matriglycan. Using high-resolution mass spectrometry and site-specific mutant mice, we show for the first time that matriglycan on the T317/T319 and T379 sites of α-dystroglycan are not identical. T379-linked matriglycan is shorter than the previously characterized T317/T319-linked matriglycan, although it maintains its laminin binding capacity. Transgenic mice with only the shorter T379-linked matriglycan exhibited mild embryonic lethality, but those that survived were healthy. The shorter T379-linked matriglycan exists in multiple tissues and maintains neuromuscular function in adult mice. In addition, the genetic transfer of α-dystroglycan carrying just the short matriglycan restored grip strength and protected skeletal muscle from eccentric contraction-induced damage in muscle-specific dystroglycan knock-out mice. Due to the effects that matriglycan imparts on the extracellular proteome and its ability to modulate cell-matrix interactions, our work suggests that differential regulation of matriglycan length in various tissues optimizes the extracellular environment for unique cell types.
2022-07-11 | Amelioration of muscle and nerve pathology of Lama2-related dystrophy by AAV9-laminin-αLN linker protein.
LAMA2 deficiency, resulting from a defective or absent laminin α2 subunit, is a common cause of congenital muscular dystrophy. It is characterized by muscle weakness from myofiber degeneration and neuropathy from Schwann cell amyelination. Previously it was shown that transgenic muscle-specific expression of αLNNd, a laminin γ1-binding linker protein that enables polymerization in defective laminins, selectively ameliorates the muscle abnormality in mouse disease models. Here, adeno-associated virus was used to deliver linker mini-genes to dystrophic dy2J/dy2J mice for expression of αLNNd in muscle, or αLNNdΔG2', a shortened linker, in muscle, nerve, and other tissues. Linker and laminin α2 levels were higher in αLNNdΔG2'-treated mice. Both αLNNd- and αLNNdΔG2'-treated mice exhibited increased forelimb grip strength. Further, αLNNdΔG2'-treated mice achieved hind limb and all-limb grip strength levels approaching those of WT mice as well as ablation of hind limb paresis and contractures. This was accompanied by restoration of sciatic nerve axonal envelopment and myelination. Improvement of muscle histology was evident in the muscle-specific αLNNd-expressing mice but more extensive in the αLNNdΔG2'-expressing mice. The results reveal that an αLN linker mini-gene, driven by a ubiquitous promoter, is superior to muscle-specific delivery because of its higher expression that extends to the peripheral nerve. These studies support a potentially novel approach of somatic gene therapy.
2022-05-20 | Nerve pathology is prevented by linker proteins in mouse models for LAMA2-related muscular dystrophy
ABSTRACT LAMA2 -related muscular dystrophy (LAMA2 MD or MDC1A) is caused by mutations in the LAMA2 gene encoding laminin-α2, the long chain of several heterotrimeric laminins. Laminins are essential components of the extracellular matrix that interface with underlying cells. The pathology of LAMA2 MD patients is dominated by the severe muscular dystrophy but also involves other tissues. In the dy W / dy W mouse model for LAMA2 MD, amelioration of muscle function by skeletal muscle-specific expression of the two linker proteins, mini-agrin and αLNNd, is sufficient to greatly increase survival. In such survivors, the phenotype is dominated by the hindlimb paralysis. We now show that ubiquitous expression of the two linker proteins in dy W / dy W mice improves muscle function and prevents hindlimb paralysis. The same ameliorating effect of the linker proteins was seen in dy 3K / dy 3K mice, which represent the most severe mouse model of LAMA2 MD. In summary, these data show that the two linker proteins can compensate the loss of laminin-α2 in many, if not all tissues affected in LAMA2 MD.
2020-05-20 | Human Laminin-111 and Laminin-211 protein therapy prevents muscle disease progression in an immune deficient mouse model of LAMA2-CMD
Abstract Background Laminin-α2 related Congenital Muscular dystrophy (LAMA2-CMD) is a devastating genetic disease caused by mutations in the LAMA2 gene. These mutations result in progressive muscle wasting and inflammation leading to delayed milestones, and reduced lifespan in affected patients. There is currently no cure or treatment for LAMA2-CMD. Preclinical studies have demonstrated that mouse Laminin-111 can serve as an effective protein replacement therapy in a mouse model of LAMA2-CMD. Methods In this study, we generated a novel immunocompromised dy W mouse model of LAMA2-CMD to study the role the immune system plays in muscle disease progression. We used this immune deficient dy W mouse model to test the therapeutic benefits of recombinant human laminin-111 and laminin-211 protein therapy on Laminin-α2 deficient muscle disease progression. Results We show that immune deficient Laminin-α2 null mice demonstrate subtle differences in muscle regeneration compared to immune competent animals during early disease stages, but overall exhibit a comparable muscle disease progression. We found human laminin-111 and laminin-211 could serve as effective protein replacement strategies with mice showing improvements in muscle pathology and function. We observed that human laminin-111 and laminin-211 exhibit differences on satellite and myoblast cell populations and differentially affect muscle repair. Conclusions This study describes the generation of a novel immune deficient mouse model that allows investigation of the role the immune system plays in LAMA2-CMD. This model can be used to assess the therapeutic potential of heterologous therapies that would illicit an immune response. Using this model, we show that recombinant human Laminin-111 can serve as effective protein replacement therapy for the treatment of LAMA2-CMD.
2019-12-13 | Linker Protein Repair of LAMA2 Dystrophic Neuromuscular Basement Membranes
An understanding of basement membrane (BM) assembly at a molecular level provides a foundation with which to develop repair strategies for diseases with defects of BM structure. As currently understood, laminins become anchored to cell surfaces through receptor-mediated interactions and polymerize. This provisional matrix binds to proteoglycans, nidogens and type IV collagen to form a mature BM. Identification of BM binding domains and their binding targets has enabled investigators to engineer proteins that link BM components to modify and improve their functions. This approach is illustrated by the development of two linker proteins to repair the LAMA2-deficient muscular dystrophy (LAMA2-MD). Dystrophy-causing mutations of the LAMA2 gene product (Lm alpha2) disrupt the BM molecular architecture, destabilizing it. In a mild ambulatory type of the dystrophy, Alpha2LN mutations in laminin-211 prevents polymerization. In the more common and severe non-ambulatory type (MDC1A), an absent Lm2 subunit is re-placed by the naturally-occurring Lm alpha4 subunit that is normally largely confined to the micro-vasculature. The compensatory laminin, however, is a poor substitute because it neither polymerizes nor binds adequately to the anchoring receptor -dystroglycan. A chimeric laminin-binding protein called alphaLNNd enables laminins with defective or absent LN domains to polymerize while another engineered protein, miniagrin (mag), promotes efficient alpha-dystroglycan receptor-binding in otherwise weakly adhesive laminins. Alone, LNNd enables Lm211 with a self-assembly defect to polymerize and was used to ameliorate a mouse model of the ambulatory dystrophy. Together, these linker proteins alter Lm411 such that it both polymerizes and binds DG such that it properly assembles. This combination was used to ameliorate a mouse model of the non-ambulatory dystrophy in which Lm411 replaced Lm211 as seen in the human disease. Collectively, these studies pave the way for the development of somatic gene delivery of repair proteins for treatment of LAMA2-MD. The studies further suggest a more general approach of linker-protein mediated repair in which a variety of existing BM protein domains can be combined together to stabilize BMs in other diseases.
oligonucleotides
2025-07-28 | Exon-Skipping Using Antisense Oligonucleotides for Laminin-Alpha2-Deficient Muscular Dystrophy.
Phosphorodiamidate morpholino oligomer (PMO)-mediated exon-skipping is among the more promising approaches available for the treatment of several neuromuscular disorders, including Duchenne muscular dystrophy. The main weakness of this treatment arises from the low efficiency and sporadic nature of the delivery of neutrally charged PMOs into muscle fibres, the mechanism of which is unknown. Recently, using wild-type and dystrophic mdx52 mice, we showed that muscle fibres took up PMOs more efficiently during myotube formation. Interestingly, we detected PMO mainly in embryonic myosin heavy chain-positive regenerating fibres through in situ hybridisation. Next, we tested the therapeutic potential of PMOs in laminin-alpha2 (laminin-α2) chain-null dy3K/dy3K mice, a model of merosin-deficient congenital muscular dystrophy 1A (MDC1A or LAMA2-related muscular dystrophy: LAMA2-MD) with active muscle regeneration. We confirmed the recovery of the laminin-α2 chain following the skipping of the mutated exon 4 in dy3K/dy3K mice, which prolonged the lifespan of the animals slightly. These findings support the theory that PMO entry into fibres is dependent on the developmental stage in myogenesis rather than on dystrophin-deficient muscle membranes, and recommend a platform for the future development of PMO-mediated therapies for a variety of muscular disorders, such as LAMA2-MD, that involve active muscle regeneration. Herein, we describe the methods for PMO transfection/injection and the evaluation of the efficacy of exon-skipping in the laminin-α2-deficient dy3K/dy3K mouse model both in vitro and in vivo.
2025-07-28 | An Overview of Recent Advances and Clinical Applications of Exon Skipping and Splice Modulation for Muscular Dystrophy and Various Genetic Diseases.
Exon skipping and splice modulation using synthetic antisense oligonucleotides (AONs) are therapeutic approaches to delay or arrest the progression of genetic diseases. AON-mediated exon skipping modifies pre-mRNA splicing to correct the reading frame of genes responsible for disease and modulate a protein structure, providing therapeutic benefits. Studied for over two decades, exon skipping AONs have received conditional marketing authorization for Duchenne muscular dystrophy (DMD). The US Food and Drug Administration (FDA) has granted accelerated approval for four AONs to skip a single DMD exon for treating patients with DMD: eteplirsen for exon 51 skipping, golodirsen and viltolarsen for exon 53 skipping, and casimersen for exon 45 skipping. Various preclinical and clinical trials are underway with AONs targeting other exons and ones loading bioconjugates, such as cell-penetrating peptides and antibodies to enhance the exon skipping ability. Besides AONs targeting pre-mRNA, genomic DNA target exon skipping using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) technology, which holds promise in current preclinical trials for DMD. In hopes of achieving clinical success parallel to DMD, exon skipping and splice modulation are studied in other muscular dystrophies, such as Fukuyama congenital muscular dystrophy (FCMD), dysferlinopathy including limb-girdle muscular dystrophy type 2B (LGMD2B), Miyoshi myopathy (MM), and distal anterior compartment myopathy (DMAT), myotonic dystrophy, and merosin-deficient congenital muscular dystrophy type 1A (MDC1A). Splice-modulating AONs have also been extensively tested in other inherited diseases, such as Usher syndrome, dystrophic epidermolysis bullosa (DEB), fibrodysplasia ossificans progressiva (FOP), and allergic diseases. This chapter will introduce the developmental status of exon skipping and splice-modulating therapies for genetic diseases.
2022-06-01 | Skeletal muscle-specific overexpression of miR-486 limits mammary tumor-induced skeletal muscle functional limitations
miR-486 is a myogenic microRNA, and its reduced skeletal muscle expression is observed in muscular dystrophy. Transgenic overexpression of miR-486 using muscle creatine kinase promoter (MCK-miR-486) partially rescues muscular dystrophy phenotype. We had previously demonstrated reduced circulating and skeletal muscle miR-486 levels with accompanying skeletal muscle defects in mammary tumor models. To determine whether skeletal muscle miR-486 is functionally similar in dystrophies and cancer, we performed functional limitations and biochemical studies of skeletal muscles of MMTV-Neu mice that mimic HER2+ breast cancer and MMTV-PyMT mice that mimic luminal subtype B breast cancer and these mice crossed to MCK-miR-486 mice. miR-486 significantly prevented tumor-induced reduction in muscle contraction force, grip strength, and rotarod performance in MMTV-Neu mice. In this model, miR-486 reversed cancer-induced skeletal muscle changes, including loss of p53, phospho-AKT, and phospho-laminin alpha 2 (LAMA2) and gain of hnRNPA0 and SRSF10 phosphorylation. LAMA2 is a part of the dystrophin-associated glycoprotein complex, and its loss of function causes congenital muscular dystrophy. Complementing these beneficial effects on muscle, miR-486 indirectly reduced tumor growth and improved survival, which is likely due to systemic effects of miR-486 on production of pro-inflammatory cytokines such as IL-6. Thus, similar to dystrophy, miR-486 has the potential to reverse skeletal muscle defects and cancer burden.
2020-05-18 | Recent advancements in exon-skipping therapies using antisense oligonucleotides and genome editing for the treatment of various muscular dystrophies.
Muscular dystrophy is a group of genetic disorders characterised by degeneration of muscles. Different forms of muscular dystrophy can show varying phenotypes with a wide range of age, severity and location of muscle deterioration. Many palliative care options are available for muscular dystrophy patients, but no curative treatment is available. Exon-skipping therapy aims to induce skipping of exons with disease-causing mutations and/or nearby exons to restore the reading frame, which results in an internally truncated, partially functional protein. In antisense-mediated exon-skipping synthetic antisense oligonucleotide binds to pre-mRNA to induce exon skipping. Recent advances in exon skipping have yielded promising results; the US Food and Drug Administration (FDA) approved eteplirsen (Exondys51) as the first exon-skipping drug for the treatment of Duchenne muscular dystrophy, and in vivo exon skipping has been demonstrated in animal models of dysferlinopathy, limb-girdle muscular dystrophy type 2C and congenital muscular dystrophy type 1A. Novel methods that induce exon skipping utilizing Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) are also being developed where splice site mutations are created within the genome to induce exon skipping. Challenges remain as exon-skipping agents can have deleterious non-specific effects and different in-frame deletions show phenotypic variance. This article reviews the state of the art of exon skipping for treating muscular dystrophy and discusses challenges and future prospects.
2018-08-31 | Tips to Design Effective Splice-Switching Antisense Oligonucleotides for Exon Skipping and Exon Inclusion
Antisense-mediated exon skipping and exon inclusion have proven to be powerful tools for treating neuromuscular diseases. The approval of Exondys 51 (eteplirsen) and Spinraza (nusinersen) for the treatment of patients with Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA) was the most noteworthy accomplishment in 2016. Exon skipping uses short DNA-like molecules called antisense oligonucleotides (AONs) to correct the disrupted reading frame, allowing the production of functional quasi-dystrophin proteins, and ameliorate the progression of the disease. Exon inclusion for SMA employs an AON targeting an intronic splice silencer site to include an exon which is otherwise spliced out. Recently, these strategies have also been explored in many other genetic disorders, including dysferlin-deficient muscular dystrophy (e.g., Miyoshi myopathy; MM, limb-girdle muscular dystrophy type 2B; LGMD2B, and distal myopathy with anterior tibial onset; DMAT), laminin α2 chain (merosin)-deficient congenital muscular dystrophy (MDC1A), sarcoglycanopathy (e.g., limb-girdle muscular dystrophy type 2C; LGMD2C), and Fukuyama congenital muscular dystrophy (FCMD). A major challenge in exon skipping and exon inclusion is the difficulty in designing effective AONs. The mechanism of mRNA splicing is highly complex, and the efficacy of AONs is often unpredictable. We will discuss the design of effective AONs for exon skipping and exon inclusion in this chapter.
small molecules
2023-10-19 | Artificial intelligence and the analysis of cryo-EM data provide structural insight into the molecular mechanisms underlying LN-lamininopathies
Laminins (Lm) are major components of basement membranes (BM), which polymerize to form a planar lattice on cell surface. Genetic alternations of Lm affect their oligomerization patterns and lead to failures in BM assembly manifesting in a group of human disorders collectively defined as Lm N-terminal domain lamininopathies (LN-lamininopathies). We have employed a recently determined cryo-EM structure of the Lm polymer node, the basic repeating unit of the Lm lattice, along with structure prediction and modeling to systematically analyze structures of twenty-three pathogenic Lm polymer nodes implicated in human disease. Our analysis provides the detailed mechanistic explanation how Lm mutations lead to failures in Lm polymerization underlining LN-lamininopathies. We propose the new categorization scheme of LN-lamininopathies based on the insight gained from the structural analysis. Our results can help to facilitate rational drug design aiming in the treatment of Lm deficiencies.
2023-05-11 | Vemurafenib improves muscle histopathology in a mouse model of LAMA2-related congenital muscular dystrophy.
Laminin-α2-related congenital muscular dystrophy (LAMA2-CMD) is a neuromuscular disease affecting around 1-9 in 1,000,000 children. LAMA2-CMD is caused by mutations in the LAMA2 gene resulting in the loss of laminin-211/221 heterotrimers in skeletal muscle. LAMA2-CMD patients exhibit severe hypotonia and progressive muscle weakness. Currently, there is no effective treatment for LAMA2-CMD and patients die prematurely. The loss of laminin-α2 results in muscle degeneration, defective muscle repair and dysregulation of multiple signaling pathways. Signaling pathways that regulate muscle metabolism, survival and fibrosis have been shown to be dysregulated in LAMA2-CMD. As vemurafenib is a US Food and Drug Administration (FDA)-approved serine/threonine kinase inhibitor, we investigated whether vemurafenib could restore some of the serine/threonine kinase-related signaling pathways and prevent disease progression in the dyW-/- mouse model of LAMA2-CMD. Our results show that vemurafenib reduced muscle fibrosis, increased myofiber size and reduced the percentage of fibers with centrally located nuclei in dyW-/- mouse hindlimbs. These studies show that treatment with vemurafenib restored the TGF-β/SMAD3 and mTORC1/p70S6K signaling pathways in skeletal muscle. Together, our results indicate that vemurafenib partially improves histopathology but does not improve muscle function in a mouse model of LAMA2-CMD.
2020-02-04 | Fibrogenesis in LAMA2-Related Muscular Dystrophy Is a Central Tenet of Disease Etiology
LAMA2-related congenital muscular dystrophy, also known as MDC1A, is caused by loss-of- function mutations in the alpha2 chain of Laminin-211. Loss of this protein interupts the connection between the muscle cell and its extracellular environment and results in an aggressive, congenital-onset muscular dystrophy characterized by severe hypotonia, lack of independent ambulation, and early mortality driven by respiratory complications and/or failure to thrive. Of the pathomechanisms of MDC1A, the earliest and most prominent is widespread and rampant fibrosis. Here, we will discuss some of the key drivers of fibrosis including TGF-beta and Renin-Angiotensin System signaling,consequences of these pathways including myofibroblast transdifferentiation and matrix remodeling. We will also highlight some of the differences in fibrogenesis in Congenital Muscular Dystrophy (CMD) with that seen in more classical Duchenne Muscular Dystrophy (DMD). Finally, we will connect the key signaling pathawys in the pathogenesis of MDC1A to the current status of the therapeutic approaches that have been tested in the preclinical models of MDC1A to treat fibrosis.
2018-11-02 | Effects of metformin on congenital muscular dystrophy type 1A disease progression in mice: a gender impact study
Congenital muscular dystrophy with laminin α2 chain-deficiency (LAMA2-CMD) is a severe muscle disorder with complex underlying pathogenesis. We have previously employed profiling techniques to elucidate molecular patterns and demonstrated significant metabolic impairment in skeletal muscle from LAMA2-CMD patients and mouse models. Thus, we hypothesize that skeletal muscle metabolism may be a promising pharmacological target to improve muscle function in LAMA2-CMD. Here, we have investigated whether the multifunctional medication metformin could be used to reduce disease in the dy2J/dy2J mouse model of LAMA2-CMD. First, we show gender disparity for several pathological hallmarks of LAMA2-CMD. Second, we demonstrate that metformin treatment significantly increases weight gain and energy efficiency, enhances muscle function and improves skeletal muscle histology in female dy2J/dy2J mice (and to a lesser extent in dy2J/dy2J males). Thus, our current data suggest that metformin may be a potential future supportive treatment that improves many of the pathological characteristics of LAMA2-CMD.
2018-08-27 | Ribitol restores functionally glycosylated α-dystroglycan and improves muscle function in dystrophic FKRP-mutant mice
Abstract O -mannosylated α-dystroglycan (α-DG) serves as receptors for cell–cell and cell–extracellular matrix adhesion and signaling. Hypoglycosylation of α-DG is involved in cancer progression and underlies dystroglycanopathy with aberrant neuronal development. Here we report that ribitol, a pentose alcohol with previously unknown function in mammalian cells, partially restores functional O -mannosylation of α-DG (F-α-DG) in the dystroglycanopathy model containing a P448L mutation in fukutin-related protein ( FKRP ) gene, which is clinically associated with severe congenital muscular dystrophy. Oral administration of ribitol increases levels of ribitol-5-phosphate and CDP-ribitol and restores therapeutic levels of F-α-DG in skeletal and cardiac muscles. Furthermore, ribitol, given before and after the onset of disease phenotype, reduces skeletal muscle pathology, significantly decreases cardiac fibrosis and improves skeletal and respiratory functions in the FKRP mutant mice. Ribitol treatment presents a new class, low risk, and easy to administer experimental therapy to restore F-α-DG in FKRP-related muscular dystrophy.
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2026-05-13 | Anti-Receptor Activator of Nuclear Factor-κB Ligand Improves Muscle Dysfunction and Strengthens Bone in Laminin-α2-Deficient dy2J/dy2J Dystrophic Mice.
Congenital muscular dystrophy type 1A (CMD1A) is a severe genetic neuromuscular disorder caused by mutations in the LAMA2 gene, which encodes the laminin-α2 subunit, an essential structural protein for maintaining muscle integrity during contraction. Affected children experience progressive muscle damage, hypotonia, delayed motor development, and respiratory tract insufficiency. CMD1A muscles undergo repeated cycles of degeneration and regeneration accompanied by chronic inflammation. Beyond its established role in bone remodeling, the receptor activator of nuclear factor-κB/receptor activator of nuclear factor-κB ligand (RANKL)/osteoprotegerin signaling axis has also been implicated in muscle pathophysiology. A 10-day treatment with full-length osteoprotegerin fused to an Fc fragment was previously shown to restore muscle function in a Duchenne muscular dystrophy mouse model. In this study, anti-RANKL therapy was evaluated in a more severe mouse model, specifically 4-week-old male dy2J/dy2J mice, which recapitulate key CMD1A features. A 1-month anti-RANKL treatment significantly improved specific muscle strength, increased myofiber cross-sectional area, and reduced edema and immune cell infiltration. It also enhanced bone strength and microarchitecture. However, absolute muscle force and global motor performance remained unchanged. Overall, anti-RANKL treatment improved muscle intrinsic properties and bone parameters in dy2J/dy2J dystrophic mice, but these improvements were insufficient to enhance absolute muscle force or global motor performance.
2024-12-02 | Systemic inhibition of bone morphogenetic protein 1.3 as a possible treatment for laminin-related congenital muscular dystrophy.
Congenital muscular dystrophy (CMD) is a group of rare neuromuscular disorders typically characterized by the onset of symptoms at birth or within the first two years of life. CMDs are relatively rare, but extremely severe pathological conditions currently without a safe and effective therapeutic solution. Merosin-deficient congenital muscular dystrophy type 1A (MDC1A) is among the most frequent CMDs and it is caused by mutations in the LAMA2 gene that encodes for the α2 chain of laminin-211 (merosin). Laminin-211 is a crucial constituent of the basement membrane that provides muscle fibre stability and signal transduction. Bone morphogenetic protein 1.3 (BMP1.3) is evolutionarily conserved and structurally related to mammalian Tolloid-like metalloproteinase (mTld) that is involved in the processing of procollagens, non-collagenous extracellular matrix proteins, and growth factor-related proteins. Recently, it has been shown that BMP1.3 is present in circulation and its levels are elevated in patients with chronic kidney failure, hepatic fibrosis, and acute myocardial infarction. It has been demonstrated that administering the BMP1.3 antibody ameliorated kidney, liver, and heart function in animal disease models. Furthermore, we observed highly enhanced BMP1.3 gene expression in the skeletal muscles of mice with congenital muscular dystrophy. Therefore, we hypothesize that BMP1.3 inhibition represents a novel therapeutic strategy for reversing the progression of CMD. The development of an anti-BMP1.3 therapy might lead to groundbreaking changes in CMD treatment and provide relief to numerous patients suffering from this disabling disease.
2017-10-01 | Immunoglobulin therapy modulates the severe inflammatory progression of neuromuscular disorders
The lack of dystrophin in muscle tissue of Duchenne muscular dystrophy (DMD) patients induces a release of DAMPs, CPK and mRNAs in the extracellular environment which interact with toll-like receptors, triggering an innate immune response, with recruitment of inflammasomes and activation of the NF-kB signaling pathway. In addition, muscle antigens are processed and can be presented to T-effector cells, mainly TCD4+ and TCD8+, activating an adaptive immune response characterized by an intensive secretion of pro-inflammatory cytokines and tissue necrosis. Immunoglobulin G (IG) modulates the inflammatory response by several mechanisms and has been widely used as a therapy in autoimmune diseases. It was recently shown that IG administration improves the clinical phenotype of mdx mice. Here we evaluated IG clinical effect in two severely affected mice models: the double mutant 2KO mdx/utr- and LAMA2dy/2j (MDC1A), both comparable to human patients' phenotype. Mice were divided in two groups: the IG treated group received 2 mg/kg of human polyclonal IG monthly and the control group received equivalent volume of standard saline solution. Comparative analysis included physical evaluation, muscle histology and survival. For both mice models, IG increased motor ability and decreased inflammatory clusters infiltrates in gastrocnemius and quadriceps muscles, maintaining tissue integrity. Moreover, in mdx/utr- mice, it significantly increased lifespan and dampened splenic inflammation. In DMD models, IG appears to have a modulating role both in innate and adaptive immunity, with a decrease in DCs activation (less expression of MHC, CD86, CD40 and FcgRI) and also in proinflammatory cytokines TNF-a, IL-1b, IFN-g and IL-2 in IG-treated mice. The results of the present study may open new perspectives for the treatment of these disorders, decreasing the progression of the dystrophic process and increasing life expectancy with less side effects than the currently used glucocorticoids.
2017-03-10 | Potent pro-inflammatory and pro-fibrotic molecules, osteopontin and galectin-3, are not major disease modulators of laminin α2 chain-deficient muscular dystrophy
A large number of human diseases are caused by chronic tissue injury with fibrosis potentially leading to organ failure. There is a need for more effective anti-fibrotic therapies. Congenital muscular dystrophy type 1A (MDC1A) is a devastating form of muscular dystrophy caused by laminin α2 chain-deficiency. It is characterized with early inflammation and build-up of fibrotic lesions, both in patients and MDC1A mouse models (e.g. dy3K/dy3K). Despite the enormous impact of inflammation on tissue remodelling in disease, the inflammatory response in MDC1A has been poorly described. Consequently, a comprehensive understanding of secondary mechanisms (impaired regeneration, enhanced fibrosis) leading to deterioration of muscle phenotype in MDC1A is missing. We have monitored inflammatory processes in dy3K/dy3K muscle and created mice deficient in laminin α2 chain and osteopontin or galectin-3, two pro-inflammatory and pro-fibrotic molecules drastically increased in dystrophic muscle. Surprisingly, deletion of osteopontin worsened the phenotype of dy3K/dy3K mice and loss of galectin-3 did not reduce muscle pathology. Our results indicate that osteopontin could even be a beneficial immunomodulator in MDC1A. This knowledge is essential for the design of future therapeutic interventions for muscular dystrophies that aim at targeting inflammation, especially that osteopontin inhibition has been suggested for Duchenne muscular dystrophy therapy.
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Drug Discovery Landscape
3 orphan drug designations for Laminin subunit alpha 2-related congenital muscular dystrophy.
3 orphan drug designations for Laminin subunit alpha 2-related congenital muscular dystrophy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
muscle-tropic derivative adeno-associated virus serotype 9 (AAV9) gene therapy product (MYO-AAV3A.CK8.GNDM.U6.sgHu) | gene therapies | FDA | — | Modalis Therapeutics |
human laminin-111 | proteins | FDA | — | Prothelia, Inc. |
Omigapil maleate | small molecules | EMA | Santhera Pharmaceuticals (Deutschland) GmbH |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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