Advances in gene therapies for limb-girdle muscular dystrophies


Advances in gene therapies for limb-girdle muscular dystrophies

Alba Judith Mateos-Aierdi1,2, Ana Aiastui2,3, Maria Goicoechea1,2 and Adolfo López de Munain1,2,4,5*

1Neuroscience Area, Instituto Biodonostia, Hospital Universitario Donostia, San Sebastian, Spain; 2CIBERNED, Instituto de Salud Carlos III, Ministry of Economy and Competitiveness, Madrid, Spain; 3Cell Culture Platform, Instituto Biodonostia, Hospital Universitario Donostia, San Sebastian, Spain; 4Department of Neurosciences, University of the Basque Country (UPV-EHU), San Sebastian, Spain; 5Department of Neurology, Hospital Universitario Donostia, San Sebastian, Spain


Limb-girdle muscular dystrophies (LGMDs) comprise a heterogeneous group of genetically determined disorders in which degeneration of the skeletal muscle is prominent. As no efficient pharmacological therapies exist that are able to reverse the course of these diseases, alternative regenerative therapies based on cell transfer or gene transfer approaches have been developed. These latter therapies will be the topic of this mini-review. To date, recombinant adeno-associated viral vectors have been reported as the best available gene transfer vectors for gene therapies targeting skeletal muscle tissue, due to their high tropism for this tissue, long-term stability, and low immunogenicity, among other features. However, the fact that these vectors cannot package large gene sizes represents a hurdle for the treatment of LGMDs caused by defects in large genes. Preclinical studies based on the transfer of disease-causing genes or muscle regulator genes that could ameliorate the course of the disease have led to a few clinical trials in which safety and efficacy studies are currently being performed. However, important barriers such as difficulties in delivering the viral vectors through all the affected skeletal muscles, the degenerative stage of the muscle at the time of treatment, and the potential immune response against the protein encoded by the transferred gene need to be overcome in order to maximize the efficacy of the therapies and prevent the development of the diseases.

Keywords: LGMD; gene therapy; muscle regeneration

*Correspondence to: Adolfo López de Munain, Instituto Biodonostia, Paseo Dr. Begiristain s/n, 20014 Donostia, Spain, Email:

Received: 27 May 2014; Accepted in revised from: 4 July 2014; Published: 25 September 2014

Advances in Regenerative Biology 2014. © 2014 Alba Judith Mateos-Aierdi et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 Unported (CC BY 4.0) License (, allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material for any purpose, even commercially, provided the original work is properly cited and states its license.

Citation: Advances in Regenerative Biology 2014, 1: 25048 -


Limb-girdle muscular dystrophies (LGMDs) comprise a heterogeneous group of genetically determined disorders that mainly affect the proximal muscles (1, 2). Due to the absence of curative therapies, therapeutic strategies in LGMDs are currently focused on the development of molecular, cell, and gene transfer approaches that are able to induce the regeneration of affected tissues. The therapeutic potential of novel molecules such as antisense oligonucleotides for exon skipping, myostatin inhibitors, and proteasome inhibitors, as well as different cell candidates for transplantation, are currently being studied. This mini-review focuses on gene therapies against LGMDs (Fig. 1) (3), summarizing the main advances and highlighting the principal difficulties that need to be overcome to achieve translation to humans.

Advances in calpainopathy

LGMD2A is caused by a deficiency of calpain 3, a calcium-dependent cysteine–protease (47). Adeno-associated virus (AAV)-mediated gene transfer of calpain 3 in a mouse model of the disease induces expression of a functionally active calpain 3 in the sarcomere, even though clinical improvement is modest (8). Restriction of calpain 3 expression to skeletal muscle prevents cardiac toxicity, thus facilitating its future applicability to patients (9).

In the same mouse model, inhibition of myostatin, a negative regulator of muscle mass, using a rAAV2/1 vector carrying a mutated version of the peptide induces muscular hypertrophy and functional improvement (10).

Advances in dysferlinopathy

LGMD2B and Miyoshi myopathy are caused by mutations in the gene encoding for dysferlin (DYSF) (11), a modular transmembrane protein involved in cell membrane repair (12). Overexpression of dysferlin in skeletal muscle is able to ameliorate a dystrophic phenotype in a mouse model of LGMD2B (13).

However, AAV-based gene transfer of full-length DYSF faces technical issues due to its excessive size, so alternative approaches are being studied. Such approaches include gene transfer of a shortened version of DYSF lacking exons 2–40 (mini-dysferlin), which is associated with a more benign phenotype (14), as well as exon-skipping approaches (15) as partial functionality of a shorter version of the protein has been confirmed.

Fig 1

Fig. 1.   Gene transfer approaches to treat LGMDs. Disease-causing genes or muscle regulator genes are encapsidated into AAV vectors to be delivered intramuscularly or systemically. Alternatively, disease-specific cells are ex vivo corrected by lentivirus-mediated gene transfer, and transplanted into the animal models. Exon skipping approaches have only been tested in vitro for LGMDs. All these studies are aimed at establishing treatments for patients, in whom the most frequently affected muscles are indicated in the figure. The different LGMDs can be distinguished by thigh or calf Magnetic Resonance Imaging cross sections (RMI of sarcoglycanopathy from ref. 3). Abbreviations: MAB (mesoangioblasts), AAV (Adeno-Associated Virus), AON (Antisense Oligonucleotide), sarco (sarcoglycan gene), X (exon), I (Intron), mut (mutation), G.T. (Gene transfer), C.T. (Cell Transfer).

In addition, full-length DYSF may be obtained by dual gene transfer delivery of DYSF cDNA distributed in two independent AAV vectors (16). However, transgene expression after systemic delivery must be improved prior to testing its efficacy in LGMD2B patients. Finally, a recent study has shown that functional recovery of full-length DYSF can be achieved by AAV5-mediated gene transfer, presumably through homologous recombination (17). This approach has a distinct advantage as only one viral vector is needed to achieve full-length expression of dysferlin. Nevertheless, all these studies need to standardize the assays used for testing the efficacy of treatments, since positive outcomes of membrane repair assays do not always correlate with histological and functional improvements (18).

Ex vivo engineered cell transplantation may also be used to deliver full-length dysferlin into muscle cells. In this regard, intramuscular (IM) injection of patient-specific, genetically corrected CD133+ cells into DYSF-deficient mice (19) restored dysferlin expression. However, the lack of improvement in histopathological markers suggests that further methodological optimization is required in order to achieve robust therapeutic effects.

Advances in sarcoglycanopathies

Mutations located within the α-, β-, γ-, and δ-sarcoglycan coding genes cause LGMD2D, LGMD2E, LGMD2C, and LGMD2F, respectively (1). These proteins form the sarcoglycan complex (SC), which is located in the sarcolemma (2022).

Gene transfer approaches for LGMD2F have evolved from the initial naked plasmid injections (23) to the use of adenoviral and AAV vectors (24, 25) in the natural Bio14.6 hamster model (2628) of the disease, and as a whole, they have led to biochemical, histological, and functional improvements (29). Importantly, some of the vectors are suitable for treating cardiac tissue in mice, which is also affected in LGMD2F (3035).

Comparable results have been obtained using the exogenous expression of α- and β-sarcoglycan in the corresponding mouse models (36, 37) at early stages (38). In addition, the toxicity induced by long-term α-sarcoglycan expression in mice has been overcome by using muscle-specific promoters (3941).

Transplantation of genetically corrected, human induced pluripotent stem cell (hiPSC)-derived mesoangioblasts shows recovery of α-sarcoglycan expression and functional improvement in the mouse model of LGMD2D (42). Nevertheless, the safety of therapies involving iPSCs needs to be thoroughly tested due to their potential oncogenic features.

Gene transfer of muscle regulators, such as Galgt2, a galNAc transferase located in the neuromuscular synapses (43), or MG53, a component of the cell membrane repair machinery (44, 45), also improves the dystrophic phenotype of sarcoglycan-deficient mice. In contrast, myostatin inhibition in LGMD2D mice does not reproduce the clinical improvement observed in LGMD2A (10).

AAV2/1-mediated gene transfer of α-sarcoglycan under the control of the muscle-specific promoters muscle creatine kinase (MCK) and truncated MCK (tMCK) is able to induce robust and long-term protein expression in mouse muscles without toxic effects (46).

In humans, two clinical trials are assessing the safety and stability of α-sarcoglycan gene transfer under the control of tMCK by IM (NCT00494195, Phase I) or intravascular administration (NCT01976091, Phase I/IIa). In the first study, a single injection of AAV1.tMCK.hSGCA into the extensor digitorum brevis of dystrophic patients induced persistent α-sarcoglycan expression and increases in muscle fiber size (47, 48). In the second clinical trial, a dose escalation study of systemic administration of scAAVrh.74.tMCK.hSGCA is being performed. As for LGMD2C, a clinical trial assessing the safety of IM injection of three experimental doses of AAV1-γ-sarcoglycan has been completed (NCT 01344798), but these results have not yet been published.

Advances in dystroglycanopathy

Mutations in the FKRP-coding gene result in hypoglycosylation of α-dystroglycan and give rise to LGMD2I. Systemic delivery of an FKRP-carrying AAV9 vector in an LGMD2I mouse model restores FKRP expression, increases glycosylation of α-dystroglycan, and results in a significant improvement of muscle function (49).


In little more than a decade, preclinical gene transfer approaches for LGMDs have been rapidly developed, leading to the first clinical trials. Initial doubts over the most suitable gene therapy vectors have been quickly addressed. rAAV vectors have shown a high tropism for skeletal and cardiac muscle tissue, they can be intramuscularly and systemically delivered, they induce stable and long-term expression of the transgene without integrating into the genome, and, most importantly, they are neither pathogenic nor immunogenic (5054). Notably, AAV2/9 has shown a high tropism for both cardiac and skeletal muscle after systemic administration, without detectable toxicity in other organs, making it suitable to treat LGMDs that involve cardiac dysfunction. However, an immune reaction induced by the transgene itself cannot be ruled out when using gene transfer approaches.

The disease severity of each patient is another issue that needs to be taken into account when transferring preclinical therapies to clinical trials. Several of the studies described in this mini-review were performed in newborn presymptomatic mice, and consequently, therapies were preventive rather than curative (55). The same studies performed in adult mice show less efficiency, suggesting that the fibrotic tissue or the inflammation found in adult mice might represent a significant barrier for viral delivery (39, 56). In conclusion, in LGMD patients, the degenerative stage of the muscular tissue may be a crucial factor affecting the success of the outcome, and therefore an early (or even prenatal) diagnosis will be crucial to limit as far as possible the progression of the diseases.


This work was supported by grants from the Spanish Ministry of Health (FIS PS 09-00660), Basque Government (SAO12-PE12BN008), Ilundain Foundation, and Isabel Gemio Foundation. MAAJ is supported by the Basque Government’s program of predoctoral fellowships.

Conflict of interest and funding

The authors have not received any funding or benefits from industry or elsewhere to conduct this study.


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About The Authors

Alba Judith Mateos-Aierdi
Neuroscience Area, Instituto Biodonostia, Hospital Universitario Donostia, San Sebastian, Spain. CIBERNED, Instituto de Salud Carlos III, Ministry of Economy and Competitiveness, Madrid, Spain.

Ana Aiastui
CIBERNED, Instituto de Salud Carlos III, Ministry of Economy and Competitiveness, Madrid, Spain. Cell Culture Platform, Instituto Biodonostia, Hospital Universitario Donostia, San Sebastian, Spain.

Maria Goicoechea
Neuroscience Area, Instituto Biodonostia, Hospital Universitario Donostia, San Sebastian, Spain. CIBERNED, Instituto de Salud Carlos III, Ministry of Economy and Competitiveness, Madrid, Spain.

Adolfo López de Munain
Neuroscience Area, Instituto Biodonostia, Hospital Universitario Donostia, San Sebastian, Spain CIBERNED, Instituto de Salud Carlos III, Ministry of Economy and Competitiveness, Madrid, Spain. Cell Culture Platform, Instituto Biodonostia, Hospital Universitario Donostia, San Sebastian, Spain. Department of Neurosciences, University of the Basque Country (UPV-EHU), San Sebastian, Spain. Department of Neurology, Hospital Universitario Donostia, San Sebastian, Spain.