B4GALNT2 (GALGT2) Gene Therapy Reduces Skeletal Muscle Pathology in the FKRP P448L Mouse Model of Limb Girdle Muscular Dystrophy 2I

Thomas, Paul J.; Xu, Rui; Martin, Paul

doi:10.1016/j.ajpath.2016.05.021

Cited by 36 publications

(29 citation statements)

References 66 publications

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“…Onset and severity of symptoms are highly heterogeneous. Putative therapeutic approaches, including gene therapy, immunomodulation and targeting glycosylation of α ‐dystroglycan, are currently being evaluated. As therapeutics are developed, it is important to establish sensitive outcome measures for clinical trials.…”

Section: Introductionmentioning

confidence: 99%

Natural history of limb girdle muscular dystrophy R9 over 6 years: searching for trial endpoints

Murphy

Morrow

Dahlqvist

et al. 2019

Ann Clin Transl Neurol

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Objective Limb girdle muscular dystrophy type R9 (LGMD R9) is an autosomal recessive muscle disease for which there is currently no causative treatment. The development of putative therapies requires sensitive outcome measures for clinical trials in this slowly progressing condition. This study extends functional assessments and MRI muscle fat fraction measurements in an LGMD R9 cohort across 6 years. Methods Twenty‐three participants with LGMD R9, previously assessed over a 1‐year period, were re‐enrolled at 6 years. Standardized functional assessments were performed including: myometry, timed tests, and spirometry testing. Quantitative MRI was used to measure fat fraction in lower limb skeletal muscle groups. Results At 6 years, all 14 muscle groups assessed demonstrated significant increases in fat fraction, compared to eight groups in the 1‐year follow‐up study. In direct contrast to the 1‐year follow‐up, the 6‐min walk test, 10‐m walk or run, timed up and go, stair ascend, stair descend and chair rise demonstrated significant decline. Among the functional tests, only FVC significantly declined over both the 1‐ and 6‐year studies. Interpretation These results further support fat fraction measurements as a primary outcome measure alongside functional assessments. The most appropriate individual muscles are the vastus lateralis, gracilis, sartorius, and gastrocnemii. Using composite groups of lower leg muscles, thigh muscles, or triceps surae, yielded high standardized response means (SRMs). Over 6 years, quantitative fat fraction assessment demonstrated higher SRM values than seen in functional tests suggesting greater responsiveness to disease progression.

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Section: Introductionmentioning

confidence: 99%

Natural history of limb girdle muscular dystrophy R9 over 6 years: searching for trial endpoints

Murphy

Morrow

Dahlqvist

et al. 2019

Ann Clin Transl Neurol

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“…Importantly, B4GALNT2 expression was able to inhibit the infection of cells with multiple strains of low passage avian influenza viruses, including H7N2, H9N2, H5N9, and H10N4 strains. As H7, H9, and H5 avian viruses have historically caused most of the severe disease in domesticated poultry as well as in humans, B4GALNT2 may be an attractive host factor to target therapeutically either via gene therapy (Thomas et al, 2016) or small molecule induction of gene transcription (Denison and Kodadek, 1998). …”

Section: Discussionmentioning

confidence: 99%

A CRISPR Activation Screen Identifies a Pan-avian Influenza Virus Inhibitory Host Factor

et al. 2017

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Summary Influenza A virus (IAV) is a pathogen that poses significant risks to human health. It is therefore critical to develop strategies to prevent influenza disease. Many loss-of-function screens have been performed to identify the host proteins required for viral infection. However, there has been no systematic screen to identify the host factors that when over-expressed are sufficient to prevent infection. In this study, we utilized CRISPR/dCas9 activation technology to perform a genome-wide overexpression screen to identify IAV restriction factors. The major hit from our screen, B4GALNT2, showed inhibitory activity against influenza viruses with an α2,3 linked sialic acid receptor preference. In fact, B4GALNT2 overexpression prevented the infection of every avian influenza virus strain tested, including the H5, H9, and H7 subtypes, which have previously caused disease in humans. Thus, we have utilized CRISPR/dCas9 activation technology to identify a factor that can completely abolish infection by avian influenza viruses.

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“…GALGT2 overexpression did not cause substantial glycosylation of αdystroglycan or increased expression of dystrophin and laminin α2 surrogates in mature skeletal myofibers, but it increased the number of embryonic myosin-positive regenerating myofibers. These data demonstrate that GALGT2 overexpression can reduce muscle pathology in the FKRP P448Lneo mice model for limb-girdle muscular dystrophy 2I, via a different mechanism from its ability to induce surrogate gene expression [53].…”

Section: α-Dystroglycanopathiesmentioning

confidence: 85%

The Limb–Girdle Muscular Dystrophies: Is Treatment on the Horizon?

Chu

Moran

2018

Neurotherapeutics

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There has been an ever-expanding list of the Limb-Girdle Muscular Dystrophies (LGMD). There are currently 8 subtypes of autosomal dominant (AD) and 26 subtypes of autosomal recessive (AR) LGMD. Despite continued research efforts to conquer this group of genetic neuromuscular disease, patients continue to be treated symptomatically with the aim of prevention or addressing complications. Mouse models have been helpful in clarifying disease pathogenesis as well as strategizing pathways for treatment. Discoveries in translational research as well as molecular therapeutic approaches have kept clinicians optimistic that more promising clinical trials will lead the way to finding the cure for these devastating disorders. It is well known that the challenge for these rare diseases is the ability to assemble adequate numbers of patients for a clinically meaningful trial, but current efforts in developing patient registries have been encouraging. Natural history studies will be essential in establishing and interpreting the appropriate outcome measures for clinical trials. Nevertheless, animal studies continue to be key in providing proof of concept that will be necessary in moving research along. This review will briefly discuss each type of LGMD, highlighting their distinguishing features, then focus on research efforts that have been published in the literature for the past few years, many of which are still in the preclinical trial stage.

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B4GALNT2 (GALGT2) Gene Therapy Reduces Skeletal Muscle Pathology in the FKRP P448L Mouse Model of Limb Girdle Muscular Dystrophy 2I

Cited by 36 publications

References 66 publications

Natural history of limb girdle muscular dystrophy R9 over 6 years: searching for trial endpoints

Natural history of limb girdle muscular dystrophy R9 over 6 years: searching for trial endpoints

A CRISPR Activation Screen Identifies a Pan-avian Influenza Virus Inhibitory Host Factor

The Limb–Girdle Muscular Dystrophies: Is Treatment on the Horizon?

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