Sustained expression and safety of human GNE in normal mice after gene transfer based on AAV8 systemic delivery

Mitrani-Rosenbaum, Stella; Yakovlev, Lena; Cohen, Michal Becker; Telem, Michal; Elbaz, Moran; Yanay, Nurit; Yotvat, Hagit; Shlomo, Uri Ben; Harazi, Avi; Fellig, Yakov; Argov, Zohar; Sela, Ilan

doi:10.1016/j.nmd.2012.03.013

Cited by 27 publications

(21 citation statements)

References 36 publications

(34 reference statements)

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“…However, understanding the underlying defect in GNE myopathy has allowed the development of targeted therapeutic strategies for the disease based on either providing precursors of the sialic acid biosynthetic pathway (sialylation-increasing therapies) or restoring UDP-GlcNAc 2-epimerase and ManNAc kinase enzymatic activities by gene or cell therapy approaches ( Table 2). Studies on murine models have been conducted for sialylation-increasing therapies, including Neu5Ac, N-acetyl-D-mannosamine (ManNAc), peracetylated ManNAc, or sialyllactose [11,67,68,82,83], and gene therapy applications [84].…”

Section: Potential Therapiesmentioning

confidence: 99%

“…The main issue with the use of rAAV is the presence of preexisting neutralizing antibodies against the rAAV capsid proteins which decrease the transduction of the gene to target tissues [100]. The AAV8 vector has shown to provide effective delivery of the GNE gene to murine and human-derived muscle cells in culture and safe systemic administration to healthy mice [84]. However, preexisting serum antibodies to a wide variety of rAAV serotypes, including rAAV8, were present in~50% of GNE myopathy patients tested in a recent study [101].…”

Section: Gene and Cell Therapiesmentioning

confidence: 99%

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GNE Myopathy: Etiology, Diagnosis, and Therapeutic Challenges

2018

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GNE myopathy, previously known as hereditary inclusion body myopathy (HIBM), or Nonaka myopathy, is a rare autosomal recessive muscle disease characterized by progressive skeletal muscle atrophy. It has an estimated prevalence of 1 to 9:1,000,000. GNE myopathy is caused by mutations in the GNE gene which encodes the rate-limiting enzyme of sialic acid biosynthesis. The pathophysiology of the disease is not entirely understood, but hyposialylation of muscle glycans is thought to play an essential role. The typical presentation is bilateral foot drop caused by weakness of the anterior tibialis muscles with onset in early adulthood. The disease slowly progresses over the next decades to involve skeletal muscles throughout the body, with relative sparing of the quadriceps until late stages of the disease. The diagnosis of GNE myopathy should be considered in young adults presenting with bilateral foot drop. Histopathologic findings on muscle biopsies include fiber size variation, atrophic fibers, lack of inflammation, and the characteristic Brimmed^vacuoles on modified Gomori trichome staining. The diagnosis is confirmed by the presence of pathogenic (mostly missense) mutations in both alleles of the GNE gene. Although there is no approved therapy for this disease, preclinical and clinical studies of several potential therapies are underway, including substrate replacement and gene therapy-based strategies. However, developing therapies for GNE myopathy is complicated by several factors, including the rare incidence of disease, limited preclinical models, lack of reliable biomarkers, and slow disease progression.

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Section: Potential Therapiesmentioning

confidence: 99%

Section: Gene and Cell Therapiesmentioning

confidence: 99%

GNE Myopathy: Etiology, Diagnosis, and Therapeutic Challenges

2018

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“…Hereby, no pathological signs of focal or general toxicity, neither from the virus particles nor from the wild type human GNE overexpression could be observed. This sustained and safety expression of human GNE in normal mice after gene transfer based on AAV8 systemic delivery suggests that GNE-based gene therapy might represent a promising concept to treat the disease [ 72 ].…”

Section: Disease Models and Pathomechanismsmentioning

confidence: 99%

GNE myopathy: from clinics and genetics to pathology and research strategies

Pogoryelova

Coraspe

Nikolenko

et al. 2018

Orphanet J Rare Dis

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GNE myopathy is an ultra-rare autosomal recessive disease, which starts as a distal muscle weakness and ultimately leads to a wheelchair bound state. Molecular research and animal modelling significantly moved forward understanding of GNE myopathy mechanisms and suggested therapeutic interventions to alleviate the symptoms. Multiple therapeutic attempts are being made to supplement sialic acid depleted in GNE myopathy muscle cells. Translational research field provided valuable knowledge through natural history studies, patient registries and clinical trial, which significantly contributed to bringing forward an era of GNE myopathy treatment. In this review, we are summarising current GNE myopathy, scientific trends and open questions, which would be of significant interest for a wide neuromuscular diseases community.

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“…GNE myopathy is an autosomal recessive disease caused by biallelic GNE gene mutations1 2 15 (figure 2). Missense mutations account for the majority of alleles and no patient with biallelic null mutations has ever been found, suggesting that probably only ‘mildly deleterious’ mutations that are not associated with complete loss of GNE protein are necessary to cause this adult-onset myopathy.…”

Section: Genetic Cause and Possible Molecular Mechanismmentioning

confidence: 99%