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Hereditary inclusion body myopathy: single patient response to intravenous dosing of GNE gene lipoplex.

ABSTRACT: Hereditary inclusion body myopathy (HIBM) is an autosomal recessive adult-onset myopathy due to mutations in the GNE (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase) gene. Affected patients have no therapeutic options. We have previously demonstrated in preclinical testing the ability to safely correct GNE gene function through liposomal delivery of the wild-type GNE gene. Results were verified in a single patient treated by intravenous infusion of GNE gene lipoplex. A single patient (patient 001) with severe HIBM treated with a compassionate investigational new drug received seven doses of GNE gene lipoplex via intravenous infusion at the following doses: 0.4, 0.4, 1.0, 4.0, 5.0, 6.0, and 7.0 mg of DNA. GNE transgene expression, downstream induction of sialic acid, safety, and muscle function were evaluated. Transient low-grade fever, myalgia, tachycardia, transaminase elevation, hyponatremia, and hypotension were observed after infusion of each dose of GNE gene lipoplex. Quadriceps muscle expression of the delivered GNE, plasmid, and RNA was observed 24 hr after the 5.0-mg dose and at significantly greater levels 72 hr after the 7.0-mg infusion in comparison with expression in quadriceps muscle immediately before infusion. Sialic acid-related proteins were increased and stabilization in the decline of muscle strength was observed. We conclude that clinical safety and activity have been demonstrated with intravenous infusion of GNE gene lipoplex. Further assessment will involve a phase I trial of intravenous administration of GNE gene lipoplex in individuals with less advanced HIBM with more muscle function.

SUBMITTER: Nemunaitis G

PROVIDER: S-EPMC3225042 | biostudies-other | 2011 Nov

REPOSITORIES: biostudies-other

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Hereditary inclusion body myopathy: single patient response to intravenous dosing of GNE gene lipoplex.

Nemunaitis Gregory G Jay Chris M CM Maples Phillip B PB Gahl William A WA Huizing Marjan M Yardeni Tal T Tong Alex W AW Phadke Anagha P AP Pappen Beena O BO Bedell Cynthia C Allen Henry H Hernandez Cathy C Templeton Nancy S NS Kuhn Joseph J Senzer Neil N Nemunaitis John J

Human gene therapy 20110425 11

Hereditary inclusion body myopathy (HIBM) is an autosomal recessive adult-onset myopathy due to mutations in the GNE (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase) gene. Affected patients have no therapeutic options. We have previously demonstrated in preclinical testing the ability to safely correct GNE gene function through liposomal delivery of the wild-type GNE gene. Results were verified in a single patient treated by intravenous infusion of GNE gene lipoplex. A single pat ...[more]

PMID: 21517694

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Project description:GNE myopathy is a slowly progressive autosomal recessive myopathy caused by mutations in the GNE (glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase) gene. This study aimed to (1) develop a nationwide patient registry for GNE myopathy in order to facilitate the planning of clinical trials and recruitment of candidates, and (2) gain further insight into the disease for the purpose of improving therapy and care.Medical records of genetically-confirmed patients with GNE myopathy at the National Center Hospital of the National Center of Neurology and Psychiatry (NCNP) were retrospectively reviewed in order to obtain data reflecting the severity and progression of the disease. We also referred to items in the datasheet of the nationwide registry of dystrophinopathy patients in the Registry of Muscular Dystrophies (Remudy). Items selected for the registration sheet included age, sex, age at onset, past history and complications, family history, body weight and height, pathological findings of muscle biopsy, grip power, walking ability, respiratory function, cardiac function, willingness to join upcoming clinical trials, and participation in patient associations. A copy of the original genetic analysis report was required of each patient.We successfully established the Remudy-GNE myopathy. Currently, 121 patients are registered nationwide, and 93 physicians from 73 hospitals collaborated to establish the registry. The mean age at onset was 27.7?±?9.6 years, and 19.8% (24/121) of patients could walk without assistance. Mean presumed durations from onset to use of assistive devices (cane and/or braces) and a wheelchair, and loss of ambulation were 12.4, 15.2, and 21.1 years, respectively. Three patients had a past history and/or complication of idiopathic thrombocytopenia. To share the progress of this study with the community, newsletters were published on a regular basis, and included information regarding new phase I clinical trials for GNE myopathy. The newsletters also served as a medium to bring attention to the importance of respiratory evaluation and care for respiratory insufficiency.The Japanese Remudy-GNE myopathy is useful for clarifying the natural history of the disease and recruiting patients with genetically-confirmed GNE myopathy for clinical trials.

Dataset Information

Hereditary inclusion body myopathy: single patient response to intravenous dosing of GNE gene lipoplex.

Publications

Hereditary inclusion body myopathy: single patient response to intravenous dosing of GNE gene lipoplex.

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