title: 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.
authors.affiliation: Mary Crowley Cancer Research Centers, Dallas, TX 75201, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Nemunaitis
authors.forename: Chris M
authors.initials: CM
authors.lastname: Jay
authors.forename: Phillip B
authors.initials: PB
authors.lastname: Maples
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
authors.forename: Marjan
authors.initials: M
authors.lastname: Huizing
authors.forename: Tal
authors.initials: T
authors.lastname: Yardeni
authors.forename: Alex W
authors.initials: AW
authors.lastname: Tong
authors.forename: Anagha P
authors.initials: AP
authors.lastname: Phadke
authors.forename: Beena O
authors.initials: BO
authors.lastname: Pappen
authors.forename: Cynthia
authors.initials: C
authors.lastname: Bedell
authors.forename: Henry
authors.initials: H
authors.lastname: Allen
authors.forename: Cathy
authors.initials: C
authors.lastname: Hernandez
authors.forename: Nancy S
authors.initials: NS
authors.lastname: Templeton
authors.forename: Joseph
authors.initials: J
authors.lastname: Kuhn
authors.forename: Neil
authors.initials: N
authors.lastname: Senzer
authors.forename: John
authors.initials: J
authors.lastname: Nemunaitis
mesh_terms: D000328:Adult; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D007262:Infusions, Intravenous; D008081:Liposomes; D009097:Multienzyme Complexes / Q000235:genetics*; D018482:Muscle, Skeletal / Q000473:pathology / Q000503:physiopathology; D018979:Myositis, Inclusion Body / Q000235:genetics / Q000628:therapy*; D012313:RNA / Q000378:metabolism
chemical_list: D008081:Liposomes; D009097:Multienzyme Complexes; C482901:UDP-N-acetylglucosamine 2-epimerase - N-acetylmannosamine kinase; D012313:RNA