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Gene Delivery for Limb-Girdle Muscular Dystrophy Type 2D by Isolated Limb Infusion.
Mendell, Jerry R; Chicoine, Louis G; Al-Zaidy, Samiah A; Sahenk, Zarife; Lehman, Kelly; Lowes, Linda; Miller, Natalie; Alfano, Lindsay; Galliers, Beverly; Lewis, Sarah; Murrey, Darren; Peterson, Ellyn; Griffin, Danielle A; Church, Kathleen; Cheatham, Sharon; Cheatham, John; Hogan, Mark J; Rodino-Klapac, Louise R.
Afiliación
  • Mendell JR; 1Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.
  • Chicoine LG; 2Department of Pediatrics, The Ohio State University, Columbus, Ohio.
  • Al-Zaidy SA; 3Department of Neurology, The Ohio State University, Columbus, Ohio.
  • Sahenk Z; 1Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.
  • Lehman K; 2Department of Pediatrics, The Ohio State University, Columbus, Ohio.
  • Lowes L; 2Department of Pediatrics, The Ohio State University, Columbus, Ohio.
  • Miller N; 1Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.
  • Alfano L; 2Department of Pediatrics, The Ohio State University, Columbus, Ohio.
  • Galliers B; 3Department of Neurology, The Ohio State University, Columbus, Ohio.
  • Lewis S; 1Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.
  • Murrey D; 1Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.
  • Peterson E; 2Department of Pediatrics, The Ohio State University, Columbus, Ohio.
  • Griffin DA; 3Department of Neurology, The Ohio State University, Columbus, Ohio.
  • Church K; 1Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.
  • Cheatham S; 1Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.
  • Cheatham J; 3Department of Neurology, The Ohio State University, Columbus, Ohio.
  • Hogan MJ; 1Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.
  • Rodino-Klapac LR; 1Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.
Hum Gene Ther ; 30(7): 794-801, 2019 07.
Article en En | MEDLINE | ID: mdl-30838895
In a previous limb-girdle muscular dystrophy type 2D (LGMD2D) clinical trial, robust alpha-sarcoglycan gene expression was confirmed following intramuscular gene (SGCA) transfer. This paved the way for first-in-human isolated limb infusion (ILI) gene transfer trial to the lower limbs. Delivery of scAAVrh74.tMCK.hSGCA via an intravascular route through the femoral artery predicted improved ambulation. This method was initially chosen to avoid safety concerns required for large systemic vascular delivery viral loads. ILI methods were adopted from the extensive chemotherapy experience for treatment of malignancies confined to the extremities. Six LGMD2D subjects were enrolled in a dose-ascending open-label clinical trial. Safety of the procedure was initially assessed in the single limb of a non-ambulant affected adult at a dose of 1 × 1012 vg/kg. Subsequently, ambulatory children (aged 8-13 years) were enrolled and dosed bilaterally with either 1 × 1012 vg/kg/limb or 3 × 1012 vg/kg/limb. The six-minute walk test (6MWT) served as the primary clinical outcome; secondary outcomes included muscle strength (maximum voluntary isometric force testing) and SGCA expression at 6 months. All ambulatory participants except one had pre- and post-treatment muscle biopsies. All four subjects biopsied had confirmed SGCA gene delivery by immunofluorescence, Western blot analysis (14-25% of normal), and vector genome copies (5.4 × 103-7.7 × 104 vg/µg). Muscle strength in the knee extensors (assessed by force generation in kilograms) showed improvement in two subjects that correlated with an increase in fiber diameter post gene delivery. Six-minute walk times decreased or remained the same. Vascular delivery of AAVrh74.tMCK.hSGCA was effective at producing SGCA protein at low doses that correlated with vector copies and local functional improvement restricted to targeted muscles. Future trials will focus on systemic administration to enable targeting of proximal muscles to maximize clinical benefit.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Terapia Genética / Técnicas de Transferencia de Gen / Transgenes / Distrofia Muscular de Cinturas / Sarcoglicanopatías / Vectores Genéticos Tipo de estudio: Prognostic_studies Límite: Animals / Child / Female / Humans / Male / Middle aged Idioma: En Revista: Hum Gene Ther Asunto de la revista: GENETICA MEDICA / TERAPEUTICA Año: 2019 Tipo del documento: Article

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Terapia Genética / Técnicas de Transferencia de Gen / Transgenes / Distrofia Muscular de Cinturas / Sarcoglicanopatías / Vectores Genéticos Tipo de estudio: Prognostic_studies Límite: Animals / Child / Female / Humans / Male / Middle aged Idioma: En Revista: Hum Gene Ther Asunto de la revista: GENETICA MEDICA / TERAPEUTICA Año: 2019 Tipo del documento: Article