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CHAPEL HILL, NC, United States

Asokan A.,University of North Carolina at Chapel Hill | Conway J.C.,University of North Carolina at Chapel Hill | Phillips J.L.,University of North Carolina at Chapel Hill | Li C.,University of North Carolina at Chapel Hill | And 9 more authors.
Nature Biotechnology | Year: 2010

Reengineering the receptor footprints of adeno-associated virus (AAV) isolates may yield variants with improved properties for clinical applications. We generated a panel of synthetic AAV2 vectors by replacing a hexapeptide sequence in a previously identified heparan sulfate receptor footprint with corresponding residues from other AAV strains. This approach yielded several chimeric capsids displaying systemic tropism after intravenous administration in mice. Of particular interest, an AAV2/AAV8 chimera designated AAV2i8 displayed an altered antigenic profile, readily traversed the blood vasculature, and selectively transduced cardiac and whole-body skeletal muscle tissues with high efficiency. Unlike other AAV serotypes, which are preferentially sequestered in the liver, AAV2i8 showed markedly reduced hepatic tropism. These features of AAV2i8 suggest that it is well suited to translational studies in gene therapy of musculoskeletal disorders. © 2010 Nature America, Inc. All rights reserved.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 2.69M | Year: 2008

DESCRIPTION (provided by applicant): This proposal intends to advance the regional delivery of a chimeric adeno-associated virus (rAAV)-based, highly-truncated dystrophin (minidystrophin) gene therapy for the treatment of Duchenes Muscular Dystrophy (DMD). Experiments focus on completing preclinical studies required to initiate, the also proposed, FDA recommended Phase Ib bridging study. The proposed Phase Ib investigates regional gene delivery to the lower extremities of DMD patients. More specifically, th e studies herein evaluate vector delivery (transduction potential) and expression profiles achieved using blood vessel-mediated, regional, isolated lower limb infusion (ILP) in large animal models [the Golden Retriever Muscular Dystrophy model (GRMD) and n on-human primates (NHP)]. The GRMD model offers the additional potential to investigate the efficacy of rAAV- minidystrophin in ameliorating the nearest pathological counterpart of DMD. Our preliminary Phase 1 data indicate rAAV-minidystrophin is well tole rated and mediates expression levels as high as 2.5 transgene copies/diploid genome when directly injected in the bicep. Additionally, initial investigations of tranvascular limb delivery in GRMD and NHP demonstrate widespread transduction potential, and s ustained high levels of gene expression. These data cumulatively allude to the positive outcomes expected from the proposed preclinical studies on which the jointly proposed Phase Ib trial is contingent. A positive outcome of rAAV-minidystrophin in Phase 1 b clinical trials is expected to immediately impact DMD patients by supporting Phase II clinical trials of regional limb delivery of rAAV-minidystrophin. More importantly advancing a gene therapy for DMD offers the significant potential for prolonged ambul ation, increased exercise capacity, and reduced disease progression to a currently incurable population whose treatments remain palliative. In recognition of this potential and in light of the preliminary studies including an Interim DSMB/IDMC Phase Ia tri al report, Asklepios Biopharmaceutical has been awarded an MDA TRAC grant funding 50% of the proposed studies. This proposal intends to advance the regional delivery of a gene therapy for the treatment of Duchenes Muscular Dystrophy (DMD). Experiments focu s on completing preclinical studies in large animal models that are required to initiate, the also proposed and FDA recommended, Phase Ib bridging study that involves regional gene delivery to the lower extremities of DMD patients. Advancing a gene therapy for DMD offers the significant potential for improved quality of life to a currently incurable population whose treatments remain palliative.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 157.07K | Year: 2005

DESCRIPTION (provided by applicant): Repair of large structural bone defects remains a major problem in orthopaedic reconstruction surgery due to the limited supply of cortical bone autograft and the poor long-term outcomes obtained with structural allografts. While there is no substitute for structural allografts, based on their biomechanical and biocompatible properties, their lack of osteogenic and osteoinductive potential, combined with the host's inability to remodel processed cortical bone, results in a high percentage of fractures. Towards the development and commercialization of the first revitalizing structural allograft, Asklepios Inc. and LAGeT Inc. have enter into a partnership that will combine core competencies in recombinant adeno-associated virus (rAAV) mediated gene transfer with orthopaedic pre-clinical and clinical development. In collaboration, we have established a murine model of femoral allograft healing and demonstrated that first generation rAAV vectors can be freeze-dried onto the cortical surface of femoral allografts and efficiently transduce proximal cells in vivo following transplantation. Furthermore, we have shown the feasibility of this approach to revitalized processed structural allografts using a constitutively active type I BMP receptor (caAlk2) target gene. Based on this success, here we propose three requisite studies towards commercialization: Specific Aim 1, to identify the optimal rAAV serotype; Specific Aim 2, to determine the optimal titer of rAAV/mmS allograft; and Specific Aim 3, perform an efficacy study that will yield quantitative micro-CT and histomorphometry data on new bone formation over the allograft that can be used to formulate methodologies and power calculations for large animal pre-clinical and clinical trials. While this application focuses on a very specific indication that has a very low prevalence, the rAAV serotype and coating technologies have enormous potential to prevent host rejection and improve engraftment and healing of all implantable and surgical materials. Thus, our success here will open many areas of investigation and opportunities in all areas of medicine.

Asklepios Biopharmaceutical, Inc. | Date: 2014-01-17

The present invention relates to a modified and optimized Factor VIII or Factor IX nucleic acid for inclusion in a chimeric virus vector. Use of such vector can be used for treatment of hemophilia.

Leone P.,Rutgers University | Shera D.,Childrens Hospital of Philadelphia | McPhee S.W.J.,Asklepios Biopharmaceutical, Inc. | Francis J.S.,Rutgers University | And 13 more authors.
Science Translational Medicine | Year: 2012

Canavan disease is a hereditary leukodystrophy caused by mutations in the aspartoacylase gene (ASPA), leading to loss of enzyme activity and increased concentrations of the substrate N-acetyl-aspartate (NAA) in the brain. Accumulation of NAA results in spongiform degeneration of white matter and severe impairment of psychomotor development. The goal of this prospective cohort study was to assess long-term safety and preliminary efficacy measures after gene therapy with an adeno-associated viral vector carrying the ASPA gene (AAV2-ASPA). Using noninvasivemagnetic resonance imaging and standardized clinical rating scales, we observed Canavan disease in 28 patients, with a subset of 13 patients being treated with AAV2-ASPA. Each patient received 9 × 1011 vector genomes via intraparenchymal delivery at six brain infusion sites. Safety data collected over a minimum 5-year follow-up period showed a lack of long-term adverse events related to the AAV2 vector. Posttreatment effects were analyzed using a generalized linear mixed model, which showed changes in predefined surrogate markers of disease progression and clinical assessment subscores. AAV2-ASPA gene therapy resulted in a decrease in elevated NAA in the brain and slowed progression of brain atrophy, with some improvement in seizure frequency and with stabilization of overall clinical status.

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