CHAPEL HILL, NC, United States

Asklepios Biopharmaceutical, Inc.
CHAPEL HILL, NC, United States
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Bowles D.E.,Duke University | McPhee S.W.J.,Asklepios Biopharmaceutical, Inc. | Li C.,University of North Carolina at Chapel Hill | Gray S.J.,University of North Carolina at Chapel Hill | And 11 more authors.
Molecular Therapy | Year: 2012

Efficient and widespread gene transfer is required for successful treatment of Duchenne muscular dystrophy (DMD). Here, we performed the first clinical trial using a chimeric adeno-associated virus (AAV) capsid variant (designated AAV2.5) derived from a rational design strategy. AAV2.5 was generated from the AAV2 capsid with five mutations from AAV1. The novel chimeric vector combines the improved muscle transduction capacity of AAV1 with reduced antigenic crossreactivity against both parental serotypes, while keeping the AAV2 receptor binding. In a randomized double-blind placebo-controlled phase I clinical study in DMD boys, AAV2.5 vector was injected into the bicep muscle in one arm, with saline control in the contralateral arm. A subset of patients received AAV empty capsid instead of saline in an effort to distinguish an immune response to vector versus minidystrophin transgene. Recombinant AAV genomes were detected in all patients with up to 2.56 vector copies per diploid genome. There was no cellular immune response to AAV2.5 capsid. This trial established that rationally designed AAV2.5 vector was safe and well tolerated, lays the foundation of customizing AAV vectors that best suit the clinical objective (e.g., limb infusion gene delivery) and should usher in the next generation of viral delivery systems for human gene transfer. © The American Society of Gene & Cell Therapy.

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.

Leone P.,Rutgers University | Shera D.,Children's 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.

Diprimio N.,University of North Carolina at Chapel Hill | McPhee S.W.J.,Asklepios Biopharmaceutical, Inc. | Samulski R.J.,University of North Carolina at Chapel Hill | Samulski R.J.,Asklepios Biopharmaceutical, Inc.
Current Opinion in Molecular Therapeutics | Year: 2010

Muscle diseases include muscular dystrophies, cardiomyopathies, neuromuscular and metabolic disorders. The loss of normal muscle structure and function is associated with significant morbidity and mortality. Patients with Duchenne muscular dystrophy usually lose ambulation in their teenage years, and frequently experience severe respiratory problems and heart failure in later stages of life. These unmet medical needs have encouraged the development of genetic strategies targeting the underlying muscle disease processes. Adeno-associated virus (AAV) vectors have been identified as promising gene delivery candidates because of their ability to transduce muscle tissue efficiently while transporting a genetic payload. There is currently significant momentum in the research of AAV-mediated delivery of muscle genes. Various AAV-based therapeutic strategies are undergoing preclinical and clinical testing, including the use of miniaturized and codon-optimized transgenes, exon skipping expression cassettes, novel tissue-specific promoters, AAV capsid mutants and chimeras, and localized intravascular administration procedures. These advancements in gene delivery have led to the generation of AAV vectors with targeted transgene expression, tissue-selective tropism and minimal off-target effects. This review describes advances in AAV gene therapy that are specific to the treatment of muscle diseases, and discusses the implications of their clinical application. © 2010 Thomson Reuters (Scientific) Ltd.

Mendell J.R.,Nationwide Childrens Hospital | Mendell J.R.,Ohio State University | Campbell K.,Nationwide Childrens Hospital | Campbell K.,Ohio State University | And 20 more authors.
New England Journal of Medicine | Year: 2010

We report on delivery of a functional dystrophin transgene to skeletal muscle in six patients with Duchenne's muscular dystrophy. Dystrophin-specific T cells were detected after treatment, providing evidence of transgene expression even when the functional protein was not visualized in skeletal muscle. Circulating dystrophin-specific T cells were unexpectedly detected in two patients before vector treatment. Revertant dystrophin fibers, which expressed functional, truncated dystrophin from the deleted endogenous gene after spontaneous in-frame splicing, contained epitopes targeted by the autoreactive T cells. The potential for T-cell immunity to self and nonself dystrophin epitopes should be considered in designing and monitoring experimental therapies for this disease. Copyright © 2010 Massachusetts Medical Society.

Asklepios Biopharmaceutical, Inc. | Date: 2015-03-18

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.

Asklepios Biopharmaceutical, Inc. | Date: 2014-03-12

The present invention relates to a modified and optimized sFlt1 nucleic acid for inclusion in a virus vector. Use of such vectors can be used for treatment of ocular disorders causing neovascularization, such as macular degeneration.

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.

Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 270.01K | Year: 2014

Abstract We propose to initiate preclinical development of a gene therapeutic targeted to Alzheimer's Disease. The World Health Organization's and Alzheimer's Disease International's report on Dementia (2012) recognizes that the global burden of AlzheimerDisease is forecast to worsen significantly with prevalence predicted to double every 20 years. Interventions that could provide a modest delay in progression would provide a significant reduction in the high level care required later in the disease. ThisPhase I proposal describes an Adeno-associated viral vector-based metabolic intervention strategy to combat age-related cognitive decline in the 5xFAD model of familial Alzheimer's disease. A broad range of neurodegenerative disorders manifest abnormalities in the metabolism of the abundant amino acid derivative N-acetyl-L-aspartic acid (NAA). Fluctuations in NAA concentration within the brain are generally accepted as an index of oxidative metabolic integrity in neurons. NAA synthesis and catabolism are p

PubMed | Asklepios Biopharmaceutical, Inc. and Universitatsklinika Giessen und Marburg GmbH
Type: | Journal: Der Unfallchirurg | Year: 2017

In clinical practice, situations continuously occur in which medical professionals and family members are confronted with decisions on whether to extend or limit treatment for severely ill patients in end of life treatment decisions. In these situations, advance directives are helpful tools in decision making according to the wishes of the patient; however, not every patient has made an advance directive and in our experience medical staff as well as patients are often not familiar with these documents. The purpose of this article is therefore to explain the currently available documents (e.g. living will, healthcare power of attorney and care directive) and the possible (legal) applications and limitations in the routine clinical practice.

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