SBIR-STTR Award

Recombinant adeno-associated viral (rAAV) vectors are to be developed for transgene delivery to the central nervous system (CNS). In particular, we are engineering rAAVs designed to transduce an expression cassette carrying the human gene for glial cell-derived neurotrophic factor (GDNF). GDNF is a novel member of the transforming growth factor-beta (TGF-beta) superfamily which displays potent trophic effects on dopamine neurons. Dopaminergic function plays a key role in affective and regulatory behaviors and in human neuropsychiatric and neurodegenerative diseases. A number of disorders, such as schizophrenia, attention deficit/hyperactivity disorder, and Parkinson's disease, involve some dysfunction in dopaminergic pathways. Gene therapy employing rAAVs may provide a means of directly altering the physiology and gene expression of the affected cells within the CNS.National Institute of Mental Health (NIMH)

The long range goal of the gene therapy program at Alkermes is to develop recombinant adeno-associated virus (rAAV) vectors to be used in the treatment of neurodegenerative disorders. In recent years there have been substantial advances in the techniques of gene transfer, the development of relevant animal models for neurodegenerative disorders, as well as clinical trial experience involving various gene therapy protocols. In this application, the development and evaluation of rAAV vectors to be used in the treatment of Parkinson's disease is proposed. Phase I studies of the interaction between AAV and the nervous system has demonstrated that this virus may be particularly well suited for gene therapy applications in the central nervous system (CNS). We have observed persistence of transgene expression in the mouse brain out to 56 days, the latest time point examined, with no evidence of virus- associated toxicity. For the treatment of Parkinson's disease, these vectors are designed to introduce and express, within the CNS, the gene encoding the human glial cell line-derived neurotrophic factor (GDNF). GDNF is a potent dopaminotrophic factor, capable of enhancing the survival of midbrain dopamine neurons, the cells most severely affected by neurodegeneration in Parkinson's disease.Proposed commercial application:Successful treatment of Parkinson's disease and other neurodegenerative disorders represents one of the most significant medical, social and commercial opportunities in health care. Diseases such as Parkinson's and Alzheimer's, which are characterized by a slow, progressive deterioration, result in enormous cumulative costs associated with the requirement for increasing levels of medical care as the disease progresses. Presently, no therapies exist which have been shown to reduce or halt the progression of these disorders. The rAAV-GDNF gene therapy vectors that are the subject of this proposal represent the first step in this direction for the treatment of Parkinson's disease.Thesaurus termsParkinson's disease, adeno associated virus group, biotechnology, gene targeting, neurotrophic factor, transfection vector dopamine, gene therapy, nonhuman therapy evaluation, pharmacokinetics, recombinant virus chromatography, histology, human tissue, laboratory rat, microorganism mass cultureNational Institute of Mental Health (NIMH)