Researchers at the University of Alabama at Birmingham reported a new gene therapy for treating Parkinson Disease at the Public Library of Science site on September 17, 2010.
Gene-based therapy is a new paradigm for the treatment of Parkinson disease (PD) and offers considerable promise for precise targeting and flexibility to impact multiple pathobiological processes for which small molecule agents are not available. Some success has been achieved utilizing adeno-associated virus for this approach, but it is likely that the characteristics of this vector system will ultimately create barriers to progress in clinical therapy. Adenovirus (Ad) vector overcomes limitations in payload size and targeting. The cellular tropism of Ad serotype 5 (Ad5)based vectors is regulated by the Ad attachment protein binding to its primary cellular receptor, the coxsackie and adenovirus receptor (CAR). Many clinically relevant tissues are refractory to Ad5 infection due to negligible CAR levels but can be targeted by tropism-modified, CAR-independent forms of Ad. Our objective was to evaluate the role of CAR protein in transduction of dopamine (DA) neurons in vivo.
These findings demonstrate that CAR deficiency limits infection of wild type DA neurons by Ad5 and provide a rationale for the development of tropism-modified, CAR-independent Ad-vectors for use in gene therapy of human PD.
Our studies highlight the importance of CAR protein in regulating the transduction of CNS neurons by Ad5 vectors, and suggest that modification of vector tropism to target CAR-deficient cells can achieve more efficient delivery of therapies to these neurons. Here we achieved increased gene delivery by transgenic overexpression of CAR, a strategy that is suitable only for establishing proof-of-concept in animal models. The most promising alternative is the use of modified forms of Ad, which do not depend on CAR for their cellular tropism. As noted above, modified vectors of this kind have proven therapeutically useful in treating a variety of non-CNS diseases in many model systems. It will be important to investigate such tropism-modified Ads to determine whether they can provide enhanced gene delivery to SNc dopamine neurons in wild-type animals expressing natively low levels of CAR, perhaps through other proteins present at post-synaptic sites. As transductional and transcriptional targeting modifications are incorporated, Ad promises to develop as a flexible platform for the delivery of novel therapeutics, allowing targeted and controlled delivery, while minimizing side effects.
Transduction of Brain Dopamine Neurons by Adenoviral Vectors Is Modulated by CAR Expression: Rationale for Tropism Modified Vectors in PD Gene Therapy
Travis B. Lewis 1,2,3, Joel N. Glasgow 2,3,4,5, Anya M. Glandon 3, David T. Curiel 2,4, David G. Standaert 3
1 Department of Cell Biology, The University of Alabama at Birmingham, Birmingham, Alabama, United States of America,
2 Division of Human Gene Therapy, Departments of Medicine, Obstetrics and Gynecology, Pathology, and Surgery, The University of Alabama at Birmingham, Birmingham, Alabama, United States of America,
3 Center for Neurodegeneration and Experimental Therapeutics, The University of Alabama at Birmingham, Birmingham, Alabama, United States of America,
4 Gene Therapy Center, The University of Alabama at Birmingham, Birmingham, Alabama, United States of America,
5 Division of Cardiovascular Disease, Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, United States of America
Citation: Lewis TB, Glasgow JN, Glandon AM, Curiel DT, Standaert DG (2010) Transduction of Brain Dopamine Neurons by Adenoviral Vectors Is Modulated by CAR Expression: Rationale for Tropism Modified Vectors in PD Gene Therapy. PLoS ONE 5(9): e12672. doi:10.1371/journal.pone.0012672