Non-Invasive Gene Therapy of Experimental Parkinson's Disease
Abstract
Neurotoxins can cause serious derangements in brain biochemistry that can compromise the cognitive and motor function of the individual. In the present studies an anima! model of neurotoxin exposure is used, wherein the neurotoxin, 6-hyrdoxydopamine, is injected into a specific region of the rat brain called the medial forebrain bundle, followed approximately 4 weeks later by a biochemical picture resembling Parkinson's disease (PD). On the side of the brain where the neurotoxin is injected, there is a 90% reduction in the level of a key enzyme, tyrosine hydroxylase (TH), which is a rate-limiting enzyme involved in dopamine production. Dopamine is the neurotransmitter that is deficient in PD. One way that brain TH levels can be restored in conditions such as PD is through gene therapy, wherein the TH gene is given to the individual afflicted with PD. However, with the conventional approach to gene therapy of the brain, there are two serious problems. First, virtually all present-day approaches use viral vectors to carry the gene to brain cells. However, these viral vectors are either highly inflammatory (such as adenovirus or herpes simplex virus) or stably alter the host genome in a random way (retrovirus, adeno-associated virus), which can lead to insertional mutagenesis and cancer. These viruses do not enter the brain from blood, because they do not cross the blood-brain barrier (BBB). This creates the second problem with present-day approaches to gene therapy, which is the viral vector is administered to the brain by craniotomy and drilling a hole in the head. However, this only distributes the virus to a tiny region of the brain at the tip of the injection needle. What is needed is a non-invasive, non-viral form of brain gene therapy wherein the therapeutic gene can be administered intravenously without viral vectors followed by widespread expression of the exogenous gene throughout the brain. This is the goal of the present research.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2004
- Accession Number
- ADA428589
Entities
People
- William M. Pardridge
Organizations
- University of California, Los Angeles