Combining Gene Transfer and Nonhuman Primates to Better Understand and Treat Parkinson's Disease

Abstract

Parkinson's disease (PD) is a progressive CNS disorder that is primarily associated with impaired movement. PD develops over decades and is linked to the gradual loss of dopamine delivery to the striatum, via the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). While the administration of L-dopa and deep brain stimulation are potent therapies, their costs, side effects and gradual loss of efficacy underlines the need to develop other approaches. Unfortunately, the lack of pertinent animal models that reproduce DA neuron loss and behavior deficits-in a timeline that mimics PD progression-has hindered the identification of alternative therapies. A complementary approach to transgenic animals is the use of nonhuman primates (NHPs) combined with the overexpression of disease-related genes using viral vectors. This approach may induce phenotypes that are not influenced by developmental compensation mechanisms, and that take into account the personality of animals. In this review article, we discuss the combination of gene transfer and NHPs to develop "genetic" models of PD that are suitable for testing therapeutic approaches.

Keywords: CAV vectors; Parkinson’s disease; dopaminergic neurons; gene transfer; primate.

Figure 1

The three major dopaminergic (DA) pathways in the brain linked to Parkinson’s Disease (PD). The nigrostriatal pathway was DA cells from substantia nigra pars compacta (SNpc) project into the striatum (in dark pink). The mesolimbic/mesocortical pathway, which corresponds to the projection of the midbrain ventral tegmental area (VTA) to the nucleus accumbens (N. Acc) in the limbic areas, and to the frontal cortex (FC), respectively.

Figure 2

Schematic representation of the helper-dependent (HD) canine adenovirus-2 (CAV-2) vector expressing leucine-rich repeat kinase 2 (LRRK2)^G2019S. While the HD genome is devoid of all viral coding sequences, it still retains the 200 bp inverted terminal repeat (ITR) at each end and the 150 bp packaging signal (ψ) at the left end of the genome. To create a stable capsid the genome must fill the interior of the capsid which therefore requires it to be 95%-105% of the 32 kbp wild type genome. Depending on the size of the expression cassette [here it contains the 600 bp Rous sarcoma virus early promoter (RSV), an internal ribosome entry signal (IRES), a green fluorescent protein cDNa 5GF] the LRRK2 cDNA and a 250 polyA signal (pA), the remaining sequence is made up of noncoding intronic sequence from the human genome.