Parkin Gene Therapy

The Parkinson's-Reversing Breakthrough

Parkinson Disease Therapy

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The apparent success of gene therapy in conferring novel capabilities to nigral and striatal cells has led some researchers to question if the pathology underlying PD can be reversed in a more physiologic manner. Genetic analyses of PD families have demonstrated a number of genes linked to the disease. These mutations seem to share a role in intracellular housekeeping and the processing of intracellular protein residue. It is estimated that approximately 0.4% to 0.7% of patients diagnosed with idiopathic PD have Parkin mutations. This proportion dramatically increases to nearly 20% in cases of early-onset sporadic PD, and to almost 50% if there is evidence of familial transmission (108). In these patients, loss of Parkin's E3 ligase activity leads to degeneration of dopaminergic neurons.

LoBianco et al. have used lentiviral delivery to increase expression of the normal Parkin gene in the substantia nigra of rats that were also transfected with the human alpha-synuclein gene. Viral expression of alpha-synuclein is known to cause degeneration of dopaminergic nigral neurons in rats. The addition of a vector delivering a wild-type parkin gene was found to have a substantial protective effect, reducing dopaminergic cell loss from 31% to 9%. Interestingly, this was accompanied by a 45% increase in alpha-synuclein inclusions, suggesting that Parkin exerts its neuroprotective effect by precipitating an otherwise soluble toxic synuclein compound (109). This has significant implications for the pathogenesis of the disease. It also suggests a potential therapy that could be used to halt the progression of PD.

A similar study has examined the effect of chaperone heat-shock protein-70 (Hsp-70) in nigral protection. Hsp-70 has been shown to be a suppressor of alpha-synuclein toxicity in Drosophila models of PD (110). A study by Dong et al. used an AAV carrier to deliver Hsp-70 to the substantia nigra of MPTP-treated mice. They demonstrated that expression of the gene reduced nigral cell loss from 37% in control animals to 16%. It also was found to produce an increase in amphetamine-induced rotational behavior, indicating that behaviorally significant neuroprotection had occurred (111). The common strategy of providing or restoring protective factors in cells failing to process cellular waste is particularly appealing, as it targets and reverses what may be the central pathology of PD.

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