Current Experimental Studies of Gene Therapy in Parkinson's Disease

Abstract

Parkinson's disease (PD) was characterized by late-onset, progressive dopamine neuron loss and movement disorders. The progresses of PD affected the neural function and integrity. To date, most researches had largely addressed the dopamine replacement therapies, but the appearance of L-dopa-induced dyskinesia hampered the use of the drug. And the mechanism of PD is so complicated that it's hard to solve the problem by just add drugs. Researchers began to focus on the genetic underpinnings of Parkinson's disease, searching for new method that may affect the neurodegeneration processes in it. In this paper, we reviewed current delivery methods used in gene therapies for PD, we also summarized the primary target of the gene therapy in the treatment of PD, such like neurotrophic factor (for regeneration), the synthesis of neurotransmitter (for prolong the duration of L-dopa), and the potential proteins that might be a target to modulate via gene therapy. Finally, we discussed RNA interference therapies used in Parkinson's disease, it might act as a new class of drug. We mainly focus on the efficiency and tooling features of different gene therapies in the treatment of PD.

Application of Precision Medicine in Neurodegenerative Diseases

“…Most of the drugs utilized for the treatment of PD essentially works by enhancing dopaminergic neurotransmission, among which Levodopa (L-Dopa) is the most effective drug to treat motor symptoms in early and advanced stages of PD ( 8 , 12 , 13 ). Except for L-Dopa (precursor of Dopamine), current therapies can be divided into “dopaminergic” and “non-dopaminergic” drugs ( 14 ). The first class of drugs includes dopamine receptor agonists (e.g., apomorphine), catechol-O-methyltransferase (COMT, e.g.…”

“…Current non-dopaminergic drugs mainly work as antagonists of NMDA (N-methyl-D-aspartate) receptor (such as Amantadine) providing mild benefits and reducing LID. Other non-dopaminergic drugs are still under preclinical and clinical trials (e.g., metabotropic glutamate receptor antagonists) ( 14 ). Moreover, small molecule epigenetic modulators targeting DNMTs (DNA methyltransferase), HDACs (Histone deacetylase) and HATs (Histone acetyltransferase) are also undergoing preclinical and clinical trials as novel therapeutic tools for PD ( 15 ).…”

“…Such a high inter-individual response to PD drugs could be explicated by the influence of specific genetic factors. Most of the knowledge about the pharmacogenomics of PD drugs deals with genes involved in dopaminergic activity, especially dopamine receptors ( DRD1, DRD2, DRD3 ), transporters ( DAT, SLC22A1 / OCT1 ) and enzymes responsible for dopamine transformation and degradation ( COMT, MAO-B, DDC ) ( 14 ). In addition, genes involved in other neurotransmission pathways have also been found to influence the response to some PD drugs.…”

“…In addition, genes involved in other neurotransmission pathways have also been found to influence the response to some PD drugs. The most investigated genes are ANKK1, CCK, APOE, BDNF, ACE, MTHFR, HTR2A , and UGTA1 ( 14 , 31 ). Among dopamine receptors genes, DRD2 was the most investigated.…”

And Then There Was Light: Perspectives of Optogenetics for Deep Brain Stimulation and Neuromodulation

“…Gene therapy (Collins and Thrasher, 2015 ) for example has been attempted long before optogenetics was even conceived. Direct insertion of functional proteins (Lin et al, 2017 ) or optic control of these proteins (Brechun et al, 2016 ) have also been suggested. The observation of Parkinson symptoms improvement after a localized brain lesion (Dubois et al, 1986 ) inspired the use of stereotactic brain surgery in patients.…”