Development of Nonviral Vectors Targeting the Brain as a Therapeutic Approach For Parkinson's Disease and Other Brain Disorders.

Parkinson's disease (PD) is a debilitating neurodegenerative disease characterized by tremor, rigidity, bradykinesia, and postural instability, for which there is no effective treatment available till date. Here, we report the development of nonviral vectors specific for neuronal cells that can deliver short interfering RNA (siRNA) against the α-synuclein gene (SNCA), and prevent PD-like symptoms both in vitro and in vivo. These vectors not only help siRNA duplexes cross the blood-brain barrier in mice, but also stabilize these siRNAs leading to a sustainable 60-90% knockdown of α-synuclein protein. Mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine rapidly develop PD-like symptoms which were significantly alleviated when SNCA was knocked down using our vectors. Together, our data not only confirm the central role of α-synuclein in the onset of PD, but also provide a proof of principle that these nonviral vectors can be used as novel tools to design effective strategies to combat central nervous system diseases.

The role of α-synuclein in neurodegenerative diseases: from molecular pathways in disease to therapeutic approaches.

Parkinson disease (PD) is the second most prevalent neurodegenerative disorder after Alzheimer's disease (AD). The formation of the cytoplasmic inclusions named "Lewy bodies" in the brain, considered to be a marker for neuronal degeneration in PD and dementia with Lewy bodies. However, Lewy bodies (LBs) are also observed in approximately 60 percent of both sporadic and familial cases with AD. LBs consist of fibrils mainly formed by post-translational modified α-synuclein (α-syn) protein. The modifications can be truncation, phosphorylation, nitration and mono-, di-, or tri-ubiquitination. Development of disease seems to be linked to events that increase the concentration of α-syn or cause its chemical modification, either of which can accelerate α-syn aggregation. Examples of such events include increased copy number of genes, decreased rate of degradation via the proteasome or other proteases, or modified forms of α-syn. As the aggregation of α-syn in the brain has been strongly implicated as a critical step in the development of several neurodegenerative diseases, the current search for disease-modifying drugs is focused on modification of the process of α-syn deposition in the brain. Recently researchers have screened and designed various molecules that are selectively focused on inhibiting or preventing α-syn aggregation and toxicity. Another strategy that has emerged is to target α-syn expression as a potential therapy for neurodegenerative diseases associated with LBs.