Abstract
Parkinson's disease (PD) is one of the most common neurodegenerative disorders that manifest various motor and nonmotor symptoms. Although currently available therapies can alleviate some of the symptoms, the disease continues to progress, leading eventually to severe motor and cognitive decline and reduced life expectancy. The past two decades have witnessed rapid progress in our understanding of the molecular and genetic pathogenesis of the disease, paving the way for the development of new therapeutic approaches to arrest or delay the neurodegenerative process. As a result of these advances, biomarker‐driven subtyping is making it possible to stratify PD patients into more homogeneous subgroups that may better respond to potential genetic‐molecular pathway targeted disease‐modifying therapies. Therapeutic nucleic acid oligomers can bind to target gene sequences with very high specificity in a base‐pairing manner and precisely modulate downstream molecular events. Recently, nucleic acid therapeutics have proven effective in the treatment of a number of severe neurological and neuromuscular disorders, drawing increasing attention to the possibility of developing novel molecular therapies for PD. In this review, we update the molecular pathogenesis of PD and discuss progress in the use of antisense oligonucleotides, small interfering RNAs, short hairpin RNAs, aptamers, and microRNA‐based therapeutics to target critical elements in the pathogenesis of PD that could have the potential to modify disease progression. In addition, recent advances in the delivery of nucleic acid compounds across the blood–brain barrier and challenges facing PD clinical trials are also reviewed.
Highlights
Parkinson's disease (PD) is the second most prevalent neurodegenerative disease and it is estimated that by 2030 it will affect at least 8 million individuals worldwide.[1]
Parkinson drew attention to the cardinal motor features of the disease: “Involuntary tremulous motion, with lessened muscular power, in parts not in action and even when supported; with a propensity to bend the trunk forward and to pass from a walking to a running pace.”[2]. It has since become apparent that the clinical phenotype is much broader and encompasses a wide range of nonmotor manifestations that includes olfactory and gastrointestinal symptoms, autonomic dysfunction, sleep disorders, depression, and cognitive impairment
This review describes advances in the understanding of the complex molecular pathogenesis of PD, and the proteins and genes that play key roles in familial PD, as well as the more prevalent sporadic form of the disease
Summary
Parkinson's disease (PD) is the second most prevalent neurodegenerative disease and it is estimated that by 2030 it will affect at least 8 million individuals worldwide.[1]. An oligonucleotide with amido‐bridged nucleic acid‐modified bases at each end and a DNA core to induce RNase H activity was designed to degrade the human SNCA transcript This compound reduced SNCA expression significantly and improved motor functions in a PD transgenic mouse model.[185] Due to the high prevalence of GBA mutations in PD patients, several therapeutic strategies including gene therapy and small molecules are under development for patients carrying this particular PD risk.[186] Chamishi Therapeutics was founded in September 2019 with a specific focus on developing ASO therapies for GBA‐associated PD. Since enhanced delivery of ASOs to the target brain region was achieved by focused ultrasound,[280] many clinical trials are applying MRI‐guided focused ultrasound, and showing safe and reversible opening of the blood–brain barrier.[281]
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