Journal of Alzheimers Disease & Parkinsonism
Open Access

Parkinsonism, a clinical syndrome characterized by tremors, bradykinesia, rigidity and postural instability, predominantly arises from Parkinson's Disease (PD), a progressive neurodegenerative disorder. The sign of PD is the loss of dopaminergic neurons in the Substantia Nigra (SN), leading to dopamine deficiency in the striatum. Current treatments focus on symptomatic relief, primarily through dopamine replacement strategies, but they do not halt disease progression. Gene therapy emerges as a need by targeting the disease's need by targeting the disease's underlying mechanisms at the molecular level.

The genetic landscape of Parkinson's disease

Genetic research has identified several mutations associated with PD, including those in the Synuclein Alpha (SNCA), Leucine-Rich Repeated Kinase 2 (LRRK2), Parkinsonism Associated Deglycase 7 (PARK7), Phosphatase and TENsin (PTEN) Induced Kinase 1 (PINK1) and Glucocerebrosidase (GBA) genes. These discoveries have prepared for gene therapy approaches that can either correct these genetic defects or modulate their effects. These genetic allows for the development of targeted therapies that can potentially modify the disease course.

Gene therapy approaches in Parkinsonism

Gene replacement and supplementation: For genes like PARK7 (DJ-1), PINK1 and GBA which encode for proteins that play important roles in mitochondrial function and cellular homeostasis, gene replacement therapy aims to supplement the deficient or dysfunctional proteins. Adeno-Associated Viruses (AAVs) are commonly used vectors to deliver functional copies of these genes to the affected neurons. Early-stage clinical trials have shown the results in improving motor functions and slowing disease progression.

Gene silencing: Mutations in the LRRK2 gene are among the most common genetic causes of familial PD. These mutations result in a hyperactive form of the LRRK2 protein contributing to neurodegeneration. Ribonucleic Acid interference (RNAi) and Antisense Oligonucleotides (ASOs) can selectively silence the mutant LRRK2 gene reducing its expression and mitigating its toxic effects. Preclinical studies have demonstrated the potential of these approaches to reduce neuroinflammation and neuronal death.

Neurotrophic factors delivery: Neurotrophic factors like Glial cell line-Derived Neurotrophic Factor (GDNF) and neurturin support the survival and function of dopaminergic neurons. Gene therapy can be used to deliver genes encoding these protective proteins directly into the brain. Clinical trials using AAV vectors to deliver GDNF have shown mixed results but recent advancements in vector design and delivery methods for improving their efficacy.

CRISPR/CAS9 genome editing: The advent of Clustered Regularly Interspaced Short Palindromic Repeats-Associated Protein 9 (CRISPR/Cas9) technology offers the potential to directly correct pathogenic mutations at the DNA level. For example correcting SNCA gene mutations which lead to the accumulation of alpha-synuclein aggregates could halt the progression of PD. While still in its infancy for PD treatment, CRISPR/Cas9-mediated approaches are a rapidly evolving field with significant potential.

Key challenges and considerations in gene therapy for Parkinson's disease

Delivery efficiency and specificity: Efficiently delivering therapeutic genes to the appropriate brain regions while avoiding off-target effects is critical. Advances in vector technology and minimally invasive delivery methods are essential to overcome these hurdles.

Long-term safety and efficacy: Long-term expression of therapeutic genes and the risk of immune responses pose significant concerns. Ongoing study aims to develop safer vectors and transient gene expression systems to address these issues.

Personalized medicine: Given the genetic heterogeneity of PD, personalized gene therapy approaches to an individual’s specific genetic are necessary. Genetic screening and biomarkers will play important role in identifying suitable candidates for different gene therapy modalities.

Ethical and regulatory considerations: As with all genetic interventions, ethical considerations regarding consent, potential risks and the long-term impact on patients and their offspring must be addressed. Regulatory frameworks need to keep pace with the rapid advancements in gene therapy technologies.