Journal of Alzheimers Disease & Parkinsonism
Open Access

Parkinson's Disease (PD) remains one of the most challenging neurological disorders to treat, affecting millions of people worldwide. Characterized by progressive motor dysfunction, tremors, rigidity and bradykinesia, PD significantly impairs the quality of life of those affected. While conventional treatments offer symptomatic relief, they do not address the underlying cause of the disease. However, recent advancements in gene therapy have sparked hope for more targeted and long-lasting interventions. In particular, the exploration of gene therapy for Parkinsonism alters the course of this debilitating condition. Parkinsonism encompasses a spectrum of disorders that share clinical features similar to PD. Among the various causative factors implicated in Parkinsonism, genetic mutations play a significant role. Mutations in genes such as Alpha Synuclein (SNCA), Leucine Rich Repeat Kinase 2 (LRRK2) and Parkin (PRKN) have been identified in familial forms of PD and Parkinsonism, shedding light on potential targets for gene therapy interventions.

The concept of gene therapy involves delivering therapeutic genes into target cells to correct or compensate for genetic abnormalities underlying disease pathology. In the context of Parkinsonism, gene therapy aims to restore dopaminergic function and mitigate neurodegeneration within the basal ganglia, the brain region primarily affected in PD.

One of the most promising approaches in Parkinsonism gene therapy involves the use of viral vectors to deliver therapeutic genes into the brain. Adeno Associated Virus (AAV) vectors, in particular, have gained traction due to their ability to efficiently transduce neurons and their favorable safety profile. Researchers have engineered AAV vectors to carry genes encoding for proteins involved in dopamine synthesis, neurotransmitter regulation and neuroprotection.

For instance, gene therapy strategies targeting the enzyme Aromatic L-Amino Acid Decarboxylase (AADC) aim to enhance dopamine production within the brain. By delivering the AADC gene into specific regions of the brain, such as the putamen, where dopamine deficiency is most pronounced, researchers seek to alleviate motor symptoms and improve dopaminergic transmission in Parkinsonism patients.

Another promising avenue in Parkinsonism gene therapy involves modulating the expression of alpha-synuclein, a protein implicated in the pathogenesis of PD. Excessive aggregation of alpha-synuclein contributes to the formation of lewy bodies, abnormal protein deposits characteristic of PD pathology. Gene therapy approaches utilizing Ribo Nucleic Acid interference (RNAi) or Antisense Oligonucleotides (ASOs) aim to suppress the expression of alpha-synuclein, potentially slowing disease progression and mitigating neurotoxicity. Furthermore, the advent of genome editing technologies such as Clustered Regularly Interspaced Short Palindromic Repeats-Cas9 (CRISPR-Cas9) offers unprecedented precision in targeting and modifying disease-causing genes. Researchers are exploring CRISPR-based approaches to correct genetic mutations associated with familial forms of PD and Parkinsonism, offering the possibility of personalized gene therapy tailored to individual patients' genetic profiles. Despite the immense potential of gene therapy in Parkinsonism, several challenges remain to be addressed. Delivery of therapeutic genes to the appropriate brain regions while minimizing off-target effects poses a significant technical hurdle. Strategies to enhance the specificity and efficiency of gene delivery, such as novel viral vectors and targeted delivery systems, are actively being pursued. Moreover, long-term safety and efficacy assessments are paramount to ensuring the viability of gene therapy interventions in clinical settings. Comprehensive preclinical studies in animal models, coupled with rigorous clinical trials in human subjects, are essential to evaluate the therapeutic benefits and potential adverse effects of gene therapy approaches for Parkinsonism. Gene therapy holds great assurance as a transformative approach in the management of Parkinsonism. By targeting the underlying genetic abnormalities implicated in disease pathogenesis, gene therapy offers the potential for disease-modifying interventions that address the root cause of Parkinsonism, rather than merely alleviating symptoms. Continued study efforts and collaborative endeavors between scientists, clinicians and pharmaceutical innovators are essential to realize the full therapeutic potential of gene therapy in Parkinsonism and improve the lives of patients afflicted by this debilitating condition.