Educating Future Researchers

Why research matters

Parkinson’s disease (PD) is a complex and multifocal neurodegenerative disorder with pathogenesis originating from the synergy of abnormal α-synuclein aggregation, neuroinflammation, and dysfunction of mitochondria, lysosomes, and synaptic transport, influenced by genetic and idiopathic factors. Monogenic forms of PD are characterized by Lewy body development due to cellular dysfunction and degeneration of the dopaminergic neurons in the substantia nigra pars compacta (SNpc). It starts by affecting reasoning, circadian rhythms, and autonomous functioning, followed by Parkinsonian motor symptoms such as muscle rigidity, hypokinesia, tremors, and impaired postural stability, which worsen with time.

Based on whether the treatment targets the underlying cause of the disease or relieves its symptoms, treatments can be categorized into disease-modifying and non-disease-modifying therapies. Non-disease-modifying therapy aims to revert dopaminergic functioning to restrict symptoms and decelerate the progression of the disease by either boosting dopamine levels or activating dopamine receptors in the brain. However, with prolonged use, adverse effects such as dyskinesia, insomnia, and hallucinations eclipse the positive impact of these drugs. Due to these drawbacks, extensive research is being done to identify disease-modifying therapies that could approach the exact target of the disease. New pharmacological targets are being identified, and by applying the concept of gene therapy targets, stem cell transplantation, and surgical interventions, the delivery of drugs to affected neurons can be achieved.

Gene editing

Among these, gene editing is the most appropriate substitute for traditional disease-modifying therapy. While it is currently not possible for neurodegenerative disorders to be treated, gene editing has the potential to do so. Over the years, gene editing technologies such as zinc-finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs) have materialized, in which various nucleases can identify and cleave intended DNA sequences. Although they indicated the beginning of precise gene editing, when applied therapeutically they turned out to be expensive because of the complex design of the nuclease.

The discovery of the clustered, regularly interspaced short palindromic repeats (CRISPR/Cas9) system is a significant scientific revolution. CRISPR/Cas9 is the most prominent and powerful tool due to its higher specificity and efficiency. CRISPR/Cas9-based gene therapy has reached the clinical trial stage for many monogenic diseases such as sickle cell anemia, β-thalassemia, and hereditary tyrosinemia type I, and is being applied in advanced preclinical testing stages of Duchenne muscular dystrophy (DMD) and hemoglobinopathies. Gene therapy has been beneficial in neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease as well.

Stem cells

Due to stem cells’ anti-inflammatory and anti-apoptotic properties, stem cell therapy is a promising approach to treat neurodegenerative diseases, especially PD, whose pathogenesis is linked to factors such as inflammation and neuronal differentiation. The aim is to restore or replace dysfunctional dopaminergic neurons and rescue abnormal motor functions. By merging the benefits of stem cells and the CRISPR/Cas9 tool, studies are being designed to create disease models, perform gene correction, generate PD-resistant cells, and execute screening to identify potential therapeutic compounds. A combination of stem cells and CRISPR/Cas9 improves the functionality of homology-directed repair (HDR) machinery through increased activation, which can help avoid unnecessary off-target mutations. Although ethical concerns have been frequently raised, stem cells are being utilized in different studies because their characteristics, such as unlimited self-renewal and the ability to differentiate into specialized adult cell types, have outweighed their disadvantages.

Source: Pinjala, P., Tryphena, K.P., Prasad, R. et al. CRISPR/Cas9 assisted stem cell therapy in Parkinson’s disease. Biomater Res 27, 46 (2023).