Understanding the Potential of Genome Editing in Parkinson’s Disease

Abstract

CRISPR is a simple and cost-efficient gene-editing technique that has become increasingly popular over the last decades. Various CRISPR/Cas-based applications have been developed to introduce changes in the genome and alter gene expression in diverse systems and tissues. These novel gene-editing techniques are particularly promising for investigating and treating neurodegenerative diseases, including Parkinson’s disease, for which we currently lack efficient disease-modifying treatment options. Gene therapy could thus provide treatment alternatives, revolutionizing our ability to treat this disease. Here, we review our current knowledge on the genetic basis of Parkinson’s disease to highlight the main biological pathways that become disrupted in Parkinson’s disease and their potential as gene therapy targets. Next, we perform a comprehensive review of novel delivery vehicles available for gene-editing applications, critical for their successful application in both innovative research and potential therapies. Finally, we review the latest developments in CRISPR-based applications and gene therapies to understand and treat Parkinson’s disease. We carefully examine their advantages and shortcomings for diverse gene-editing applications in the brain, highlighting promising avenues for future research.

Genome-wide association study of glucocerebrosidase activity modifiers

“…We also found an additional association with the ANK2 locus. Phosphorylation in the ANK2 region has been proposed to play a role in PD neurodegeneration through the inhibition of organelle autophagy, but its connection to GCase activity is not clear from the current literature and will need further research [34]. There are also multiple notable associations with ties to GCase activity that may have only failed multiple testing correction due to sample size.…”

Tailoring Magnetite-Nanoparticle-Based Nanocarriers for Gene Delivery: Exploiting CRISPRa Potential in Reducing Conditions

“…Incorporating translocating agents with endosome escape properties is crucial to address this issue. Our tDNA-AEDP-MNP-OmpA nanobioconjugates (Figure 1A) exhibit an increased likelihood of reaching the cytosol and delivering their cargo [30,46].…”

“…One of IONs' key features is their surface chemical versatility, allowing the conjugation of a wide range of molecules, including polymers, proteins, and peptides. This capability enables the delivery of therapeutic agents and imaging reagents, expanding the potential applications across various fields [29][30][31]. PEGylation is a popular functionalization strategy that enhances stability and prevents nanoparticle aggregation in physiological media [18].…”

“…These are all crucial attributes for in vitro and in vivo delivery applications [28]. Furthermore, ION functionalization with translocating proteins and peptides, such as the Escherichia coli outer membrane Protein A (OmpA) and the frog skin peptide Buforin II (BUF-II), can enhance cell internalization and cytosol coverage by evading endolysosomal trafficking pathways [30]. Another popular chemical modification involves pH-sensitive crosslinkers that facilitate cargo release under the cytosol's typical reducing conditions [32].…”

Advances in graphene-based nanoplatforms and their application in Parkinson's disease

“…These familial PD cases have been attributed to variants in genes such as SNCA , PRKN , PINK1 , LRRK2 , PARK2 , and PARK7 . 3 The current evidence on PD suggests that the illness has a complex etiology rather than a single cause. Not all PD patients experience all symptoms at the same time or with the same severity.…”