Targeted Molecular Therapeutics for Parkinson's Disease: A Role for Antisense Oligonucleotides?

Li, Dunhui; Mastaglia, Frank; Yau, Wai Yan; Chen, Shengdi; Wilton, Steve; Akkari, P. Anthony

doi:10.1002/mds.29201

Cited by 4 publications

(2 citation statements)

References 38 publications

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“…Moreover, comparison of our RNA-seq data to PD patient postmortem brain tissue RNA-seq data (Feleke et al, 2021) (that was obtained from patients with PD and related synucleinopathies (PD with dementia (PDD) and dementia with Lewy Bodies (DLB)) showed overlap with transcripts that are differentially spliced. Taken together, our data support the idea that the pre-mRNA splicing pattern defects we observe in hPSC-derived midbrain DA neurons (mDA) in vitro are relevant to PD, that these transcript isoforms may serve as useful biomarkers, and might be amenable to RNA therapeutics (Anthony, 2022, Li et al, 2022a, Rogalska et al, 2023).…”

Section: Introductionsupporting

confidence: 83%

Comparison of Alternative pre-mRNA Splicing and Gene Expression Patterns in Midbrain Lineage Cells Carrying Familial Parkinson’s Disease Mutations

Lee,

Syed,

Busquets

et al. 2024

Preprint

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SummaryParkinson’s disease (PD) is a devastating neurodegenerative disorder, with both genetic and environmental causes. Human genetic studies have identified ∼20 inherited familial genes that cause monogenic forms of PD. We have investigated the effects of individual familial PD mutations by developing a medium-throughput platform using genome-editing to install individual PD mutations in human pluripotent stem cells (hPSCs) that we subsequently differentiated into midbrain lineage cells including dopaminergic (DA) neurons in cell culture. Both global gene expression and pre-mRNA splicing patterns in midbrain cultures carrying inherited, pathogenic PD mutations in the PRKN and SNCA genes were analyzed. This analysis revealed that PD mutations lead to many more pre-mRNA splicing changes than changes in overall gene RNA expression levels. Importantly, we have also shown that these splicing changes overlap with changes found in PD patient postmortem brain sample RNA-seq datasets. These pre-mRNA splicing changes are in genes related to cytoskeletal and neuronal process formation, as well as splicing factors and spliceosome components. We predict that these mutation-specific pre-mRNA isoforms can be used as biomarkers for PD that are linked to the familial PD mutant genotypes.

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Section: Introductionsupporting

confidence: 83%

Comparison of Alternative pre-mRNA Splicing and Gene Expression Patterns in Midbrain Lineage Cells Carrying Familial Parkinson’s Disease Mutations

Lee,

Syed,

Busquets

et al. 2024

Preprint

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“…ASOs are regarded as supreme to siRNA technologies, and the first ASO-based therapy has been approved by the Food and Drug Administration (FDA) for the treatment of MSA and other neurological disorders. ASOs could be useful in terms of correction of splice-site mutations and splicing defects (as in the case of DJ-1 ) [ 177 ]. Adeno-associated virus (AAV) serotypes 2 and 9 demonstrated an excellent tropism for the CNS, ability to cross the BBB and, in contrast to lentiviral vectors (LVs), they have limited risk of insertional mutagenesis upon integration into the host genome.…”

Section: Drugs Targeting α-Synucleinmentioning

confidence: 99%

Inhibition of Protein Aggregation and Endoplasmic Reticulum Stress as a Targeted Therapy for α-Synucleinopathy

Siwecka,

Saramowicz,

Galita

et al. 2023

Pharmaceutics

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α-synuclein (α-syn) is an intrinsically disordered protein abundant in the central nervous system. Physiologically, the protein regulates vesicle trafficking and neurotransmitter release in the presynaptic terminals. Pathologies related to misfolding and aggregation of α-syn are referred to as α-synucleinopathies, and they constitute a frequent cause of neurodegeneration. The most common α-synucleinopathy, Parkinson’s disease (PD), is caused by abnormal accumulation of α-syn in the dopaminergic neurons of the midbrain. This results in protein overload, activation of endoplasmic reticulum (ER) stress, and, ultimately, neural cell apoptosis and neurodegeneration. To date, the available treatment options for PD are only symptomatic and rely on dopamine replacement therapy or palliative surgery. As the prevalence of PD has skyrocketed in recent years, there is a pending issue for development of new disease-modifying strategies. These include anti-aggregative agents that target α-syn directly (gene therapy, small molecules and immunization), indirectly (modulators of ER stress, oxidative stress and clearance pathways) or combine both actions (natural compounds). Herein, we provide an overview on the characteristic features of the structure and pathogenic mechanisms of α-syn that could be targeted with novel molecular-based therapies.

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Nanotherapeutic approaches for managing phospholipase-mediated neurodegenerative and metabolic diseases

Afnan,

Khan,

Swaliha

et al. 2023

Phospholipases in Physiology and Pathology

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Targeted Molecular Therapeutics for Parkinson's Disease: A Role for Antisense Oligonucleotides?

Cited by 4 publications

References 38 publications

Comparison of Alternative pre-mRNA Splicing and Gene Expression Patterns in Midbrain Lineage Cells Carrying Familial Parkinson’s Disease Mutations

Comparison of Alternative pre-mRNA Splicing and Gene Expression Patterns in Midbrain Lineage Cells Carrying Familial Parkinson’s Disease Mutations

Inhibition of Protein Aggregation and Endoplasmic Reticulum Stress as a Targeted Therapy for α-Synucleinopathy

Nanotherapeutic approaches for managing phospholipase-mediated neurodegenerative and metabolic diseases

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