Are Therapies That Target α-Synuclein Effective at Halting Parkinson’s Disease Progression? A Systematic Review
Abstract
:1. Introduction
1.1. Pathophysiology of Parkinson’s Disease
1.1.1. Genetics of PD
1.1.2. Neuroanatomy of PD
1.2. α-Syn Toxicity in PD
1.3. α-Synuclein as a PD Therapeutic Target
2. Materials and Methods
2.1. Information Sources and Search Strategy
2.2. Eligibility Criteria
2.3. Study Selection and Data Collection Process
3. Results
3.1. Background Mechanisms
3.1.1. Immunotherapeutic Interventions
3.1.2. Therapeutic Interventions That Target the SNCA Gene
3.1.3. Interventions That Target the Reduction of α-Syn Aggregates
3.2. Study Characteristics
3.3. Biochemical and Immunohistochemical Outcomes
3.3.1. Immunotherapeutic Outcomes
3.3.2. Gene-Therapy Outcomes
3.3.3. Outcomes from Agents That Reduce the Levels of α-Syn Aggregates
4. Discussion
4.1. Mechanisms of Immunotherapeutic Interventions Targeting α-Syn
4.1.1. Active Immunotherapy
4.1.2. Passive Immunotherapy
4.1.3. Alternative Immunotherapies
4.1.4. Immunotherapeutic Conclusions
4.2. Mechanisms of Targeting SNCA Expression
Viral and Non-Viral Delivery of RNA-Based Gene Therapy
4.3. Inhibition of α-Syn Aggregation
4.3.1. Small Molecules That Inhibit α-Syn Aggregation
4.3.2. Enhancing α-Syn Degradation
4.4. Study Limitations
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Study | Agent | Type of Study | Treatment Strategy and Study Objectives |
---|---|---|---|
Sanchez-Guajardo et al., 2013 [35] | rAAv-α-syn | in vivo | Application of a neuroprotective vaccine to potentiate natural immune tolerance to α-syn. |
Chatterjee et al., 2018 [36] | VH14*PEST and NbSyn87*PEST | in vivo | Utilization of human anti-α-syn nanobody constructs fused to a proteasome-targeting PEST sequence to enhance the clearance of target (α-syn) antigens. |
Jankovic et al., 2018 (NCT02157714) and NCT03100149 [37,38] | PRX002 | Phase I and II Clinical Trials | Assessment of the efficacy and safety of the humanized monoclonal antibody, prasinezumab, directed against the C-terminus of α-syn designed to prevent α-syn aggregation and its cell-to-cell transmission. |
Ren et al., 2019 [39] | RVG-exosome aptamer | in vivo | RVG-exosome delivery of aptamers that recognize α-syn to reduce the formation of α-syn aggregates. |
Schofield et al., 2019 [40] | MEDI1341 | in vivo | Application of a high affinity antibody directed to the C-terminal of α-syn to sequester extracellular α-syn and attenuate α-syn spreading. |
Volc et al., 2020 [41] | PD01A | Phase I Clinical Trial | Assessment of safety and tolerability of epitope mimetics of a C-terminal region of α-syn conjugated to a carrier protein to break immune tolerance and produce antigen-specific antibodies. |
Poewe et al., 2021 [42] | PD03A | Phase I Clinical Trial | |
Butler et al., 2022 [43] | AAV-EGFP-PFFNB2 | in vivo | Utilization of an anti-α-syn nanobody (PFFNB2) fused with an AAV-EGFP to dissociate α-syn fibrils and limit α-syn spread. |
Schmidhuber et al., 2022 [44] | WISIT vaccine | in vivo | Utilization of a DNA vaccine for multiple epitopes to reduce α-syn aggregation and propagation. |
Roshanbin et al., 2022 [45] | RmAbSynO2-scFv8D3 | in vivo | Utilization of a bispecific antibody to α-syn and the transferrin receptor to facilitate uptake across the BBB to target α-syn aggregates. |
Study | Agent | Category of Gene Therapy | Treatment Strategy |
---|---|---|---|
Helmschrodt et al., 2017 [46] | PEI/SNCA-siRNA | Non-viral | Utilization of nanoparticle PEI to mediate the delivery of siRNA into the brains of mice to reduce expression of the SNCA gene and α-syn protein production. |
Alarcón-Arís et al., 2018 [47] | IND-siRNA or IND-1233-ASO | Non-viral ASOs | Utilization of indatraline-conjugated ASO or siRNA to knockdown expression of the SNCA gene and α-syn protein production. |
Izco et al., 2019 [48] | RVG-exosomes with anti-GFP shRNA-MCs | Viral delivery | Nanoparticle delivery of shRNA-MCs into the brain via RVG-exosomes to knockdown SNCA gene expression to limit the formation of α-syn aggregates. |
Spencer et al., 2019 [49] | ApoB11 | Non-viral | Conjugation of an 11 amino acid sequence of ApoB protein coupled to a 9 amino acid linker to deliver siRNA across the BBB to reduce α-syn levels. |
Cole et al., 2021 [50] | ASO1 | Non-viral ASOs | Utilization of ASOs targeting the SNCA gene to reduce the production of α-syn protein. |
Jin et al., 2021 [51] | Tat-βsyn-degron | Non-viral | Utilization of Tat-βsyn-degron, a three-domain synthetic peptide designed to cross the BBB, bind to endogenous α-syn, and target it for proteasomal degradation. |
Cao et al., 2022 [52] | HDOs | Non-viral | Utilization of HDOs to knockdown expression of the SNCA gene and α-syn protein production. |
Study | Agent | Intervention Category | Mechanism of Action |
---|---|---|---|
Wagner et al., 2013 [53] | Anle138b | Small molecule | Utilization of anle138b as an α-syn aggregation inhibitor derived from DPP. |
Davies et al., 2014 [54] | Nedd4 | Degradation enhancer | Utilization of Nedd4 as a ubiquitin ligase to target α-syn for lysosomal degradation. |
Savolainen et al., 2014 [55] | KYP-2047 | Degradation enhancer | Utilization of KYP-2047, a PREP inhibitor, to enhance clearance of α-syn via autophagy. |
Wrasidlo et al., 2016 [56] | NPT100-18A | Small molecule | Utilization of NPT100-18A, a cyclic peptidomimetic derived from small peptides analogous to the 96–102 domain of α-syn, capable of displacing membrane-associated α-syn and reducing oligomer formation. |
Kim et al., 2018 [57] | GQDs | Small molecule | Utilization of GQDs to inhibit fibrillization and enhance α-syn disaggregation. |
Bengoa-Vergniory et al., 2020 [58] | CLR01 | Small molecule | Utilization of CLR01 as a molecular tweezer to decrease α-syn aggregation. |
Xu et al., 2022 [59] | Harmol | Degradation enhancer | Utilization of harmol to promote α-syn degradation by an autophagic-lysosomal pathway. |
Arotcarena et al., 2022 [60] | aNPs | Degradation enhancer | Utilization of aNPs to promote α-syn degradation by enhanced lysosomal activity. |
Kim et al., 2022 [61] | PCiv | Small molecule | Utilization of PCiv as an α-syn disaggregation agent. |
Liu et al., 2022 [62] | RVG29-RBCm/Cur-NCs | Small molecule | Utilization of RVG29-RBCm/Cur-NCs a nanodecoy to act as an α-syn aggregation inhibitor able to cross the BBB. |
Study | Agent | Changes in α-Syn and TH in Intervention Groups (vs. PD Model) | Type of α-Syn Species Targeted | Level of Significance |
---|---|---|---|---|
Sanchez-Guajardo et al., 2013 [35] | rAAv-α-syn | ↓α-syn aggregates TH levels similar to control | Aggregates | (p < 0.05) ND |
Chatterjee et al., 2018 [36] | VH14/ NbSyn87*PEST | ↓α-syn aggregates ↑TH-labelled cells | Aggregates | (p < 0.05) (p < 0.01) (VH14*PEST) |
Jankovic et al., 2018 [37] | PRX002 | ↓Free-to-total serum α-syn | Aggregates | (p < 0.001) |
Ren et al., 2019 [39] | RVG-exosome aptamer | ↓α-syn | Fibrils aggregates | (p < 0.01) |
Schofield et al., 2019 [40] | MEDI1341 | ↓α-syn | Oligomers | Hippocampal (p < 0.001) Neocortical (p < 0.001) |
Volc et al., 2020 [41] | PD01A | ↓α-syn | Oligomers | CSF (↓51% after 26 weeks at 75 µg), significance ND |
Poewe et al., 2021 [42] | PD03A | ND | Oligomers | ND |
Butler et al., 2022 [43] | AAV-EGFP-PFFNB2 | ↓α-syn aggregates (pS129) | Fibrils aggregates | Cortex (p < 0.001) |
Schmidhuber et al., 2022 [44] | WISIT candidate type 1 | ↓α-syn aggregates (pS129) | Aggregates | (p < 0.05) |
Roshanbin et al., 2022 [45] | RmAbSynO2-scFv8D3 | α-syn (total) ↓α-syn oligomers | Oligomers aggregates | No change Cortex (p < 0.05) Midbrain (p < 0.005) |
Study | Agent | Changes in SNCA, α-Syn, TH, or Dopamine in Intervention Groups (vs. PD Model) | Location and Level of Significance for α-Syn, TH, or Dopamine |
---|---|---|---|
Helmschrodt et al., 2017 [46] | PEI/siRNA | ↓mRNA and α-syn protein | Striatum (medial) (p = 0.018) |
Alarcón-Arís et al., 2018 [47] | IND-siRNA or IND-1233-ASO | ↓mRNA and α-syn protein ↑DA | SNc (p < 0.05) with IND-499-siRNA SNc (p < 0.05) with IND-1233-ASO CPu and medial PFC in response to veratridine (p < 0.05) with IND-1233-ASO |
Izco et al., 2019 [48] | Exosomal RVG-anti-GFP shRNA-MCs | ↓α-syn protein ↑TH-labelled cells | Midbrain, 90 day treatment (p = 0.033) (p = 0.028) |
Spencer et al., 2019 [49] | ApoB11-siRNA | ↓α-syn protein ↑TH-labelled cells | (p < 0.05) Striatum (p < 0.05) |
Cole et al., 2021 [50] | ASO1 | ↓mRNA and α-syn aggregates ↑TH-labelled cells | SN (p < 0.001) for 100 and 300 µg dosing, (p < 0.0001) for 1000 µg dosing (p < 0.05) |
Jin et al., 2021 [51] | Tat-βsyn-degron | ↓α-syn ↑TH-labelled cells | SN (p < 0.01) SN (p < 0.05) |
Cao et al., 2022 [52] | HDO | ↓α-syn ↑TH-labelled cells | SN (p < 0.05) SN (p < 0.01) |
Study | Agent | Changes in α-Syn, Dopamine, and TH in Intervention Groups (vs. PD Model) | Type of α-Syn Species Targeted | Level of Significance |
---|---|---|---|---|
Wagner et al., (2013) [53] | Anle138b | ↓α-syn | Oligomeric | (p < 0.001) |
Davies et al., 2014 [54] | Nedd4 | ↓α-syn ↑TH-labelled cells | Oligomeric | (p = 0.022) (p < 0.05) |
Savolainen et al., 2014 [55] | KYP-2047 | ↓α-syn ↑DA TH | Oligomeric | 28-d treatment: (p = 0.0028) 28-d treatment: (p = 0.01) NS |
Wrasidlo et al., 2016 [56] | NPT100-18A | ↓α-syn | Oligomeric | (p < 0.05) |
Kim et al., 2018 [57] | GQDs | ↓α-syn ↑TH-labelled cells | Fibrillar | (p < 0.001) (p = 0.0156) |
Bengoa-Vergniory et al., 2020 [58] | CLR01 | ↓α-syn ↑TH-labelled cells | Oligomeric | (p = 0.0286) (p = 0.0177) |
Xu et al., 2022 [59] | Harmol | ↓α-syn | Total | SN and PFC (p < 0.05) |
Arotcarena et al., 2022 [60] | aNPs | α-syn (pSer129) ↑TH-labelled cells | Aggregates | NS (total/proteinase K-resistant), pSer129 (p < 0.05) (p < 0.05) |
Kim et al., 2022 [61] | PCiv | ↓α-syn (pSer129) ↑TH-labelled cells | Aggregates | SN (p < 0.01) SN (p < 0.001) |
Liu et al., 2022 [62] | RVG29-RBCm/Cur-NCs | ↓α-syn ↑DA ↑TH | Total | Midbrain and striatum (p < 0.01) (p < 0.001) Midbrain and striatum (p < 0.01) |
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Rodger, A.T.; ALNasser, M.; Carter, W.G. Are Therapies That Target α-Synuclein Effective at Halting Parkinson’s Disease Progression? A Systematic Review. Int. J. Mol. Sci. 2023, 24, 11022. https://doi.org/10.3390/ijms241311022
Rodger AT, ALNasser M, Carter WG. Are Therapies That Target α-Synuclein Effective at Halting Parkinson’s Disease Progression? A Systematic Review. International Journal of Molecular Sciences. 2023; 24(13):11022. https://doi.org/10.3390/ijms241311022
Chicago/Turabian StyleRodger, Abbie T., Maryam ALNasser, and Wayne G. Carter. 2023. "Are Therapies That Target α-Synuclein Effective at Halting Parkinson’s Disease Progression? A Systematic Review" International Journal of Molecular Sciences 24, no. 13: 11022. https://doi.org/10.3390/ijms241311022