Alpha-Synuclein Targeting Therapeutics for Parkinson's Disease and Related Synucleinopathies
α-Synuclein (asyn) is a key pathogenetic factor in a group of neurodegenerative diseases generically known as synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Although the initial triggers of pathology and progression are...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-05-01
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| Series: | Frontiers in Neurology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fneur.2022.852003/full |
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| author | Sindhu Menon Sabrina Armstrong Amir Hamzeh Naomi P. Visanji Naomi P. Visanji Naomi P. Visanji Sergio Pablo Sardi Anurag Tandon Anurag Tandon |
| author_facet | Sindhu Menon Sabrina Armstrong Amir Hamzeh Naomi P. Visanji Naomi P. Visanji Naomi P. Visanji Sergio Pablo Sardi Anurag Tandon Anurag Tandon |
| author_sort | Sindhu Menon |
| collection | DOAJ |
| description | α-Synuclein (asyn) is a key pathogenetic factor in a group of neurodegenerative diseases generically known as synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Although the initial triggers of pathology and progression are unclear, multiple lines of evidence support therapeutic targeting of asyn in order to limit its prion-like misfolding. Here, we review recent pre-clinical and clinical work that offers promising treatment strategies to sequester, degrade, or silence asyn expression as a means to reduce the levels of seed or substrate. These diverse approaches include removal of aggregated asyn with passive or active immunization or by expression of vectorized antibodies, modulating kinetics of misfolding with small molecule anti-aggregants, lowering asyn gene expression by antisense oligonucleotides or inhibitory RNA, and pharmacological activation of asyn degradation pathways. We also discuss recent technological advances in combining low intensity focused ultrasound with intravenous microbubbles to transiently increase blood-brain barrier permeability for improved brain delivery and target engagement of these large molecule anti-asyn biologics. |
| first_indexed | 2024-04-13T08:50:08Z |
| format | Article |
| id | doaj.art-a3dc4d1b756f4e508aec3604a1ec394a |
| institution | Directory Open Access Journal |
| issn | 1664-2295 |
| language | English |
| last_indexed | 2024-04-13T08:50:08Z |
| publishDate | 2022-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neurology |
| spelling | doaj.art-a3dc4d1b756f4e508aec3604a1ec394a2022-12-22T02:53:30ZengFrontiers Media S.A.Frontiers in Neurology1664-22952022-05-011310.3389/fneur.2022.852003852003Alpha-Synuclein Targeting Therapeutics for Parkinson's Disease and Related SynucleinopathiesSindhu Menon0Sabrina Armstrong1Amir Hamzeh2Naomi P. Visanji3Naomi P. Visanji4Naomi P. Visanji5Sergio Pablo Sardi6Anurag Tandon7Anurag Tandon8Tanz Centre for Research in Neurodegenerative Diseases, Toronto, ON, CanadaTanz Centre for Research in Neurodegenerative Diseases, Toronto, ON, CanadaTanz Centre for Research in Neurodegenerative Diseases, Toronto, ON, CanadaTanz Centre for Research in Neurodegenerative Diseases, Toronto, ON, CanadaDepartment of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, CanadaKrembil Research Institute, Toronto, ON, CanadaSanofi, Framingham, MA, United StatesTanz Centre for Research in Neurodegenerative Diseases, Toronto, ON, CanadaDepartment of Medicine, University of Toronto, Toronto, ON, Canadaα-Synuclein (asyn) is a key pathogenetic factor in a group of neurodegenerative diseases generically known as synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Although the initial triggers of pathology and progression are unclear, multiple lines of evidence support therapeutic targeting of asyn in order to limit its prion-like misfolding. Here, we review recent pre-clinical and clinical work that offers promising treatment strategies to sequester, degrade, or silence asyn expression as a means to reduce the levels of seed or substrate. These diverse approaches include removal of aggregated asyn with passive or active immunization or by expression of vectorized antibodies, modulating kinetics of misfolding with small molecule anti-aggregants, lowering asyn gene expression by antisense oligonucleotides or inhibitory RNA, and pharmacological activation of asyn degradation pathways. We also discuss recent technological advances in combining low intensity focused ultrasound with intravenous microbubbles to transiently increase blood-brain barrier permeability for improved brain delivery and target engagement of these large molecule anti-asyn biologics.https://www.frontiersin.org/articles/10.3389/fneur.2022.852003/fullParkinson's diseasepriongene therapyanti-aggregationbrain delivery of drugsimmunization |
| spellingShingle | Sindhu Menon Sabrina Armstrong Amir Hamzeh Naomi P. Visanji Naomi P. Visanji Naomi P. Visanji Sergio Pablo Sardi Anurag Tandon Anurag Tandon Alpha-Synuclein Targeting Therapeutics for Parkinson's Disease and Related Synucleinopathies Frontiers in Neurology Parkinson's disease prion gene therapy anti-aggregation brain delivery of drugs immunization |
| title | Alpha-Synuclein Targeting Therapeutics for Parkinson's Disease and Related Synucleinopathies |
| title_full | Alpha-Synuclein Targeting Therapeutics for Parkinson's Disease and Related Synucleinopathies |
| title_fullStr | Alpha-Synuclein Targeting Therapeutics for Parkinson's Disease and Related Synucleinopathies |
| title_full_unstemmed | Alpha-Synuclein Targeting Therapeutics for Parkinson's Disease and Related Synucleinopathies |
| title_short | Alpha-Synuclein Targeting Therapeutics for Parkinson's Disease and Related Synucleinopathies |
| title_sort | alpha synuclein targeting therapeutics for parkinson s disease and related synucleinopathies |
| topic | Parkinson's disease prion gene therapy anti-aggregation brain delivery of drugs immunization |
| url | https://www.frontiersin.org/articles/10.3389/fneur.2022.852003/full |
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