Alpha-Synuclein Inhibitors Clinical Trial Pipeline Expands to 22+ Therapies.

Alpha-synuclein inhibitors are investigational therapies targeting alpha-synuclein, a protein linked to neurodegenerative diseases like Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies. DelveInsight's report highlights a robust pipeline with 20+ active players and 22+ pipeline alpha-synuclein inhibitors, including promising candidates like Buntanetap, UCB 0599, and Prasinezumab. Companies like Annovis Bio, UCB Biopharma, and Alterity Therapeutics are advancing pipeline alpha-synuclein inhibitors.

Alpha-synuclein (asyn) is a key player in a group of neurodegenerative diseases known as synucleinopathies, which includes Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) [1]. The pathological accumulation of asyn is the hallmark of these disorders, and its misfolding into beta sheet-enriched conformations leads to the formation of oligomers and aggregates [1].

Recent research has focused on developing therapies that target asyn to prevent its misfolding and aggregation. DelveInsight's report on the alpha-synuclein inhibitor pipeline highlights a robust and diverse range of approaches being pursued by over 20 active players [2].

One strategy is to remove aggregated asyn using passive or active immunization or by expressing vectorized antibodies [1]. For example, Buntanetap, an investigational therapy from Anavex Life Sciences, is a small molecule that binds to misfolded asyn and facilitates its clearance [2]. UCB 0599, another potential alpha-synuclein inhibitor, is an antibody-based therapy that targets aggregated asyn [2].

Another approach is to modulate the kinetics of asyn misfolding using small molecule anti-aggregants [1]. These compounds prevent the formation of toxic oligomers and aggregates, thereby reducing the overall levels of pathological asyn in the brain. Prasinezumab, an alpha-synuclein inhibitor from Biogen, is a monoclonal antibody that binds to oligomeric and fibrillar forms of asyn and prevents their aggregation [2].

Lowering asyn gene expression is another strategy being pursued. Antisense oligonucleotides (ASOs) and inhibitory RNAs (siRNAs) can be used to specifically target and degrade asyn mRNA, thereby reducing the overall levels of asyn protein in the brain [1]. Annovis Bio, UCB Biopharma, and Alterity Therapeutics are some of the companies advancing pipeline alpha-synuclein inhibitors using this approach [2].

Finally, pharmacological activation of asyn degradation pathways is another promising approach. This can be achieved by using compounds that enhance the activity of cellular enzymes responsible for breaking down asyn, such as the ubiquitin-proteasome system [1].

Recent technological advances have also improved the delivery and target engagement of these large molecule anti-asyn biologics. Combining low intensity focused ultrasound with intravenous microbubbles can transiently increase blood-brain barrier permeability, allowing for improved brain delivery and target engagement of these therapies [1].

In conclusion, the development of alpha-synuclein inhibitors is a promising approach to combating neurodegenerative diseases such as PD, DLB, and MSA. The pipeline is robust and diverse, with over 20 active players and 22+ pipeline alpha-synuclein inhibitors being pursued. The strategies being used include removal of aggregated asyn, modulation of asyn misfolding, lowering asyn gene expression, and pharmacological activation of asyn degradation pathways.

References:
[1] DelveInsight. Alpha-Synuclein Inhibitors Pipeline Insight, 2022. https://www.delveinsight.com/reports/Alpha-Synuclein-Inhibitors-Pipeline-Insight
[2] National Center for Biotechnology Information. Alpha-Synuclein: A Key Pathogenetic Factor in Synucleinopathies. https://pmc.ncbi.nlm.nih.gov/articles/PMC9124903/