Treatments and compositions targeting α-synuclein: a patent review (2010-2016)

ABSTRACT

Introduction: Abnormal deposition of α-synuclein (ASN) is a hallmark and possible central mechanism of Parkinson’s disease and other synucleinopathies. Their therapy is currently hampered by the lack of early, screening-compatible diagnostic methods and efficient treatments.

Areas covered: Patent applications related to synucleinopathies obtained from Patentscope and Espacenet databases are described against the background of current knowledge regarding the regulatory mechanisms of ASN behavior including alternative splicing, post-translational modifications, molecular interactions, aggregation, degradation, and changes in localization.

Expert opinion: As the central pathological feature and possibly one of root causes in a number of neurodegenerative diseases, deregulation of ASN is a potentially optimal diagnostic and therapeutic target. Changes in total ASN may have diagnostic value, especially if non-invasive /peripheral tissue tests can be developed. Targeting the whole ASN pool for therapeutic purposes may be problematic, however. ASN mutations, truncation, and post-translational modifications have great potential value; therapeutic approaches selective towards aggregated or aggregation-prone ASN forms may lead to more successful and safe treatments. Numerous ASN interactions with signaling pathways, protein degradation and stress mechanisms widen its potential therapeutic significance dramatically. However, significant improvement in the basic knowledge on ASN is necessary to fully exploit these opportunities.

KEYWORDS:

• Antibody
• α-synuclein
• immunization
• gene expression
• gene methylation
• signaling pathways
• synucleinopathy
• neurodegeneration
• post-translational modification
• protein aggregation

Article highlights

• Synucleinopathies are characterized by long period of ‘silent’ development and when symptoms are evident, neurodegeneration is already deep and irrecoverable. Moreover, currently available therapy cannot influence the progress of the neurodegeneration and is hampered by lack of early and screening-compatible tests.

• SNCA gene regulation, α-synuclein (ASN) protein concentration in body fluids and tissues are widely considered as targets in early disease detection. The potential value of therapeutic reduction of general ASN levels is difficult to prove currently, as ASN expression appears to require tight regulation to avoid pathological gain- or loss-of-function.

• Many suggested therapies propose inhibition of ASN deposition and removal of its aggregation-prone (e.g. truncated, nitrated) and aggregated ASN forms (such as protofibrils). Targeting the numerous post-translational ASN modifications may also offer significant advantage as these impact ASN function and tendency towards aggregation.

• ASN-related mitochondrial deregulation, increased ROS, or endoplasmic reticulum stress may also constitute plausible therapeutic targets.

• The interactions of ASN with cellular signaling, neurotransmission, and immune system are potentially highly valuable targets. However, their full potential may require significant advancement of current basic knowledge.

This box summarizes key points contained in the article.

Acknowledgments

Supported by Mossakowski Medical Research Centre, Polish Academy of Sciences, statutory theme no. 8.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This article has been supported by Mossakowski Medical Research Centre, Polish Academy of Sciences, statutory theme no. 8.