Brain-penetrating antisense oligonucleotide to down-regulate alpha-synuclein

Antisense oligonucleotides (ASOs) offer a new therapeutic strategy in Parkinson’s disease (PD) because they can be readily targeted to genes causally linked to PD development or progression. Consequently, they may treat the underlying pathology of PD, not just symptoms, and hence profoundly alter its relentless progression and impact on patients.

To be effective in PD, ASOs must get into the brain, however ASOs show almost no brain penetration following intravenous or subcutaneous administration. A requirement for intrathecal administration would severely limit the number of PD patients who could benefit from ASO therapies due to cost, access and capacity of clinical services.

This project will develop an ASO therapy that reduces alpha-synuclein expression in the brain following subcutaneous administration. The target product brings together two proven technologies – an ASO that has already shown efficacy in downregulating human alpha-synuclein expression following intracranial injection in transgenic mice, conjugated to our proprietary brain-penetrating peptide (BPP) that we have shown enables other ASOs to get into the brain following peripheral administration in neonatal and adult mice.

Many lines of evidence implicate alpha-synuclein in a causative role in PD and its progression, including over-expression being sufficient to cause an autosomal dominant form of the disease.

This project will assess the ability of BPP-ASO conjugates to downregulate human alpha-synuclein mRNA and protein expression in vitro in human cell lines and in vivo in brains of adult transgenic mice overexpressing human alpha-synuclein following subcutaneous injection. We will optimise the chemistry of the ASO and BPP to select a lead BPP-ASO candidate and assess its in vivo pharmacokinetics (dose-effect, time-course) and toxicity.

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