Developing and testing PEGylated GAS6 as a potential remyelinative therapy for multiple sclerosis
Multiple sclerosis (MS) is a common neurological disease caused in part by inflammation in the central nervous system (CNS). Most MS therapies treat the inflammation and reduce symptoms in the early stages of MS.
However, no current therapy averts the risk of entering the progressive phase of MS – which is characterised by the ongoing degeneration of the protective layer that surrounds brain cells and an unavoidable decline in functioning. The lack of therapies that target the progressive phase of MS is a significant unmet need in the field.
This project will address the need for remyelinative and neuroprotective therapies to prevent and treat progressive MS. To do so, we will take the crucial next steps in developing a clinic-ready modified version of GAS6 – a promising therapy with compelling pre-clinical data supporting its development as a regenerative therapy. Our Lab, and others, have shown that GAS6 is therapeutically beneficial in mouse models of demyelination, reducing neuroinflammation and enhancing remyelination, and improving clinical outcomes. Our ambition is to take GAS6 to clinical trials as an MS therapy, but first we must address some immediate hurdles.
A key impediment to developing therapies for progressive MS is the inaccessibility of the CNS. Development of small molecule agonists for the type of receptors targeted by GAS6 has proven to be challenging. A viable alternative is to provide GAS6 directly to the CNS using intrathecal injections; however, prolonged CNS residence time and activity are crucial to enable infrequent CSF injections to be efficacious. PEGylation is one approach that already has been successfully used to increase the half-life of many proteins, resulting in approved drugs for multiple diseases. In this project, we will use PEGylation to extend the half-life of GAS6. We will benchmark the activity of PEGylated GAS6 against native GAS6 in a pre-clinical model of MS. We will also assess the functional, electrophysiologically-based, outcome of GAS6 therapy using a clinically relevant method that can be adapted for use as an outcome measure in clinical testing of GAS6-based therapeutics.
We are providing important proof of principle that prolonged therapeutic activity of GAS6 can be achieved using well-established approaches, allowing rapid translation to the clinic. We will also define functional benefits of GAS6 therapy using clinically relevant methodology, enabling direct translation to outcome measures in clinical trials of this therapy in the future.