Dynamin Drug Discovery Team Win Prestigious International Epilepsy Grant.

A drug discovery and development collaboration between leading Australian Institutions, the Children’s Medical Research Institute (CMRI), University of Newcastle, University of Melbourne and Bio-Link Partners Ltd., has been announced as the Epilepsy Therapy Project, June 2008 New Therapy Grant winners. This prestigious research grant recognises their promising drug discovery program, which is focussed on development and commercialisation of small molecule inhibitors of the GTPase Dynamin, a key component of the synaptic vesicle cycle and a novel approach to treatment of epilepsy.

The Epilepsy Therapy Project seeks to advance the development of new therapies for epilepsy, including new medicines and therapeutic devices. The grants committee consists of leading opinion leaders in the fields of epilepsy clinical practice and anti-epileptic drug (AED) research. The Program attracts applications from leading research groups and biotech companies worldwide. Consistent with the theme of translational research, all grant proposals must demonstrate a clear path from the lab to the patient.

The grant to the Dynamin Drug Discovery Program will support the refinement of lead classes of inhibitors which have demonstrated efficacy in animal models towards clinical development and commercialisation. The Dynamin Drug Discovery Program consists of leading expertise in synaptic vesicle endocytosis and dynamin biology, medicinal chemistry and translational studies in acquired epilepsy models. Award of the New Therapy Grant recognises the potential of dynamin as a new molecular target for the design of a new class of therapeutics to treat epilepsy. In announcing the award, Joyce Cramer, President of the Epilepsy Therapy Project said “The Australian group exemplifies the ideal of collaboration among experts to work on a novel approach to limiting seizure propagation.   We are eager to watch their progress toward human studies that will reveal the full potential of this effect of brain signaling”.

A common feature of all AEDs is a reduction in synaptic transmission.  The GTPase Dynamin represents a potentially highly efficacious target that indirectly modulates neurotransmitter loading, leading to reduced epileptic synaptic transmission, while limiting potential side effects. Dynamin mediates synaptic vesicle endocytosis (SVE), a process which replenishes synaptic vesicles prior to reloading and subsequent neurotransmitter release. Modulation of Dynamin limits the efficiency of SVE to retrieve vesicles, decreasing the rate at which neurons can recycle them to sustain synaptic transmission. Hence seizure activity is minimized through depleting the sustainability of neuronal burst firing, without directly influencing the synaptic transmission process. During regular physiological conditions synaptic transmission does not rely on such rapid vesicle replenishment limiting potential mechanistic side effects.

The Dynamin Drug Discovery Program represents an extensive collaboration between Professor Phil Robinson, CMRI (Dynamin Biology), Associate Professor Adam McCluskey, University of Newcastle (Medicinal Chemistry), Associate Professor Terence O’Brien, University of Melbourne, Department of Medicine, Royal Melbourne Hospital (Translational Models) and Bio-Link Partners Ltd. (Commercialisation Strategy and Implementation). The program consists of an iterative drug discovery and development cycle for development of dynamin inhibitors as novel therapeutic candidates for epilepsy, other CNS disorders and cancer. The Robinson group originally cloned the human dynamin 1 isoform, and are leaders in the understanding of its biological functions and development of in vitro and cell function assays. In conjunction with the medicinal chemistry expertise of the McCluskey group, a large number of classes of small molecule and peptide inhibitors of dynamin have been developed. Ongoing collaborations with the Anticonvulsant Screening Program at the US National Institute of Neurological Disorders and Stroke and the O’Brien group have provided deep insights and capabilities in in vivo screening in a large range of different seizure models. Associate Professor O’Brien also provides clinical insights and expertise for lead selection and clinical testing. The Program technology is protected by an expanding patent estate covering broad composition of matter and method of use patents over compound and peptide classes and assay technologies. Overall, the Program represents a unique capability to exploit the potential of Dynamin as a novel therapeutic target for epilepsy.

Approximately one in 120 people have epilepsy, while up to 5% of the world’s population may have a seizure at some time in their lives. Epilepsy is diagnosed when seizures are unprovoked and recurrent. Approximately only 70% of patients with epilepsy benefit from current treatments. There is a large unmet medical need for new therapeutic approaches to help those patients that do not receive benefit from current treatments, or suffer from undue side effects.