Professors Kirill Volynski and Dimitri Kullmann of the UCL Queen Square Institute of Neurology, in partnership with Dr. Shyam Krishnakumar from Yale School of Medicine's Department of Neurology, have received a 4- year project grant from the Medical Research Council (part of UK Research and Innovation) to study neurodevelopmental disorders caused by VAMP2 mutations.

Project summary:

Recent years have seen the discovery of genetic mutations underlying many neurodevelopmental diseases, which, although individually rare, collectively account for a substantial burden to individuals, their families and society. How these mutations result in learning disability, autism, speech problems, and epilepsy is gradually emerging, prompting the search for new treatments to mitigate the symptoms. However, there is an important group of disorders for which the consequences of the mutations at the microscopic level remain very poorly understood: these disorders are caused by mutations that affect how neurons signal to other neurons or muscle cells. Such signalling takes place at synapses and is fundamental for all brain functions, as well as the control of movements and the function of many other organs. At the core of synaptic communication is the precise discharge of packets of chemical messengers (neurotransmitters). We now have a highly detailed understanding of how the so-called SNARE proteins assemble to bring these packets, known as synaptic vesicles, to the membrane and then discharge the neurotransmitter into the synaptic cleft upon arrival of an electrical signal. We refer to the neurodevelopmental disorders caused by defects of SNAREs and functionally associated proteins collectively as ‘SNAREopathies’.

The goal of our proposal is to understand how these defects alter the discharge of neurotransmitters from synaptic vesicles and the consequences for brain circuit function and also investigate whether these effects could potentially be reversed by harnessing powerful new tools for genetic therapy.

An especially difficult challenge for many SNAREopathies is that they are suspected of acting in a genetically dominant manner. That is, if only one of the two copies of the gene encoding a SNARE protein carries a mutation, it may suppress the function of the entire SNARE protein complex, including the normal, unaffected copy of the gene. We have chosen to focus exclusively on mutations of a gene that encodes the essential SNARE protein known as vesicle-associated membrane protein 2, or VAMP2.

Our proposal brings together complementary expertise. We are able to characterize the molecular machinery of SNARE proteins by stripping neurotransmitter vesicle trafficking down to the essential steps of assembly of VAMP2 with its partners and the detailed rearrangements that occur upon the arrival of a signal to discharge the vesicle contents. We will combine this approach with highly sensitive measurements of how precisely neurotransmitter is released at individual synapses and how this process is affected by different VAMP2 mutations. We will also address the consequences for the function of small neuronal circuits in a mouse model carrying a human mutation. Finally, guided by a quantitative understanding of how many copies of each of the key molecules interact to support normal vesicle trafficking, we will design a therapy aimed at rescuing the effects of the mutation, and ask which aspects of the disease are potentially amenable to rescue in the mouse model: if the therapy is delivered once symptoms have manifested,  can we only suppress seizures, or can we also improve learning and other defects which might have arisen during early development before symptom onset?

The proposed research will provide much-needed clarity on the mechanisms of VAMP2 mutations, build towards a viable treatment option that can be translated to the clinic in due course, and define a research pipeline that can be applied to other SNAREopathies.

VAMP2 is a likely candidate for gene therapy

-Gene therapy is a treatment that introduces new genetic material into a person’s cells to modify or manipulate the expression of a gene product or alter the biological properties of living cells to treat or cure disease.

- Gene therapy makes use of safe virus’s called Adeno Associated Virus (AAV) which is used as a vehicle to transport the VAMP2 gene therapy to the patient’s cells

- A number of gene therapies are now approved for other

genetic disorders and available for therapeutic use eg Zolgensma® for the treatment of Spinal Muscular Atrophy.

- There are more than 4,000 gene therapy clinical trials in

various phases of development