93800Novel protective 'self'-antibodies for disease modification in Huntington’s DiseaseClosedCollaborative R&DInnovate UKAlchemab Therapeutics has a new way of approaching drug discovery by focussing on what keeps people well, sometimes against the odds. All of us produce a vast repertoire of different antibodies as part of our usual immune responses to fend off pathogens and to help the body maintain its health status. We believe that some individuals are able to use this mechanism to protect themselves against diseases to which they are pre-disposed. Huntington's disease (HD) is a devastating neurodegenerative disease, without any current medicines to slow or stop its progress. It has a genetic cause that is screened for in members of HD high-risk families. Surprisingly, some rare individuals with known genetic HD risk factors have far out-lived the age at which they would be expected to develop clear symptoms, and the underlying reason is not fully understood. Alchemab analysed B cells (which produce antibodies) of some of these resilient patients and identified antibodies common to those individuals resisting disease and not present in those patients who are showing symptoms. This grant will fund work to determine what the molecular target of these antibodies is (what they bind to), and whether they can protect against pathological mechanisms of HD. Our aim is to develop and test these antibodies as therapies to help other individuals living with a HD diagnosis that may not have been so lucky as to develop a protective antibody response themselves, which could be transformative in slowing the course of the disease. To do this, we intend to work with UK experts in complex cellular models of neurodegeneration, including those at the Medicines Discovery Catapult. Accessing human brain cells for neurodegeneration research is difficult, and so methods have been developed to reprogramme, in the lab, cells taken from skin into the cell types found in the brain. This can also be done with cells taken from Huntington's disease patients. We will use these human cell-based systems to find out how our antibodies change the biology that is different between healthy and HD. By using these cells for our studies, we are able to stay as close to the human biology of patients which led us to the discovery of these antibody candidates as possible, and this may give us a better chance of success in clinical trials. We hope this will help us to bring much needed therapies to Huntington's Disease patients faster than traditional drug discovery.