SPOTLIGHT ON DR JOHN SKIDMORE

Recent advance from the ADDI: The ADDI is working on a number of new targets but our work remains largely confidential. We are currently assessing molecules against three proteostasis targets for their potential in mouse models of protein misfolding. Amongst our new areas of interest is a collaboration developing antagonists of the protein STING for the treatment of a range of neurodegenerative diseases, including Parkinson’s disease. Our STING project is a collaboration with, amongst others, Marko Hyvönen in the Department of Biochemistry. We have a number of exciting hit series for which Marko’s team have solved X-ray structures to enable optimisation towards a molecule for in vivo testing. Earlier projects, now published, include our work on the PI5P4 kinases (Boffey et al, J Med Chem 2022).

Key challenge for the field: The development of disease modifying drugs for the treatment of dementia is a huge challenge. The biggest issue in the field is the limitations in our models. On the one hand, we have iPSC neuronal models based on the human disease that do not develop a full disease phenotype and on the other hand models in mice and other species that fail to reflect the full complexity and biology of the aged human brain. Our validation experiments are limited by this, with the best strategy being to combine both approaches with as much patient-derived data as possible.

Most exciting basic or clinical breakthrough in the past few years: The field is excited, although still quite cautious, about emerging reports of clinical successes with beta-amyloid targeting antibodies. It seems unlikely that a monotherapy will address this huge clinical challenge; instead many in the field feel that we will eventually target dementias with combination therapies; the development of the first drugs that we can use to explore such combinations would be a huge step on this path.