The focus of our research is to understand more about the cell-protective properties of heat-shock proteins and to create new therapies for degenerative diseases of the central nervous system and muscles.
Heat-shock proteins are known as molecular chaperones because they play a role in helping proteins to function properly when cells are under stress. They also help to transport non-functional proteins to the right place inside cells; either to be recovered or broken down.
Lysosomal storage diseases
Lysosomes are essential compartments of cells, where waste products are sent to be broken down and recycled. They contain enzymes which act like molecular scissors to digest these waste products. If, as a result of a genetic mutation, one of these digestive enzymes does not function properly, the waste product will accumulate inside the lysosome and eventually become toxic to cells. Digestive enzymes are proteins, and their dysfunction can be the result of a failure to fold into the correct shape or because they are incomplete. In some cases, cells don’t produce a specific digestive enzyme at all. The extent of the digestive enzyme dysfunction depends on the genetic mutations. These mutations are inherited from both parents who are carriers of the mutation.
Broadly, our research in lysosomal storage diseases focuses on the natural cellular machinery that helps proteins to remain folded in their active state. In particular, we conduct research on heat-shock protein family members called HSP70, which we have shown to be effective in correcting conditions of lysosomal deficiency by helping to refold non-functional digestive enzymes and guiding them to the lysosome, where they’re needed. Our preclinical research focuses on the beneficial effects of increasing the production of HSP70 in Niemann-Pick disease Type C and Gaucher disease, as well as several other lysosomal storage diseases. For a more detailed scientific explanation, you can read about the research which underpins our work (Kirkegaard et al. Nature 2010; Kirkegaard et al. Science Translational Medicine 2016).
If a protein does not fold properly or if it is produced in the wrong part of the cell, it can clump together with other proteins, creating accumulations or aggregates. These aggregates can cause the cells stress and toxicity and are a major component of the pathology in many neurodegenerative and other progressive diseases.
HSP70 has been shown to resolve aggregates and to help chaperone-misfolded proteins to be degraded by the cells’ recycling systems. It can also protect newly-built proteins from misfolding and aggregating. Through collaborations with world-leading academic researchers, arimoclomol has been tested in preclinical studies to assess the impact of amplifying the production of heat-shock proteins in a number of protein-aggregation disorders, including sporadic Inclusion Body Myositis (sIBM) and SOD1-associated Amyloid Lateral Sclerosis (SOD1-ALS).