| Abstract |
Lysosomal storage disorders (LSDs) comprise >70 genetic diseases, caused by defects in lysosomal enzymes and membrane proteins, with a combined incidence of ~1/5,000 live births, and estimated 6,200 UK patients. Although each is genetically distinct, there are features common to most LSDs. Most common (>2/3 LSDs) is neurological involvement, comprising intellectual disability, developmental regression, ataxia, seizures and neurodegeneration including hallmarks of Alzheimer and Parkinson diseases. At the cellular level, LSDs are characterised by macromolecule accumulation (both primary storage of enzyme/transporter substrates and secondary storage of difficult-to-digest molecules that accumulate due to disrupted lysosomal function), endocytic trafficking and autophagy abnormalities. Therapeutic options are extremely limited. The therapeutic mainstay is enzyme replacement, where a functional version of the deficient enzyme is infused into the bloodstream, but this cannot address brain disease. Translational LSD research focusses on gene therapy delivered directly to the brain, exemplified by the recently approved therapy for metachromatic leukodystrophy. In addition to the huge expense, which will limit access to wider populations, gene therapy cannot correct every cell in the brain and cannot address peripheral symptoms. An attenuated chronic disease, requiring further therapy via a CNS-penetrant small molecule, will likely persist following treatment. Small molecule therapies, which include substrate reduction to inhibit synthesis of storage molecules and chaperones to stabilise misfolded enzymes, are not common and not satisfactory; they are not suitable for all patients or have minimal effects on disease progression. A major barrier to developing LSD therapies is the small market size for individual diseases – the most common LSD, Gaucher disease, occurs at ~1/40,000 live births – making therapies for all but the most common commercially unattractive. We propose a revolutionary approach targeting multiple LSDs based on a shared pathogenic mechanism, the presence of toxic lyso-glycosphingolipids, thus addressing unmet medical need and increasing potential market size. Lyso-glycosphingolipids, barely detectable in healthy individuals, are formed via gain-of-function degradation of glycosphingolipids, elevated in >20 LSDs, by lysosomal enzyme acid ceramidase (AC). They are central to pathology in diseases where they are elevated, including type 3 Gaucher (GD3), Krabbe and Fabry diseases, as they cause neuronal death, demyelination, neuropathic pain and inflammation. We will initially focus on GD3, a neurodegenerative LSD caused by mutations in the GBA1 gene, for which there is no therapy and where a pathogenic role for lyso-glycosphingolipid glucosylsphingosine has been demonstrated. GD3 is a gateway indication for future trials in Parkinson disease associated with GBA1 mutations (GBA-PD), comprising 5-15% all Parkinson disease patients, which shares lyso-glycosphingolipid mediated toxicity but where patient heterogeneity makes clinical trials difficult. This would address a further unmet need and provide a very attractive investment opportunity. Current AC inhibitors are unsuitable for chronic CNS administration. The prototypical inhibitor, carmofur, is covalent, and is a prodrug of the toxic chemotherapy agent 5-fluorouracil. Other AC inhibitors in early development are more selective but also covalent, risking over-inhibition. This is important as >94% loss of AC activity causes infantile Farber disease, another neurodegenerative LSD. We have identified two series of non-covalent AC inhibitors that are potent, selective, stable and brain penetrant. This project will continue to develop these through lead optimisation to identify a molecule suitable for in vivo proof-of-concept studies in GD3 mice. In parallel, we will optimise treatment protocols that avoid over-inhibition to generate an attractive data package for onward investment. |
