MICA: Development of a small molecule therapeutic for the treatment of prion infection of humans

Prion diseases such as Creutzfeldt-Jakob disease (CJD) are invariably fatal neurodegenerative diseases for which there is no effective treatment. As part of a unique collaboration with GlaxoSmithKline (GSK) we have identified compounds which dramatically lower prion levels in cells and have already demonstrated that they are effective in treating mice infected with prion disease. We now propose to develop these compounds further, such that they have the same properties as drugs, and are able to achieve their effects at lower doses which could be administered to humans. We will do this by synthesising compounds which are similar to the ones we have already identified, and then determining their properties and potency in reducing prion levels in cells. Small numbers of compound will then be tested for efficacy in prion-infected mice. We will then undertake preliminary safety and toxicity studies using high doses of compound as a first step to determining whether the compounds are safe to administer to humans.

Prion diseases are rapidly progressive, invariably fatal, neurodegenerative conditions for which there is currently no treatment. Although rare, they are seen as prototypic neurodegenerative diseases of protein misfolding and also as tractable for therapeutics. Laboratory animals are naturally susceptible to prion diseases and so therapeutics can be tested against the disease itself rather than in animal models of uncertain validity. As part of a unique collaboration with GlaxoSmithKline we have identified and progressed a series of compounds that dramatically lower prion levels in cell assays. Significantly, tool compounds from this lead series are effective when administered orally in the treatment of prion-infected mice with well-established neuropathology. In sharp distinction to other neurodegenerative diseases, where therapeutic biomarkers are of uncertain relevance to underlying disease mechanisms or activity, we are able to follow the infectious prion titre directly in mice using a resource unique to the MRC Prion Unit, an automated cell-based prion bioassay, such that such studies are more akin to those of HIV trials for example, where effect of drugs on viral load can be studied. Neurodegenerative dementias pose a massive and increasing challenge to healthcare systems and these studies provide an unique opportunity to target a rare but clearly defined human dementia: it is anticipated much may be learned of wider relevance for the commoner neurodegenerative diseases, all of which involve accumulation of misfolded host proteins. We now propose to complete optimisation of this lead series to deliver a clinical candidate compound.

The primary beneficiaries of the research will be patients diagnosed with sporadic, acquired (iatrogenic or variant CJD) or inherited prion disease (~100 new cases per annum in UK): an invariably fatal disease with no other treatment option. In addition, there are many individuals at risk of developing prion disease, including gene mutation carriers and the ~6000 who have been notified that they are at risk as a result of exposure to prion-contaminated blood products or surgery. The Health Protection Agency estimate 1 in 2000 of the UK population may be infected as a result of exposure to BSE prions (Gill et al., 2013). It is unknown how many of these will eventually develop disease (human prion incubation periods may span 50 years and persistent carrier states are recognised in animals) but all may pose a risk of secondary transmission as blood or organ donors or via contamination of surgical instruments.
Effective treatment of a neurodegenerative dementia, albeit a rare one, would be ground breaking and likely to provide key insights of wider relevance to diseases of major and increasing public health importance. The development of such a therapeutic may be of commercial value to our UK-based industrial collaborators (GlaxoSmithKline) and may well act as a stimulus to research on therapeutics for other more common neurodegenerative conditions, an area which despite the very substantial unmet clinical need, has recently seen a number of high-profile failures in Phase III clinical trials. While speculative at present (and outside the scope of this focused proposal), we consider it prudent to evaluate the lead compounds in animal models of other conditions associated with accumulation of misfolded proteins (Alzheimer's disease, Motor Neurone Disease and Frontotemporal Dementia). Should the compounds prove to be effective in these models then wider clinical evaluation may be appropriate, and there is the potential for treating some of the hundreds of thousands of UK individuals suffering from neurodegenerative disease for which there is currently no disease-modifying treatment.
The work on developing and validating biomarkers may assist in the development of improved blood, urine and CSF prion infectivity assays which may be applied to improve early diagnosis of prion infection and in risk management to reduce iatrogenic infections. We have already engaged with the National Blood Service, Health Protection Agency, Department of Health and commercial blood screening companies about application of our existing prion assay technology to improve safety of blood and blood products and high risk surgical procedures.