Our Science & Technology
Cell cycle hypothesis
Defects in cell cycle regulation play a fundamental role in several diseases. It is now widely accepted that the pathogenesis of Alzheimer’s disease (AD) involves similar cell cycle mechanisms, but the underlying biology is not well understood. The complete absence of the cell cycle was believed to be a core feature of neurons – meaning they never enter the cell cycle process. Now, an increasing body of evidence suggests that this is not the case, and that neurons must in fact continually hold their cell cycle in check. If this check mechanism fails then they enter an abnormal, hyper metabolic state that could represent an important risk factor for the development of AD and other dementias.
Many cellular processes are controlled by the mammalian target of rapamycin (mTOR). mTOR is a kinase enzyme that phosphorylates serine and threonine and is a master regulator of cell growth and metabolism. The complex mTOR pathway is essential for the co-ordination of intra and extra-cellular signals and a link between mTOR and cell cycle control is clearly established. Differentially expressed mTOR pathway genes may regulate key functions linked to AD.
The application of SNP profiling to risk stratification
Clinically, Mild Cognitive Impairment (MCI) is a condition of subtle cognitive change which often, but by no means always, represents the first manifestation of AD. Since we believe that we need to treat AD very early and we need to assess whether such early treatments work in slowing progression, there is a requirement to get better both at diagnosing those within the MCI cohort who have early AD, and also identifying the variables which determine their rate of conversion to full blown disease. In both cases, genetic analysis is a promising route to this important clinical dissection.
Cytox’s aim is to identify genetic risk variants, or single nucleotide polymorphisms (SNPs), which can be used ultimately, in the definition of an algorithm to predict AD progression. In turn, this would be expected to facilitate AD clinical trials by reducing both misdiagnosis rates and enabling better prediction of expected disease progression rates. Proprietary data suggests that an assessment of disease risk may be possible using a customised genetic variation (SNP) panel associated with mTOR signalling and other pathways. We are carrying out whole exome association analysis, testing genetic variants across the genome, in highly selected and characterised clinical samples. In addition, we apply disease risk prediction modelling to quantify the utility of the associated variants.
The further definition and validation of this panel for future at risk individuals with MCI is a key goal, with further work ongoing to assess whether sufficient sensitivity and specificity performance consistent with potential clinical utility, could be achieved.