Gamma Secretase Inhibition as a means to treat Alzheimer's disease
Addressing the underlying cause of Alzheimer's disease by developing agents to attenuate the enzyme responsible for beta amyloid production
The majority of drugs aimed at reducing the accumulation of beta amyloid (A) by targeting the gamma secretase enzyme have failed pre-clinical trials. A reason for this is that this enzyme is also important for normal cellular function. The challenge is therefore to identify the critical site within the gamma secretase that is responsible for generating A, without affecting normal cellular function.
The market for Alzheimer's disease (AD) drugs is estimated to grow at 15% annually and reach $5.5 billion by 2009. However, currently marketed drugs such acetylcholinesterase inhibitors (donepezil, rivastigmine and galantamine) and the N-methyl-D-aspartate receptor antagonist, memantine only treat disease symptoms without targeting underlying degeneration of neuronal cells. Therefore, new, disease modifying treatments are urgently needed.
ECUs novel approach is to identify sites within this enzyme that are specifically responsible for generating A without altering its activity on other proteins. Once this site has been identified, an in-vitro assay can be developed to allow screening of potential drugs aimed at lowering A levels with high specificity.
Professor Ralph Martins and his team at ECU have currently reconstructed the gamma secretase enzyme complex in vitro. The next stage is to validate its activity and to identify particular sites within the enzyme that are critical for its activity on A. Although currently in its initial stages, the outcomes of this project would be appealing to the pharmaceutical industry.