Development of Disease-Modifying Therapeutics in Alzheimer's disease and Dementia with Lewy Body (DLB)

Abstract

Neurodegenerative diseases are a growing problem as our lifespans continue to increase, such that Alzheimer’s disease and other forms of dementia represent a major cause of disability and death worldwide. Researchers are working to unravel the brain chemistry that leads to these diseases of old age and to develop therapies to slow cognitive decline. Professor Kohji Fukunaga and his team have been working in this field for many years. He says: ‘We are now on the brink of introducing a novel drug that has been shown to improve memory and learning faculties in mice models of Alzheimer’s disease (AD).’ Fukunaga is lead researcher at the Department of Pharmacology in the Tohoku University Graduate School of Pharmaceutical Sciences in Japan, and heads up the current project stream of AMED for the development of disease-modifying therapeutics for Alzheimer’s disease, Parkinson’s disease and dementia with Lewy Bodies. A target molecular pathway was identified in 2013, and was optimised during the following year. The Japanese Agency for Medical Research thereafter funded preclinical research focusing on synthesis techniques, toxicology, pharmacokinetic and pharmacodynamic studies. The new compound is called SAK3 and has demonstrated cognitive enhancement superior to that of existing drugs currently used to slow the onset of AD on transgenic mice. Exhaustive safety trials have also been undertaken on larger animal models. The team is now seeking funding and pharmaceutical partners for human clinical trials, with a view to licensing and eventual commercialisation over the next five years. SAK3 has been tested on two different mouse models of AD: olfactory bulbectomised, APP23 and APP knock-in. The first display cognitive impairment and depressive behaviours, while the latter have a seven-fold increase in a mutant form of amyloid beta precursor proteins in their synapses. Both exhibit elevated levels of Abeta production in the brain. Fukunaga says: ‘Two months after administering our SAK3 compound to APP23 or APP knock-in mice, we observed reduced Abeta accumulations. Also, we used a novel object recognition task to assess cognitive performance and found a significant improvement.’ SAK3’s effects were compared to those of existing ACh release and stimulation agents ST101 and Donepezil, and shown to be significantly superior. These drugs are both produced by Fukunaga’s long-term US collaborators, Sonexa Therapeutics Inc.