MTI Biotech Incorporated — Department of Health and Human Services SBIR Phase II: NIA

Description

Approximately million Americans are affected by Alzheimer s disease AD and up to million will be affected by At present there is no preventive or curative treatment for AD or in age related cognitive decline and clinical trials of cognitive modifying compounds have not succeeded in identifying an effective treatment Despite a lot of efforts no candidates are available to slow down the development or even cure this devastating disease Although most of the efforts are focusing on the amyloid and the tau pathways we have taken a different approach and targeted oxidative stress Oxidative stress is a major pathogenic mechanism that underlies both the pre clinical development and subsequent progression of AD and one that could potentially be targeted preventively as well as therapeutically Levels of reactive oxygen species ROS increase during inflammation mitochondrial dysfunction and metal redox cycling catalyzed by A all processes associated with AD development ROS catalyzed lipid peroxidation generates bifunctional electrophiles BFEs We have shown that BFEs generated by oxidative stress accelerate A oligomerization generating oligomers that have similar neurotoxicity and immunoreactivity as the amyloid derived diffusible ligands They inhibit proteosomal activity cause mitochondrial dysfunction and promote dendritic cell activation of T cells Importantly we have shown that levels of BFE adducts on proteins are significantly elevated in hippocampus of AD post mortem human brains and correlate positively with both the CERAD plaque score and the Braak stage We have found that hydroxybenzylamine HOBA reacts fold faster with BFEs than lysine preventing protein modification in vitro and in vivo Importantly in hApoE transgenic mice HOBA inhibits all the effects of BFEs described above and prevents working memory deficit HOBA a natural product present in buckwheat seeds has been developed for use in humans by Metabolic Technologies Inc MTI Ames IA The chemical manufacturing and control data have been generated and pre clinical pharmacology and toxicology data are currently being collected In this project we propose to do single and multiple escalation dose studies necessary to characterize pharmacokinetics metabolism and safety of HOBA We also propose to establish brain penetrance of HOBA and to determine whether it reduces blood and CSF markers of oxidative modification of proteins Alzheimer s disease is the th cause of death for people over and over million Americans suffer from it If no treatment is developed to slow down or even cure the disease it is estimated that over million Americans will have AD by The goal of our proposed research is to perform human studies for a natural occurring small molecule that will be effective in arresting the progression of AD and could help target the mechanism of tissue injury that occurs at all stages of AD development and with of age related cognitive decline in healthy adults