Amadorins for Ameliorating Alzheimer's Disease and Related Dementias (ADRD)

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PROJECT SUMMARY Alzheimer’s Disease (AD) is recognized as a major public health issue that is projected to worsen in the aging U.S. population — the number of people of age 65 and older in the U.S. will reach 88 million by 2050. However, despite intensive efforts, there is an absence of sufficiently effective therapeutic options. AGE formation is an established pathogenic factor in AD progression, impacting putative pathogenic mechanisms involving both amyloid beta and tau. Brains are replete with glucose and ascorbate, both of which fuel AGE formation. AGE formation is also an oxidative chemical reaction requiring redox metal ion catalysis, and it is known that AD progression leads to brain accumulation of pro-oxidant copper and iron. These AGE accelerants generate free radicals and reactive oxygen species (ROS) that are independently causative of neuronal damage. Our hypothesis is that a drug candidate that: (1) is brain penetrant, (2) inhibits AGE formation and (3) reduces oxidation by redox metal ions will exhibit efficacy in treating AD/ADRD. We advance in this proposal the novel “Amadorin” drug candidate PTG-630, a potent inhibitor of advanced glycation end products (AGEs) that also has the dual potential as an antioxidant due to its excellent binding of redox metal ions, particularly Cu2+. We recently discovered that PTG-630 prevents mild cognitive impairment in diabetic rats and in a transgenic mouse model of AD when treatment was begun at onset of disease. We now propose to evaluate the therapeutic potential of PTG-630 in reversing established cognitive dysfunction and neurodegeneration in multiple animal models of AD, as this is the most likely scenario for clinical use of a therapeutic agent. We plan to achieve our goals through two specific aims: (1) Test the efficacy of PTG-630 against central nervous system (CNS) dysfunction in an intervention paradigm; and (2) complete safety assessments of PTG-630 tri-HCl and initiate PK and safety studies in dog in preparation for pre-IND requirements. To mirror the most likely clinical use as an AD/ADRD therapeutic, we will start treatment with PTG-630 only when CNS dysfunctions are established. Studies will be performed using a suite of established mouse models of AD, namely mice overexpressing a) human non-mutant tau (htau), b) a mutant form of APP (Tg2567) or c) a triple transgenic (3xTg) model overexpressing mutant APP, mutant tau and mutant presenilin. We will also evaluate the ability of PTG-630 to reverse established loss of corneal nerves in the mouse models of AD, exploring whether corneal neuropathy can serve as a novel biomarker for early AD that will predict efficacy of intervention against CNS dysfunction. For Specific Aim 2, we will carry out non-GLP studies through pharmacokinetics, metabolism, and pharm-tox screening. We will also initiate dog safety and pharmacology studies. Praetego’s Amadorin PTG-630 is expected to offer a disease modifying breakthrough against AD/ADRD. Successful completion of this project will establish efficacy in reversing ADRD and provide sufficient experimental data to support a pre-IND FDA meeting towards therapeutic translation to humans.