Novel Disease-modifying Small Molecules for Treatment of Alzheimer's Disease”

PROJECT SUMMARY
Alzheimer's disease (AD) is the most frequently diagnosed type of dementia within the Veterans Affairs (VA)
Medical System. Currently no treatment is available to slow down or stop neurodegenerative processes of AD.
My research program has an ongoing interest of developing IND-enabling novel therapeutic strategies for AD.
We focus on studying a novel target to improve cognitive function, called synaptojanin 1 (synj1) and several lines
of data from my research group as well as others suggest beneficial effects of synj1 reduction in AD. Synj1 is
the main phosphoinositol bisphosphate (PIP2) degrading enzyme in the brain and synapses. Increased synj1
expression and activities have been associated with cognitive decline and pathological processes of AD, such
as enlargement of early endosomes and ApoE4-induced cognitive deficits. The synj1 polymorphisms identified
in early- and late-onset familial AD subjects are associated with age of onset, and increased synj1 expression
correlates with cognitive deficits and place cell dysfunction. In addition, insoluble synj1 is increased and
accumulated around plaque-associated dystrophic neurites and neurofibrillary tangles in AD human brains,
particularly in APOE4+ AD brains. Genetic knockdown of synj1 attenuates AD-related pathological changes and
behavioral deficits. Specifically, down-regulation of synj1 with elevated PIP2 levels protect against oligomer Ab-
induced toxic effects on synaptic integrity and promotes Aβ clearance through the endo-lysosomal pathway.
Partial knockdown of synj1 reverses ApoE4-induced lysosomal defects and improves behavior deficits in ApoE4
knock-in mouse models, as well as multiple animal models of familial AD (FAD) and Down syndrome. Down-
regulation of synj1 also rescues mild traumatic brain injury (mTBI)-induced PIP2 dysregulation and prevents
development of tau hyper-phosphorylation. Recently, we have gathered data suggesting a role of synj1 reduction
in modulating microglial function and neuro-inflammation in AD. Together, these studies support beneficial
effects of synj1 reduction in AD. We have been developing scaffolds of novel small molecules with synj1-lowering
capabilities and identified an FDA-approved drug (nimodipine) that reduces synj1 protein and Aβ levels both in
vitro and in vivo. It also improved cognitive function in AD mouse models in short-term treatment. However,
chronic administration of nimodipine failed to reduce brain Aβ42 levels (particularly insoluble fractions), or to
improve cognitive function. We then developed nimodipine structural analogs using medicinal chemistry
approaches to potentiate its synj1-lowering effects (on-target effects) and reduce its calcium channel activity (off-
target side effects). Two nimodipine derivatives: SynaptoCpd #9 and Cpd #6 were selected from hit-to-lead
screening and lead optimization, exhibiting improved oral bioavailability and increased long-term in vivo efficacy
when compared to their parent compound nimodipine using both familial and sporadic AD mouse models
(PCT/US2018/062020 filed by the VA Tech Transfer). These findings establish the foundation at the level of
Proof-of-Concept (PoC) to treat AD with synj1-lowering agents. The objectives of the project are to perform the
IND-enabling studies of two lead compounds in preparation of the IND application and phase I clinical trial
studies. We will: 1) perform in vitro ADME and in vivo DMPK studies of SynaptoCpd #9 and Cpd #6 (Aim 1);
followed by 2) pharmacodynamic studies (acute dosing range finding and chronic efficacy studies) as well as
exploratory toxicity studies (Aim 2); 3) develop target engagement and surrogate biomarkers for SynaptoCpd
#9 and Cpd #6 (Aim 3) using previously stored plasma samples from mice treated with SynaptoCpd #9 and Cpd
#6 (preventive and therapeutic treatment paradigms), as well as new samples collected from DMPK studies
(Aim 1) and PD/toxicity studies (Aim 2). The goals of this application aim to facilitate next step IND application
with ultimate goals of transitioning into clinical studies and the commercialization of our novel AD therapies.

Grant Number: 5I01BX005934-04
NIH Institute/Center: VA
Principal Investigator: Dongming Cai