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Principal Investigator: Rana Rais
Organization: JOHNS HOPKINS UNIVERSITY
Fiscal Year: 2024
Award: $471,402
Funding agency: National Institute on Aging
The number of people suffering from Alzheimer's disease (AD) is steadily rising and current treatments only
provide minor symptom amelioration. Results from recent clinical trials targeting amyloid-β (Aβ) production or
clearance were disappointing, prompting a reexamination of approaches to AD treatment. Brains from AD
patients exhibit accumulation of ceramide, a signaling molecule and an integral component of exosomal
membranes. One major source of ceramide is through the hydrolysis of sphingomyelin catalyzed by neutral
sphingomyelinase 2 (nSmase2). Even though transient increases in ceramide through nSMase2 upregulation
are part of normal brain functioning, experimental evidence indicates that chronic nSMase2 upregulation results
in negative effects including neuroinflammation and oxidative stress. Recent studies implicate nSMase2 in both
Aβ aggregation and tau protein propagation through exosome secretion from glial cells. Moreover, inhibition of
exosome synthesis by genetic or pharmacological inhibition of nSMase2 was shown to block Aβ aggregation
and tau propagation in both in vitro and in vivo AD models, thus opening a new avenue for AD therapeutics.
Unfortunately, there are no clinically useful nSMase2 inhibitors. Current inhibitors are weak (µM-mM) with poor
physicochemical properties and/or limited brain penetration. In collaboration with NCATS we carried out a human
nSMase2 high throughput screen (HTS) of >350,000 compounds. Filtering and analysis of HTS hits led to
discovery of 2,6-dimethoxy-4-(5-phenyl-4-(thiophen-2-yl)-1H-imidazol -2-yl) phenol (DPTIP) the first nM inhibitor
(IC50 = 30 nM). DPTIP was found to be selective and capable of dose-dependently inhibiting exosome release
in glial cultures. Unfortunately, in vivo DPTIP exhibited rapid clearance resulting in a short half-life (t1/2< 0.5h)
and had poor oral bioavailability (F<5%). Structural modifications (~200 analogs synthesized by our group) have
not led to substantial improvements. Given its significant clinical potential, we propose to address the
pharmacokinetic limitations by utilizing dendrimer nanoparticles to deliver DPTIP selectively to activated glial
cells in the brain. Our team discovered that systemically-administered hydroxyl-terminated poly(amidoamine)
(PAMAM) dendrimers (~4 nm in size) target activated glia in the injured brain, without the need for targeting
ligands, showing minimal uptake in healthy brains. While the dendrimers are endocytosed and retained by
activated glial cells in the brain maintaining exposure for >2 weeks, they are rapidly cleared from the periphery
(plasma t1/2 ~ 6-24 h). We have validated the brain targeting, safety, and efficacy in multiple small and large
animal models, and are in Phase 1 clinical trials with our first dendrimer product (D-NAC in childhood
cerebral adrenoleukodystrophy). Herein, we propose to synthesize and evaluate the in vivo
pharmacokinetics and target engagement of two differently sized dendrimers conjugated to DPTIP (D-DPTIP)
following peroral administration. The optimal conjugate assessed by brain imaging, LC/MS bioanalysis, and
functional inhibition of glial nSMase2 activity will be tested for efficacy and safety in two established mouse
models of AD. We have assembled a highly experienced team with expertise in dendrimer nanoparticles
(Rangaramanujam), pharmacokinetics, biomarkers and target engagement studies (Rais) and
pharmacology, drug discovery and clinical translation (Slusher).
Terms: <3xTg><3xTg-AD mice><3xTg-AD mouse><65 and older><65 or older><65 years of age and older><65 years of age or more><65 years of age or older><65+ years><65+ years old><> 65 years><AD dementia><AD model><Abeta synthesis><Acquired brain injury><Addison disease-cerebral sclerosis syndrome><Addison disease-spastic paraplegia syndrome><Addison-Schilder syndrome><Address><Adrenoleukodystrophy><Aged 65 and Over><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's brain><Alzheimer's disease brain><Alzheimer's disease model><Alzheimer's disease patient><Alzheimer's disease therapeutic><Alzheimer's patient><Alzheimer's therapeutic><Alzheimers Dementia><American><Amyloid (Aβ) plaques><Amyloid Plaques><Amyloid β production><Amyloid β synthesis><Animal Model><Animal Models and Related Studies><Animals><Assay><Aβ production><Aβ synthesis><Bioassay><Bioavailability><Biochemical><Biodistribution><Biogenesis><Biological Assay><Biological Availability><Biological Markers><Blood Plasma><Body Weight><Brain><Brain Injuries><Brain Nervous System><Brain imaging><Bronze Schilder disease><Carbol><Carbolic Acid><Causality><Cell Body><Cells><Ceramides><Cerebrum><Chemicals><Chemistry><Childhood><Chronic><Circulation><Clinical><Clinical Chemistry><Clinical Trials><Cognition><Cognitive><Collaborations><Cy5><Data><Dendrimers><Dendritic Compounds><Dendrons><Disease><Disease Progression><Disorder><Dose><Drug Kinetics><Drugs><Early-Stage Clinical Trials><Encephalon><Enzyme Gene><Enzymes><Ester Hydrolase><Etiology><Exhibits><Experimental Models><Fanconi-Prader syndrome><Fluorescence Spectroscopy><Future><Generations><Genetic><Glia><Glial Cells><Half-Life><High Throughput Assay><Histologic><Histologically><Histology><Hortega cell><Human><Hydrolysis><Hydroxybenzene><Hydroxyl><Hydroxyl Radical><Immunoblotting><In Vitro><Kinetics><Kolliker's reticulum><LC/MS><Label><Ligands><Liquid substance><MT-bound tau><Mediating><Medication><Membrane><Metabolic><Methods><Mice><Mice Mammals><Microglia><Minor><Modern Man><Modification><Murine><Mus><N Methyl D aspartic Acid><N methyl D aspartate><N-Methyl-D-aspartate><N-Methylaspartate><NCATS><NIR dye><NMDA><National Center for Advancing Translational Sciences><Neuritic Plaques><Neuroglia><Neuroglial Cells><Non-Polyadenylated RNA><Non-neuronal cell><Nonneuronal cell><Oral><Origin of Life><Oxidative Stress><Pathologic><Penetration><Persons><Pharmaceutical Preparations><Pharmacokinetics><Pharmacology><Phase 1 Clinical Trials><Phase I Clinical Trials><Phenols><Physiologic Availability><Plasma><Plasma Serum><Play><Primary Senile Degenerative Dementia><Production><Property><Proteins><RNA><RNA Gene Products><Radial><Radius><Reticuloendothelial System, Serum, Plasma><Ribonucleic Acid><Role><Safety><Schilder-Addison Complex><Senile Plaques><Siemerling-Creutzfeldt disease><Siemerling-Creutzfeldt syndrome><Signaling Molecule><Slice><Source><Sphingomyelin Cholinephosphohydrolase><Sphingomyelin Cleaving Enzyme><Sphingomyelin Phosphodiesterase><Sphingomyelinase><Sphingomyelinase C><Sphingomyelins><Stimulus><Stomach><Synapses><Synaptic><Testing><Therapeutic><Time><Treatment Period><Up-Regulation><Upregulation><Western Blotting><Western Immunoblotting><Work><X-Linked Adrenoleukodystrophy><abeta accumulation><abeta aggregation><abeta production><above age 65><adrenocortical atrophy-cerebral sclerosis syndrome><adrenoleukomyeloneuropathy><after age 65><age 65 and greater><age 65 and older><age 65 or older><age > 65><age of 65 years onward><aged 65 and greater><aged 65+><aged ≥65><alleviate symptom><alzheimer model><ameliorating symptom><amyloid beta accumulation><amyloid beta aggregation><amyloid beta plaque><amyloid beta production><amyloid beta synthesis><amyloid β accumulation><amyloid β aggregation><amyloid-b plaque><analog><arm><aβ accumulation><aβ aggregation><aβ plaques><bio-markers><biologic marker><biomarker><brain damage><brain visualization><brain volume><brain-injured><causation><cerebral><chemical stability><clinical translation><clinically translatable><cohort><cored plaque><cyanine dye 5><decrease symptom><diffuse plaque><disease causation><drug discovery><drug/agent><efficacy testing><esterase><exosome><experience><extracellular vesicles><fewer symptoms><fluid><gastric><gitter cell><high throughput analysis><high throughput screening><human old age (65+)><improved><in vivo><inhibitor><liquid><liquid chromatography mass spectrometry><melanodermic leukodystrophy><membrane structure><mesoglia><meter><microglial cell><microgliocyte><microtubule bound tau><microtubule-bound tau><model of animal><mouse model><multidisciplinary><murine model><nano particle><nano-sized particle><nanoparticle><nanosized particle><near IR dye><near infrared dye><nerve cell death><nerve cell loss><nerve cement><neural inflammation><neural network><neuroinflammation><neuroinflammatory><neuron cell death><neuron cell loss><neuron death><neuron loss><neuronal cell death><neuronal cell loss><neuronal death><neuronal loss><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><old age><over 65 years><patient living with Alzheimer's disease><patient suffering from Alzheimer's disease><patient with Alzheimer's><patient with Alzheimer's disease><pediatric><perivascular glial cell><pharmacologic><phase I protocol><primary degenerative dementia><protein blotting><reduce symptoms><relieves symptoms><response><senile dementia of the Alzheimer type><social role><symptom alleviation><symptom reduction><symptom relief><synapse><tau><tau Proteins><tau factor><therapeutic target><treatment days><treatment duration><uptake><vesicle release><vesicular release><water maze><τ Proteins><≥65 years>