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PET Imaging to Evaluate a Novel Chemokine Antagonist to Protect Synapses in ADRD

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R43AG085779-01
Agency Tracking Number: R43AG085779
Amount: $324,790.00
Phase: Phase I
Program: SBIR
Solicitation Topic Code: NIA
Solicitation Number: PAS22-196
Timeline
Solicitation Year: 2022
Award Year: 2023
Award Start Date (Proposal Award Date): 2023-09-30
Award End Date (Contract End Date): 2025-06-30
Small Business Information
10319 GLEN RD
Potomac, MD 20854-1836
United States
DUNS: 080691955
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 MICHAEL RUFF
 (240) 893-7400
 mruff@creativebiopeptides.com
Business Contact
 MICHAEL RUFF
Phone: (240) 893-7400
Email: mruff@creativebiopeptides.com
Research Institution
N/A
Abstract

7. Project Summary
ADRD dementias account for up to 25% of all dementias in patients older than 65 years and there is strong
evidence of co-morbid pathologies caused by (amyloid β (Aβ), tau and α-synuclein (αSyn). The degree of AD-
related pathology in Lewy Body Dementias (LBD) is moderate or severe in 50% of PDD and more than 70% of
DLB patients have concomitant AD-related pathology so that these patients experience a more heterogeneous,
faster, and severe clinical phenotype. Cognitive impairment is closely associated with synapse loss which occurs
significantly prior to neuronal loss suggesting that synaptic dysfunction is the key treatment target and that
ultimately synapse loss by multiple toxic oligomers (αSyn, Aβ, and tau), that begins with their binding to PrPc,
must be stopped. Our results show that RAP-103, a small oral peptide CCR5 antagonist potently prevents both
αSyn and Aβ-mediated spine and synapse loss in rodent and human neurons by blocking PrPc activation that
disrupts microtubules, spine structure and synapse function. RAP-103 protected rodent and human neuron
spines and synapses from αSyn and Aβ-induced loss, and in a pilot study of the human αSyn expressing animal
model Line 6116, prevented cognitive deficits. By binding to neuronal CCR5, RAP-103 exerts an allosteric
inhibitory effect on membrane bound PrPc/NOX complex activation to block multiple toxic oligomers to stop,
possibly reverse, synapse loss and cognitive decline in ADRD including LBD. Utilizing the Tg4510 mixed α-
Syn/Tauopathy animal model we will conduct a definitive in vivo study of RAP-103 protective effects on synapse
density and disease biomarkers relevant to ADRDs by brain histochemical analysis. We will compare in vivo
histochemical analysis of synapse density to live animal SV2A PET imaging with [18F]SynVesT-1 as a
quantitative biomarker of synaptogenesis. We will administer RAP-103 by oral dosing from months 6 to 7 when
animals experience synapse loss. We will determine RAP-103 effects on markers of brain synapse density in
cortex and hippocampus by quantitative methods measuring expression of Synaptophysin 1, a synaptic vesicle
protein and SVA2, the target of the PET imaging tracer and normalize to total neuron density with NeuN in pre-
identified regions of interest. We will also determine RAP-103 effects on disease biomarkers by measuring the
number of neurofibrillary tangles-NFT load, oligomeric Tau, pThr231Tau, Multimeric total αSyn and pSer129
αSyn. Successful completion of the Aims will support further development of RAP-103 for synapse protecting
effects and suggest using SV2A PET imaging with [18F]SynVesT-1 as a quantitative biomarker of
synaptogenesis in ADRDs, which can then be correlated with biomarkers and cognitive benefits for use in human
testing.

* Information listed above is at the time of submission. *

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