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NIH grant 1R21NS139533-01A1: PNA5, an Angiotensin-(1-7) glycopeptide, to treat dementia in Parkinson's disease
Institute: {'code': 'NS', 'abbreviation': 'NINDS', 'name': 'National Institute of Neurological Disorders and Stroke', 'admin_org_id': '12500053', 'admin_funding_url': ''}. PI: TORSTEN FALK. Award: $427625.
Start: 2026-08-22T00:00:00.
ABSTRACT
Parkinson’s disease Dementia (PDD) is common in PD and there are no adequate therapeutics available. There
is a critical need in this population for disease modifying therapeutics that help to alleviate cognitive decline
associated with PD. Our premise for a novel treatment is to modulate peptide signaling systems to intervene in
multiple disease-relevant pathways in order to achieve a disease modifying effect. Peptide-based therapeutics
are an attractive approach to treatment of chronic diseases because of the safety profile associated with drug
metabolites. However, peptides have short half-lives making translation into a clinical setting difficult. We have
utilized an approach involving adding sugars to improve stability and ability to enter the brain. We chose
modulation of the Renin Angiotensin System (RAS) within the brain. This signaling is associated with cognition
enhancement and neuroprotection by promoting blood flow, inhibiting reactive oxygen species production and
inflammation. In addition, activation can lead to decreased cytokine production, improved mitochondrial
dynamics, promotion of anti-oxidative molecules, and improved neuronal health. Our lead candidate, the
glycopeptide PNA5, protects against cognitive decline in preclinical models of another form of dementia, vascular
dementia. We have performed studies in a PD model that shows cognitive decline, mice overexpressing the
wild-type form of human alpha-synuclein (hSyn), and we demonstrate that systemic PNA5 mitigates cognitive
decline by modulating neuroinflammation. In the proposed work, we plan to test whether PNA5 also improves
the phenotype of mice injected with Syn preformed fibrils (PFFs), another established preclinical model that
also shows cognitive decline. In Aim 1 we plan to test if PNA5 improves cognitive deficits and pathology in PFF
injected male mice, compared to controls (mice injected with a scrambled glycopeptide and mice given vehicle).
Post-hoc molecular and histological analyses, following behavioral tests, will determine if PNA5 modulates Syn
pathology and neuroinflammation associated processes as previously observed. We will also evaluate clinically
relevant biomarkers in brain tissue and plasma for target engagement, with a focus on cytokines. Based on pilot
data showing reduced blood levels after PNA5 injection the most promising candidate is Macrophage Induced
Protein 1B (MIP-1B). In Aim 2 we will extend the studies to female mice (intact and ovariectomized), mimicking
pre- and post-menopausal females, performing similar analyses as outlined in Aim 1. In summary, for the first
time, we plan to determine the translational utility of the glycopeptide PNA5 for cognitive deficits in PD, including
testing for possible sex-specific effects. The studies will also delineate the cellular and molecular processes key
to therapeutic effects of PNA5, and identify a blood biomarker for target engagement. Given the first in human
trials for PNA5 planned for Quarter 4 in 2025, this will set the stage for rapid future clinical trials to test PNA5
treatment in individuals with PD associated dementia.document fetched 2026-08-30 02:46