# Autophagon: an Autophagy-Functionalizing Gene Therapy Tool for Neurodegenerative Diseases

> **NIH NIH R01** · UNIVERSITY OF NORTH DAKOTA · 2022 · $568,004

## Abstract

Project Summary
Neurodegenerative diseases, especially Alzheimer’s Disease (AD) and Parkinson’s Disease (PD), affect
millions of people globally and represent a US major healthcare burden. AD is the world’s most common cause
of dementia, and is the sixth leading cause of death in the US. PD is motor disabling condition that advances to
cognitive deficits. Currently there exist no effective therapies for AD or PD; even some of the drugs used to
ameliorate symptoms, such as in PD, cause serious long-term side effects that may be worse than the disease
itself. In AD and PD, accumulation of Amyloid-β (Aβ) or α-Synuclein (α-Syn) and their subsequent aggregation,
cause neuronal toxicity, including neuroinflammation, synaptic deficits and neurodegeneration, leading to
cognitive or motor deficits. In this application, we conceive an innovative genetic tool (named Autophagon, or
AFN) to be developed as a gene therapy that helps target toxic Aβ or α-Syn species to autophagy, an
important degradative pathway that is usually impaired in AD and PD. AFN will feature a synthetic gene
fragment to help sequester Aβ or α-Syn aggregates and deliver them to the autophagic vesicles for clearance
from the neurons. Using viral vectors, we will deliver AFN to cells or to mouse brain via specific stereotaxic
injections. First, we will test AFN in vitro using 2D and 3D (brain organoid) neuronal cultures derived from
iPSCs harboring APP/PSEN1 or α-Syn mutations that drive Aβ or α-Syn aggregation, respectively, and assess
the ability of AFN to suppress aggregate formation and neuronal toxicity. Second, we will use mouse models of
AD (with a genetic knock-in of human APP mutations that cause Aβ aggregation) and PD (expressing
aggregation-prone mutant human α-Syn) to test the therapeutic potential of AFN and its ability to prevent
aggregate formation, neurodegeneration, and cognitive or motor deficits in vivo. If successful, the proposed
project will have a major impact on the neurodegenerative diseases field, by developing an effective potential
gene therapy for AD and PD, and set the foundation for the next steps of preclinical and clinical testing of this
suggested therapy. It may also provide a proof-of-concept for therapy development for other
neurodegenerative disorders associated with protein aggregation.

## Key facts

- **NIH application ID:** 10334114
- **Project number:** 1R01AG074899-01
- **Recipient organization:** UNIVERSITY OF NORTH DAKOTA
- **Principal Investigator:** Abraam M. Yakoub
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $568,004
- **Award type:** 1
- **Project period:** 2022-03-15 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10334114

## Citation

> US National Institutes of Health, RePORTER application 10334114, Autophagon: an Autophagy-Functionalizing Gene Therapy Tool for Neurodegenerative Diseases (1R01AG074899-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10334114. Licensed CC0.

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