# High-throughput optimization of gene editing systems for treating Amyotrophic lateral sclerosis

> **NIH NIH R43** · ACROBAT GENOMICS, INC. · 2024 · $228,019

## Abstract

Project Summary
Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurological disease in which motor neurons
degenerate, thereby leading to paralysis and death due to respiratory failure. The incidence of ALS differs based
on ancestral origin, with ~5.5 cases per 100,000 persons in the United States. In addition to motor function
impairment, a subset of patients (~15%) suffers from frontotemporal dementia (FTD), leading to low quality of
life and extreme emotional strain on the patient’s caregivers. From a genetic perspective, ALS pathogenesis is
commonly driven by GGGGCC (G4C2) repeat expansions in the C9ORF72 gene, which cause a disease subtype
of ALS referred to as c9ALS/FTD. The repeat expansions lead to C9ORF72 haploinsufficiency, accumulation of
repeat RNA, and the production of aggregation-prone proteins composed of repeating dipeptides. While
antisense oligonucleotides and RNA interference (RNAi) approaches have been used to target the causal
mutations of ALS, these approaches are limited due to their transient effect, lack of specificity, and inability to
multiplex. Gene editing technologies have emerged as powerful approaches to target causal drivers of rare
diseases and engineer cell-based therapeutics. Therefore, there is a critical need for a gene editing-based
therapy that can safely and efficiently deplete the disease-causing mutant C9ORF72. The original CRISPR/Cas9
system that targets DNA is limited in this context since repeat expansions are at the kilobase scale and cannot
be efficiently deleted with current Cas9-based technologies. The overall goal of this proposal is to develop a
gene therapy for ALS using the Acrobat Genomics proprietary enARGN gene editing system, which is more
compact than the CRISPR/Cas9 system and more deliverable. Preliminary studies have demonstrated the
activity of Acrobat Genomics ARGN gene editing system. In this Phase I SBIR project, Acrobat Genomics plans
to develop a high-throughput protein engineering platform (AcrobaTx) to enhance ARGN gene editing activity.
The protein engineering approach is enabled by advancements in high-throughput oligonucleotide synthesis,
sequencing technologies, and protein language models. Notably, the approach utilizes pooled screening and is
highly parallel to enable the study of thousands of proteins in a single experiment (Specific Aim 1). With an
optimized ARGN protein, a novel editing strategy will be developed to deplete expression of mutant C9ORF72
and restore expression of the wild-type allele (Specific Aim 2). In summary, by protein engineering the ARGN
system, Acrobat Genomics will develop a new therapy for ALS, which is currently a devastating and incurable
disease with few treatment options. In addition to the proposed research investigations, this application will lay
the foundation for the entrepreneurial career development of the PI. The PI is the co-inventor of foundational
technologies used in this proposal and has co-founded Acrobat Genomics...

## Key facts

- **NIH application ID:** 10975019
- **Project number:** 1R43AG088777-01
- **Recipient organization:** ACROBAT GENOMICS, INC.
- **Principal Investigator:** Nicholas Hughes
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $228,019
- **Award type:** 1
- **Project period:** 2024-09-20 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10975019

## Citation

> US National Institutes of Health, RePORTER application 10975019, High-throughput optimization of gene editing systems for treating Amyotrophic lateral sclerosis (1R43AG088777-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10975019. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*