# Multi-Targeting Oligonucleotide Therapeutics for Familial and Sporadic Amyotrophic Lateral Sclerosis

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2024 · $665,737

## Abstract

Project Summary
 Neurodegenerative diseases are devastating age-related disorders that represent a tremendous disease
burden worldwide. The need for effective therapies is increasingly urgent as the population ages. Most familial
adult-onset neurodegenerative disorders are caused by dominantly-transmitted gene defects (e.g. C9ORF72
and SOD1 in ALS, HTT in Huntington’s, -synuclein in Parkinson’s). Thus, one approach toward primary
therapy for such disorders is to suppress expression of the offending genes. RNA-targeted medicines,
including antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), are a promising class of
therapeutics for dominantly-inherited neurodegenerative disorders. Two ASOs have been approved to treat
spinal muscular atrophy and SOD1-dependent ALS, while dozens of others are in clinical trials for
Huntington’s, Alzheimer’s disease, ALS, Parkinson’s disease, genetic epilepsies, and more.
 Nevertheless, there are two key unmet needs in the field of RNA-targeted medicines which require urgent
and focused investment. The first is that the phosphorothioate backbone used in most oligonucleotide drugs
often causes some toxicity when administered into the central nervous system, giving these drugs a narrow
therapeutic index. The second key unmet need is that for many neurodegenerative diseases, silencing one
gene may not be sufficient to provide a meaningful change in disease course. Given the complexity of many of
these diseases, target combinations are likely to have a broader effect on the outcomes than single targets.
 We have developed a platform technology that addresses both of these limitations: during the first term of
our R01 we found that a conjugated molecule containing an siRNA domain and an ASO domain shows very
high safety and efficacy throughout the CNS. We will further develop this ‘platform technology’, seek to
understand the mechanism for its high safety and efficacy relative to previous technologies, and test its ability
to modulate the expression and processing of targets relevant to ALS.
 Applying these insights, we will advance six drug candidates for ALS into extensive testing in iPSC-derived
neurons and animal models of ALS. We will examine the safety, efficacy and duration of effect of our advanced
molecules both at the molecular level and at the level of change in disease phenotype.
 In this proposal, our laboratories will combine innovative chemistry with deep expertise in neurology and
disease-relevant mouse models. We aim to develop broadly applicable platform technology with a substantial
improvement in therapeutic index relative to the ASOs and siRNAs currently in clinical development. Moreover,
we will develop three drugs that silence pairs of targets, and another three drugs that silence one target in
combination with splice modulation of a second target. Successful completion of our work would allow these
candidates to reach the point of readiness for IND-enabling studies and clinical ...

## Key facts

- **NIH application ID:** 11000079
- **Project number:** 2R01NS111990-06
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Robert H Brown
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $665,737
- **Award type:** 2
- **Project period:** 2019-05-15 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11000079

## Citation

> US National Institutes of Health, RePORTER application 11000079, Multi-Targeting Oligonucleotide Therapeutics for Familial and Sporadic Amyotrophic Lateral Sclerosis (2R01NS111990-06). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/11000079. Licensed CC0.

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