# Next-generation antisense therapeutics for ALS and frontotemporal dementia

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2022 · $635,090

## 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, α-synuclein in Parkinson's). Thus, one approach toward primary
therapy for such disorders is to suppress expression of the offending genes. Antisense oligonucleotides
(ASOs) are a promising class of therapeutics for dominantly-inherited neurodegenerative disorders. One ASO
has been approved to treat spinal muscular atrophy, and five others are in clinical trials for Huntington's,
Alzheimer's disease, ALS, and frontotemporal dementia (FTD).
 Nevertheless, there are two key unmet needs in the field of ASO therapeutics which require urgent and
focused investment. The first is that the phosphorothioate backbone used in most oligonucleotide drugs often
causes toxicity when administered into the central nervous system. We have identified ways to mitigate this
toxicity through changes in the backbone modification pattern. However, the current approaches increase
susceptibility to nuclease digestion, which will reduce duration of effect. In this proposal we will develop novel
mixed-backbone oligonucleotides that combine further increases in potency and decreases in toxicity with long
duration of effect.
 The second key unmet need is that for many disease genes, successful therapeutic approaches would
need to discriminate between the mutant and wild-type (healthy) alleles, silencing the mutant copy while
leaving the wild-type copy intact. We will use both innovative assays and novel chemical modifications to
improve the ability of ASOs to discriminate between these alleles.
 Applying these insights, we will advance drug candidates for two ALS and ALS-FTD genes (C9orf72 and
profilin1) into extensive testing in animal models we have established of these diseases. We will examine the
safety, efficacy and duration of effect of our advanced ASOs 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 currently in clinical development. Moreover, we will
identify novel allele-selective candidate drug candidates for C9orf72- and profilin1-dependent ALS-FTD.

## Key facts

- **NIH application ID:** 10374767
- **Project number:** 5R01NS111990-04
- **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:** 2022
- **Award amount:** $635,090
- **Award type:** 5
- **Project period:** 2019-05-15 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10374767

## Citation

> US National Institutes of Health, RePORTER application 10374767, Next-generation antisense therapeutics for ALS and frontotemporal dementia (5R01NS111990-04). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10374767. Licensed CC0.

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