# Expanding the chemical diversity of therapeutic oligonucleotides to treat neurodegenerative disorders

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2020 · $659,650

## Abstract

ABSTRACT:
Therapeutic oligonucleotides (e.g., small interfering RNAs (siRNAs) and antisense) hold promise as
transformative drugs for the treatment of genetically defined neurodegenerative disorders, including
Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). siRNAs silence disease-causing genes by
targeting their cognate mRNAs for degradation, thereby preventing the expression of toxic gene products.
Their inherent sequence specificity and prolonged activity provide a powerful therapeutic platform, as long as
the disease is genetically defined and delivery to the relevant target tissue is achievable. However, siRNAs do
not cross the blood–brain barrier and local CNS delivery by injection often results in poor retention, distribution
or toxicity. Thus, efficient and non-toxic delivery represents a major hurdle in the development of RNAi-based
drugs to treat neurodegenerative disorders.
 The goal of this proposal is to develop and characterize novel chemical scaffolds that promote simple,
efficient, and non-toxic delivery of oligonucleotides and potent silencing of therapeutic targets in the central
nervous system. We describe a class of fully chemically stabilized hydrophobic siRNAs (hsiRNAs) that elicit
durable and potent silencing throughout the brain following bolus cerebrospinal fluid (CSF) infusion.
Modifications include oligonucleotides structure, ribose, backbone and the addition of lipophilic conjugates—
e.g., neuroactive steroids, endocannabinoid-like lipids, gangliosides. Extensive structure-activity relationship
studies reveal that the type of conjugate defines the distribution, retention, efficacy, duration of effect, and
toxicity of hsiRNA-conjugates in the central nervous system.
 Completion of this proposal will (i) define and characterize two novel chemical scaffolds that support
potent, specific, and long-lasting silencing of target genes in the central nervous system, and (ii) validate this
new platform in animal models of HD and ALS, establishing a path towards novel treatments for two
neurodegenerative diseases. This proposal establishes a platform that allows direct targeting of any gene
expressed in any region of the central nervous system in a rodent. Successful completion of this work will
enable studies of gene function in the central nervous system and pave the way towards development of novel
oligonucleotide-based therapies for genetically defined neurodegenerative diseases.

## Key facts

- **NIH application ID:** 9971607
- **Project number:** 5R01NS104022-04
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** ANASTASIA KHVOROVA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $659,650
- **Award type:** 5
- **Project period:** 2017-09-25 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9971607

## Citation

> US National Institutes of Health, RePORTER application 9971607, Expanding the chemical diversity of therapeutic oligonucleotides to treat neurodegenerative disorders (5R01NS104022-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9971607. Licensed CC0.

---

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