# Splicing Modulators for Rare Disease Indications

> **NIH NIH R01** · UNIVERSITY OF NOTRE DAME · 2022 · $401,631

## Abstract

Several years ago we identified polyketides GEX1A (herboxidiene) and the pladienolides as potential
lead compounds for two indications that are not addressed but current chemotherapeutic treatments.
Niemann-Pick Type C is a rare, lethal genetic disease associated with aberrant cholesterol and
sphingolipid storage within the lysosome with no current FDA-approved treatment and recent
disappointing results of candidates in late-stage trials. During the most recent research period of our NIH
R01 grant, we complemented this discovery with new results that show GEX1A has potent and selective
activity against acute myeloid leukemia with mutations within the FMS-like tyrosine kinase 3 (FLT3)
gene. FLT3 mutations are the most common somatic mutations observed in acute myeloid leukemia
(AML) and their presence may be a prognostic factor for poor outcome and remain a clinical challenge in
need of new treatment options. Although originally investigated for their anti-cancer potential, preliminary
results with these polyketides point to related and/or additional activity associated with modulation of
mutant NPC1 protein and other gene products through pre-RNA splicing modulation. Recent FDA-
approved drugs and candidates in current clinic suggests that modulation of RNA-splicing and the
spliceosome are biological targets with growing clinical relevance. In both indications we have
demonstrated activity through in vitro cellular studies and in vivo mouse models. Thus, therapeutic
dosages have been identified without potential toxicity and thus our continued effort is seen as both
significant and innovative with respect to fundamental and translational research. The collaborative,
multidisciplinary strategy utilizes bacterial fermentation, natural product degradation and semi-synthesis
as a complement to total synthesis as means to provide access to compounds for biological studies and
pharmacological optimization. We will determine the solution conformational preferences of GEX1A and
pladienolides and apply this information to the design and synthesis of conformational analogues through
total chemical synthesis. The combination of synthetic technologies will ensure an adequate supply of
GEX1A and related analogues for a number of key biochemical experiments to help establish and
correlate the mechanisms of action in both indications. Finally, we will continue our efforts to evaluate the
translational potential of optimized congeners through exploration of their in vivo activity in mouse
models of NPC disease. Two murine, whole animal models will be assessed. A greater understanding of
the mode of action can help identify commonalities between Niemann-Pick Type C, other lysosomal
disorders, and more common diseases. About 25M Americans are affected by a rare disease and rare
disease research has the potential to increase our understanding of more common afflictions through
their study.

## Key facts

- **NIH application ID:** 10501840
- **Project number:** 1R01GM147637-01
- **Recipient organization:** UNIVERSITY OF NOTRE DAME
- **Principal Investigator:** STEPHEN Laurence STURLEY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $401,631
- **Award type:** 1
- **Project period:** 2022-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10501840

## Citation

> US National Institutes of Health, RePORTER application 10501840, Splicing Modulators for Rare Disease Indications (1R01GM147637-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10501840. Licensed CC0.

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