# Synthetic introns for selective targeting of RNA splicing factor-mutant leukemia

> **NIH NIH R01** · FRED HUTCHINSON CANCER CENTER · 2024 · $683,443

## Abstract

SUMMARY
Many cancers carry recurrent, change-of-function mutations affecting RNA splicing factors, resulting in
sequence-specific changes in RNA splicing that promote disease initiation and progression. These
“spliceosomal mutations” are the most common class of mutations in myelodysplastic syndromes (MDS) and
related hematologic disorders, which have few effective, FDA-approved treatments. Despite the high frequency
of spliceosomal mutations and corresponding need for new therapeutics, there currently exist no therapies that
specifically and selectively target these lesions.
Here, we propose to address this clinical need by creating new precision therapeutics that selectively
kill cells with spliceosomal mutations. Our interdisciplinary team consists of a physician-scientist with expertise
in cancer biology and patient care (Abdel-Wahab), a basic scientist with expertise in RNA splicing and
functional genomics (Bradley), and a bioengineer with expertise in drug delivery (Heller). In preliminary
experiments, we developed the “synthetic intron” technology to harness altered RNA splicing activity
caused by spliceosomal mutations to drive cancer-specific gene expression, showed that synthetic
introns permit highly selective expression of therapeutic payloads in cancer cells while leaving healthy
cells unharmed, and used this system to suppress the growth of diverse cancer types in vivo (North et
al, Nature Biotechnology, 2022). We additionally demonstrated that synthetic introns enable simultaneous and
selective delivery of multiple therapeutic payloads and allow for detailed mechanistic dissection of the cis- and
trans-acting sequence elements and splicing factors that govern pro-tumorigenic mis-splicing caused by
recurrent spliceosomal mutations.
We will now build on these preliminary studies to develop synthetic intron-based therapeutics for
myeloid neoplasms, including MDS, acute myeloid leukemia (AML), and chronic myelomonocytic leukemia
(CMML), and additionally utilize synthetic introns to understand the mechanistic basis for aberrant splicing in
these diseases as follows: Aim 1, Dissect and exploit the molecular mechanisms underlying common as well
as allele-specific splicing changes induced by different SF3B1 mutations; Aim 2, Develop synthetic introns that
enable selective therapeutic protein expression for each of the commonly mutated RNA splicing factors in
leukemia; Aim 3, Optimize in vivo delivery and rigorously test an immunostimulatory therapy for treating
SF3B1-mutant hematopoietic malignancies.
The significance of these studies is that they will develop a new
technology that enables mechanistic studies of cancer-associated spliceosomal mutations and also provides a
specific means for therapeutically targeting these mutations. The health relatedness is that the proposed work
will create specific therapeutic products for treating cancer types that currently have few effective, FDA-
approved treatments.

## Key facts

- **NIH application ID:** 10891693
- **Project number:** 5R01CA283364-02
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** Omar Abdel-Wahab
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $683,443
- **Award type:** 5
- **Project period:** 2023-08-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10891693

## Citation

> US National Institutes of Health, RePORTER application 10891693, Synthetic introns for selective targeting of RNA splicing factor-mutant leukemia (5R01CA283364-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10891693. Licensed CC0.

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