# A novel exon-specific U1 snRNA strategy to correct splicing in Familial Dysautonomia

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $495,463

## Abstract

Familial dysautonomia (FD) is a recessive neurodegenerative disease caused by a splice mutation in the
IKBKAP gene that leads to tissue-specific variable skipping of exon 20. This, in turn, leads to a drastic reduction
of IKAP/ELP1 protein in the central and peripheral nervous system. Although FD patients suffer from multiple
neurological symptoms, progressive blindness drastically reduces quality of life and is a major concern of
patients and their families. In this proposal, we outline a novel strategy to target mRNA splicing in the retina as
a potential therapy for retinal degeneration in FD. Dr. Franco Pagani's laboratory has developed novel modified
versions of the spliceosomal U1snRNAs (ExSpeU1s) that can be specifically targeted to improve inclusion of
skipped exons. This strategy has proven successful in several other splicing disorders, including spinal muscular
atrophy and cystic fibrosis. Recently, his lab has created IKBKAP specific U1s with precisely targeted base-
pairing and together we have shown that they correct splicing and increase IKAP protein both in FD cells and in
vivo by intraperitoneal delivery using AAV9. For the past several years, we have worked to generate a new FD
mouse model that both recapitulates the human disease phenotype and the tissue-specific splice defect. Our
new mouse is the only model that can be used to evaluate the therapeutic effect of IKBKAP splicing modulation
on disease phenotype. Mutations that alter mRNA splicing account for a large fraction of all human genetic
disease, and methods to correct splicing, including small molecules and oligos, are already in clinical trials.
mRNA splicing is a complex process, and therefore it is impossible to predict the efficacy of these methods
across various mutations, and in fact it is likely that combination therapies will ultimately be necessary. In this
proposal we will study a novel therapeutic strategy, namely the delivery of exon-targeted U1 snRNAs, and we
will test their efficacy specifically in the retina given the speed with which AAV directed gene therapy for retinal
disease is moving into the clinic. We have assembled an expert team and our studies will not only address a
critical unmet medical need in FD but will also allow us to uncover the precise mechanism by which these exon
targeted molecules correct splicing. Successful completion of the stated Aims will certainly have implications for
treating genetic splicing disease beyond FD, further increasing the significance of this proposal.

## Key facts

- **NIH application ID:** 9999571
- **Project number:** 5R01EY029544-03
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Susan A Slaugenhaupt
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $495,463
- **Award type:** 5
- **Project period:** 2018-09-30 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9999571

## Citation

> US National Institutes of Health, RePORTER application 9999571, A novel exon-specific U1 snRNA strategy to correct splicing in Familial Dysautonomia (5R01EY029544-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9999571. Licensed CC0.

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