# Novel Selective SGLT-1 Inhibitors for Adjunctive Therapy for Cystic Fibrosis Associated Metabolic Diseases

> **NIH NIH R42** · GENETOBE INC. · 2024 · $306,779

## Abstract

PROJECT SUMMARY
CF associated metabolic diseases including CF-associated liver disease (CFLD) and CF-related diabetes
(CFRD) are leading extrapulmonary causes of mortality in CF. In 2019, the US Food and Drug Administration
(FDA) approved Trikafta for CF. Of concern, clinical follow-up studies show that Trikafta, despite its significant
benefits on pulmonary function, may worsen metabolic related conditions. How to mitigate CFLD and CFRD in
the post- Trikafta era now becomes a priority research topic. Genetobe is a small business that is dedicated to
the development of therapies for rare diseases. In the present work, we propose to develop novel, selective,
sodium-dependent glucose cotransporter 1 (SGLT1) compounds as an adjunctive therapy for CF. This is based
on the following considerations: (i) the novel CF rabbit model that the PI has developed manifests many key
features of CF related metabolic disorders; (ii) the PI’s team recently reported that SGLT1, but not SGLT2, is
upregulated in CF affected organs in CF rabbits and CF patient samples; (iii) many SGLT inhibitor drugs have
gained successes in recent years, treating diabetes as well as additional indications (e.g., heart failure).
However, all these drugs on the market are more SGLT2 selective than SGLT1 selective; (iii) the GeneToBe
team have many prior successes in developing small molecule compounds including Lipitor and Vizimpro. Here
we hypothesize that SGLT1 selective inhibition will mitigate CF metabolic disorders and provide additive benefits
to CF patients taking Trikafta as a primary medicine. In Phase I, we’ll use artificial intelligence (AI) assisted drug
design and rational drug design to identify novel SGLT1 inhibitor compounds. These will be prioritized,
synthesized and characterized. In Phase II, we will conduct preclinical experiments in CF rabbits that carry the
most prevalent CF mutation (i.e., dF508) to test if SGLT1 inhibition by novel compounds discovered in Phase I
can alleviate CF associated metabolic disorders, with a focus on CFLD and CFRD, in combination with Trikafta
which is now the first-line medicine for CF patients with the dF508 mutation. The success of our work will
introduce a first-in-class orally available SGLT1 selective compound as a potential adjunctive therapy for treating
CF associated metabolic diseases.

## Key facts

- **NIH application ID:** 11006091
- **Project number:** 1R42DK141338-01
- **Recipient organization:** GENETOBE INC.
- **Principal Investigator:** Jessica Reed
- **Activity code:** R42 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $306,779
- **Award type:** 1
- **Project period:** 2024-09-10 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11006091

## Citation

> US National Institutes of Health, RePORTER application 11006091, Novel Selective SGLT-1 Inhibitors for Adjunctive Therapy for Cystic Fibrosis Associated Metabolic Diseases (1R42DK141338-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/11006091. Licensed CC0.

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