Novel selective sglt-1 inhibitors for adjunctive therapy for cystic fibrosis associated metabolic diseases
Ended Project Grant Awarded Last action
- Award ID
- R42DK141338
- Recipient
-
Genetobe Inc. UEI FXRCJNY4PJL1
- Awarding agency
-
National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $610,525
Award facts
- Assistance listing
- 93.847 Diabetes, Digestive, and Kidney Diseases Extramural Research
- Completion date
- Place of performance
- Michigan, USA
Award details come from USAspending.gov.
Description
- Abstract
- 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.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | -$3,034 | |
| Amendment | $0 | |
| Amendment | $306,779 | |
| Original award | $306,779 |
Quick answers
Who received award R42DK141338?
R42DK141338 was awarded to Genetobe Inc. by National Institute of Diabetes and Digestive and Kidney Diseases (National Institutes of Health) on September 10, 2024.
How much is award R42DK141338 worth?
$610,525 has been obligated on R42DK141338.
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