Blocking Protein of Glucose Uptake, SGLT1, May Help in Treating CF
Blocking the protein SGLT1, which regulates glucose uptake in cells, may be a useful in treating cystic fibrosis (CF), according to research done in a cell model of the disease.
SGLT1 inhibitors are likely less effective that currently approved modulators for patients with eligible mutations, its scientists noted, but they could have “synergistic effects” when used in combination.
Findings were in the study, “The sodium/glucose cotransporters as potential therapeutic targets for cystic fibrosis lung diseases revealed by human lung organoid swelling assay,” published in the journal Molecular Therapy – Methods & Clinical Development.
CF is caused by mutations in the gene that codes for the CFTR protein. Normally, this protein functions like a gate at the surface of cells, regulating the movement of chloride and water in and out. (Chloride is a salt ion, half of “sodium chloride” or table salt.)
In recent years, several CFTR modulators — such as the dual-combination therapy Orkambi and the triple-combination Trikafta, both sold by Vertex Pharmaceuticals — have widespread approval. These medications can help the CFTR protein to function correctly in people with certain disease-causing mutations, but about one in every 10 CF patients has a mutation that is not amenable to modulator treatment.
Laboratory models are crucial in identifying new treatment strategies and in testing potential therapies. A team of U.S.-based researchers previously generated such a model for CF called human proximal lung organoids (HLOs).
Essentially, HLOs involve collecting cells from a patient and programming those cells to grow into lung cells through a series of biochemical manipulations. The lung cells are then grown in a three-dimensional structure meant to mimic the physical architecture of cells in a human lung.
The team had previously shown that the HLO model can be used to test CFTR function in a simple assay: when the HLOs are treated with a compound called forskolin, they normally swell up. However, when CFTR is impaired, these organoids do not swell.
These researchers now demonstrated that HLO models with specific mutations responded as expected to treatment with the CFTR modulators found in Orkambi, either alone (as lumacaftor and as ivacaftor) or in combination.
“These data demonstrate that the swelling assay on HLOs faithfully reflect the mutation dependent response to CFTR modulators, supporting the use of this system in preclinical CF drug development,” the scientists wrote.
Mutations tested were delF508, the disease’s most common, in both gene copies, and one copy of the delF508 and one of the G551D mutation. HLOs can be engineered to carry various CF-causing mutations, including rare ones, the study noted.
The team then sought to use the model to test a new treatment approach for CF. The investigators focused on a protein called SGLT1, which mediates the sodium-dependent uptake of glucose into cells. Notably, SGLT1 is found in CF-relevant tissues such as the lungs and the intestine.
“We selected SGLT1 as a target because some studies including ours have indicated increased SGLT1 activity in CF patients and in CF animals,” the researchers wrote.
Treating the CF organoids with SGLT1 inhibitors promoted swelling to a similar extent to Orkambi.
“Using this [HLO] platform, we revealed promoting effects of [SGLT1 inhibitors] on CF HLO swelling, presenting inhibiting SGLTs as a potential new strategy to attenuate CF lung diseases,” the scientists wrote.
One of the SGLT1 inhibitors tested was sotagliflozin, a medication approved in Europe to help treat diabetes. The U.S. Food and Drug Administration (FDA) rejected an application for sotagliflozin’s approval as an oral diabetes treatment this year, citing safety concerns.
Further experiments showed that the effects of SGLT1 inhibition were independent of CFTR function, as swelling was promoted in the HLOs even when CFTR activity was blocked.
“Because the promoting effect appears to be CFTR independent, SGLT1 inhibitor drugs such as Sota [sotagliflozin] may serve as a candidate ‘bridge’ drug to treat CF patients … who currently do not benefit from Trikafta or any other drugs,” the researchers wrote.
SGLT1 inhibitors are unlikely to provide superior benefits to CFTR modulators in patients eligible for those treatments, the scientists noted. But, they added, the “combinational use of Sota and Trikafta might bring synergistic effects.”
The team also noted that, since SGLT1 is expressed in tissue other than the lung, blocking this protein may provide benefits to CF patients outside of those possible for the lungs.
Other experiments suggested a potential mechanism for the effects of SGLT1 inhibitors: these medications lead to an increase in the expression of AQP5, which is an aquaphorin — a protein channel that controls the movement of water in and out of cells.
Previous work has suggested that increasing AQP5 levels could reduce fluid viscosity [resistance to flow] in the airways, a hallmark of CF.
“In the present work, we provide support for this hypothesis: AQP5 is downregulated in CF HLOs, Sota treatment effectively elevated AQP5 [production] coinciding with the improved swelling assay results, and knockdown of AQP5 cancels Sota’s promoting effects,” the researchers wrote.
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