Researchers at Washington University School of Medicine in St. Louis have transformed human stem cells into insulin-producing cells and used the gene-editing tool CRISPR-Cas9 to correct a genetic defect that had caused the syndrome of a rare form of diabetes.
After transforming and editing the induced pluripotent stem cells produced from the skin of a patient with a rare, genetic form of insulin-dependent diabetes called Wolfram syndrome, the researchers implanted the cells into lab mice and cured the unrelenting diabetes in those mice.
The researchers first discovered how to convert human stem cells into pancreatic beta cells a few years ago.
When such cells encounter blood sugar, they secrete insulin. In this study, they took the additional steps of deriving these cells from patients and using the CRISPR-Cas9 gene-editing tool on those cells to correct a mutation to the gene that causes Wolfram syndrome (WFS1). Then, the researchers compared the gene-edited cells to insulin-secreting beta cells from the same batch of stem cells that had not undergone editing with CRISPR.
In the test tube and in mice with a severe form of diabetes, the newly grown beta cells that were edited with CRISPR more efficiently secreted insulin in response to glucose. Diabetes disappeared quickly in mice with the CRISPR-edited cells implanted beneath the skin, and the animals’ blood sugar levels remained in normal range for the entire six months they were monitored.
Animals receiving unedited beta cells remained diabetic. Their newly implanted beta cells could produce insulin, just not enough to reverse their diabetes. “We basically were able to use these cells to cure the problem, making normal beta cells by correcting this mutation,” said co-senior investigator Fumihiko Urano, a professor of medicine as well as a professor of pathology and immunology.
“It’s a proof of concept demonstrating that correcting gene defects that cause or contribute to diabetes – in this case, in the Wolfram syndrome gene – we can make beta cells that more effectively control blood sugar. It’s also possible that by correcting the genetic defects in these cells, we may correct other problems Wolfram syndrome patients experience, such as visual impairment and neurodegeneration.”
In the future, using CRISPR to correct certain mutations in beta cells may help patients whose diabetes is the result of multiple genetic and environmental factors, such as type 1, caused by an autoimmune process that destroys beta cells, and type 2, which is closely linked to obesity and a systemic process called insulin resistance, the researchers said.
Moving forward, the researchers are working on developing stem cells from urine samples. Patients with Wolfram syndrome develop diabetes during childhood or adolescence and quickly require insulin-replacement therapy, requiring insulin injections multiple times each day. Most go on to develop problems with vision and balance, as well as other issues, and in many patients, the syndrome contributes to an early death.
The study was published online on Wednesday in the journal Science Translational Medicine.
