First Reversal of Type 1 Diabetes Using Precision Medicine

Houston, TX - Oct 8, 2020 - In a letter published today in the New England Journal of Medicine, a team of physicians from Baylor College of Medicine, Texas Children’s Hospital, and the University of California, San Francisco, describe a remarkable case of a Type 1 diabetes (T1D) patient, who no longer needs insulin to maintain optimal blood sugar levels. The physicians employed a precision/personalized medicine approach to specifically target the underlying genetic mutation, which was the primary driver of this patient’s diabetes.

“To the best of our knowledge, this is the first example of a T1D patient who has experienced a complete reversal of insulin-dependence and we are excited by the prospect that that could be a viable therapeutic strategy for a subset of T1D patients” said corresponding author Dr. Lisa R. Forbes, deputy director for clinical services and community outreach for the Texas Children’s William T. Shearer Center for Human Immunobiology and assistant professor of Pediatrics, Immunology, Allergy and Retrovirology at Baylor.

T1D is a chronic condition in which the pancreas produces little to no insulin, a hormone that maintains sugar levels in the blood. Currently, the treatment options available to T1D patients consist of managing blood sugar levels with insulin, diet and exercise to prevent further complications.

Multiple factors that include both genetic and environmental contribute to T1D. Although this condition usually appears during childhood or adolescence, it can also develop in adults and there is a global trend towards increased prevalence of T1D.

The NEJM letter describes a young male patient who at seventeen years of age was diagnosed with classical autoimmune presentation of T1D. In addition to T1D, the patient had also had recurrent episodes of respiratory infections. The combination of these findings led to his referral to Dr. Forbes’ team.

A deeper investigation into the patient’s genome revealed that he harbored a harmful mutation in the gene STAT1 (signal transducer and activator of transcription 1) that dangerously heightened the activity of the STAT1 protein. This genetic diagnosis explained the patient’s many seemingly unrelated clinical problems - other mutations that boost STAT1 activity are known to drive respiratory infections as well as various autoimmune conditions, including T1D.

A few months later, the patient was started on a regimen of ruxolitinib, a potent inhibitor of the Jak/STAT signaling pathway, which had been shown previously to improve many symptoms related to upregulated JAK/STAT signaling.

Over the next few months, treatment with ruxolitinib significantly lowered the frequency of the patient’s chronic infections and — strikingly — reduced his dependence on insulin to control blood sugar levels.

A year after the initiation of ruxolitinib therapy (and close to two years after his T1D diagnosis), the patient was able to discontinue daily injections of insulin and yet, maintain normal blood glucose levels. For almost a two years now, the patient has not needed insulin.

"This case was quite fascinating!” said Dr. Sophia Ebenezer, assistant professor of pediatric endocrinology at Baylor and Texas Children’s and a lead author. “For the first few months after diagnosis, many T1D patients have an initial 'honeymoon phase', when their insulin requirements are minimal or even non-existent. However, slowly over time their dependence on insulin begins to rise. Consistent with that pattern, shortly after T1D diagnosis, this patient also needed low doses of insulin. However, surprisingly, about a year after starting ruxolitinib therapy, he no longer needs daily insulin injections, has shown full remission of other clinical signs of T1D along with marked improvements in his quality-of-life. This is the first clinical demonstration that ruxolitinib can reverse insulin-dependence in T1D patients with STAT1 mutations, which is a very exciting prospect.”

While these results are promising, it remains plausible that this could be a transient effect and could recur at a later stage, the authors say. A longer clinical assessment of the patient is required to confirm if he can remain insulin-free permanently.

“We are encouraged by the amazing outcome of using a targeted approach to control T1D in this patient. We think these positive results warrant further careful evaluation on how the reversal occurred and also raise the possibility that immune- modulating drugs like ruxolitinib should be given careful consideration for use in future clinical trials for reversing T1D,” concluded Dr. Mark Anderson, a professor and Michelle M. Friend Endowed Chair in Diabetes Research at the UCSF Diabetes Center and one of the study’s lead authors.

A complete list of authors and funders is available here.