Established T1D Patient Insulin Independent. Is It really a Practical Cure?

October 3, 2024

This week, the hot news item in T1D research revolves around a twenty-five-year-old patient, diagnosed with T1D eleven years ago, who used her own stem cells to achieve insulin independence in a clinical study. Some online newsstands are hailing this treatment as a ‘cure’ or ‘reversal’ of the disease and are describing certain study tactics as the first of its kind.
 
JDCA reviewed details of the study results to answer the question: Is this a potential Practical Cure?
 
The short answer is ‘no,’ as the individual was on a regimen of full-body immunosuppressants throughout the trial due to previous liver transplants. Furthermore, the study appears to use similar immunosuppression moving forward, though the specifics of the other two test subjects are unknown. That said, the results are unique in several ways and could pave the way for new methods toward achieving a Practical Cure.
 

Study Highlights    
Study results were published in the prestigious medical journal, Cell, on September 26.
 
The clinical trial, taking place at Tianjin First Center Hospital in Tianjin, China, released initial one-year results of the first patient enrolled. The study is testing a method that claims to be the first of its kind, using autologous, chemically-induced pluripotent stem cells (CiPSCs) transplanted into patients’ abdominal muscles. The trial does not use gene-editing techniques.
 
According to the publication, “The patient achieved sustained insulin independence starting 75-days post-transplantation,” and has maintained independence through the one-year assessment. Time in range increased from 43% at the beginning of the study to above 98% at the last appointment. All safety and efficacy endpoints have been met.
 
The promising results attracted the attention of renowned James Shapiro, lead investigator on the Edmonton Protocol, now a standardized procedure for cadaver-sourced islet transplantation. In an article from Nature, Shapiro commented on the results of this study: “They’ve completely reversed diabetes in the patient, who was requiring substantial amounts of insulin beforehand.” In an interview with JDCA last year, Shapiro remarked on similar research at his lab. Though still in development today, the goal was to create islets from patients’ own blood.
 

Why Isn’t This a Practical Cure?

Despite the positive results, the trial is not considered a Practical Cure in its current state. The patient making headlines for insulin independence had undergone two liver transplants prior to enrollment, requiring a permanent regimen of immunosuppressive drugs to protect the transplanted organ from immune system rejection. This is interesting since immunosuppression is not explicitly listed as a study intervention in the clinical trial description, but it does specify individuals with T1D, “including those who have received organ transplantation such as liver and kidney.”
 
These immunosuppressive drugs also protected the transplanted islets from the patient’s autoimmune attack, similar to how chronic, full-body immunosuppression has been proven effective at keeping beta cells alive in some traditional islet cell transplantation patients. Furthermore, the official publication remarks, “Because T1D is an autoimmune disease, an autologous islet transplant would likely still necessitate the use of immunosuppressants,” indicating immunosuppression will likely be a protocol in the future.
 
To be a Practical Cure, the trial will need to find a way to protect the cells from the autoimmune attack without immunosuppression. Trial enrollment must also be expanded beyond N=3 to determine the effectiveness of the transplanted cells in a larger group of people and for a longer duration.
 

Methods and Implications

The clinical trial in question, though not a Practical Cure in its current state, appears to be unique in regard to its approach to cell development and the transplantation site. However, as with all trials attempting islet transplantation, certain obstacles must be overcome for the therapy to succeed.

Cell Development 
The cells used in the trial are autologous, meaning they are taken from the same patient who will later receive them. The primary benefit of using a patient’s own cells is that once transplanted, they are less likely to be seen as ‘foreign’ and targeted by the immune system. A secondary benefit is that patients will not be dependent on external supply, an issue seen most often in trials requiring donated cadaverous islets. After the fully-matured cells are extracted from the patient, they are chemically treated with small molecules and reverted to a malleable, earlier stage of development. These ‘blank slate’ cells are then ‘trained’ to function as islets.
 
One key issue is scalability. Since the treatment would be performed on an individual basis as opposed to a generalized approach, the effort, cost, and risks pose a unique hurdle. In comparison, a single embryonic stem cell can be replicated indefinitely and manufactured at scale, though the cells are more likely to be targeted by the patient’s own immune system.

Transplantation Site 
The islet transplantation site—the patients’ abdominal muscle—is uncommon in human trials, but there is growing interest. The site allows for regular monitoring of implanted CiPSCs via ultrasounds and MRIs. Different sites for islet transplantation have been investigated at length by diabetes researchers, namely the liver and omentum. Transplantation sites cannot perfectly mimic the hospitality of a fully functioning pancreas, so researchers must ensure the new site allows cells to receive enough oxygen and blood flow to survive.

This same threat exists for all islet transplantation sites. Cells must have immediate access to blood and oxygen to survive in the short-term, and the ability for cells to survive long-term without declining in function. Although the cells have survived in this new site thus far, success cannot be determined until more time has passed.