March 28, 2024
There are three main medical research pathways toward a Practical Cure for T1D: Cell Supply Solutions, Cell Protection Solutions, and Advanced Insulin Delivery Systems. Each of these main pathways can be addressed by a variety of different research approaches, like branches of a tree.
This report provides a quick description and summary of the three main pathways and the most important research branches for each. Ultimately, a full Practical Cure for T1D is likely to be a combination of two or more pathways and branches. Several current and active clinical trials have already begun combining two or more pathways.
This report follows last week’s infographic defining a Practical Cure.
Cell Supply Solutions
The Cell Supply Solution pathway aims to replace the insulin-producing beta cells that have been lost because of the immune system attacking its own healthy cells. This pathway contains two notable branches: Cell Transplantation and Cell Regeneration.
1. Cell Transplantation:
A procedure to transplant insulin-producing cells into a person with T1D to achieve insulin independence. This method relies on finding a sustainable and scalable cell supply, a suitable site to place the cells in the body, and a way to protect the implanted cells from autoimmune attack.
Stem Cell-Derived Beta Cells (sBCs)
Xenotransplantation
sBCs created via embryonic or adult stem cells are gaining popularity in today’s T1D research. Embryonic stem cells (having the ability to evolve into any cell type) are collected at the beginning of cell development within one week of fertilization and 'trained’ to develop into functioning beta cells. Adult stem cells are the result of a process that transforms an individual’s fully developed cells into beta cells. The process re-programs these cells into an earlier unmapped state, allowing controlled evolution into beta cells. Since adult cells can be taken from the same T1D patients who later receive them, transplanted cells will not be seen as foreign entities by the immune system, and immunosuppression would not be necessary. A single line of sBCs can be replicated indefinitely into a potentially limitless supply.
This notable, lesser-known branch of islet transplantation aims to circumvent the cell supply issue by using beta cells from non-human animals, such as pigs. Xenotransplantation as a source of cell supply has been in development for several decades but, to date, without positive results. However, new advances are reopening the potential of Xenotransplantation for T1D.
2. Cell Regeneration:
This approach seeks to boost the reproduction of the few beta cells that remain in the body for many years after diagnosis. While there is evidence that beta cells can exist for decades, the amount is small and the path to substantial reproduction is unknown. However, if these latent beta cells can be triggered to reproduce at scale and are sufficiently protected, insulin independence just might be achieved.
This branch must ensure that once insulin-producing cells are created and ‘reawakened,’ they will not be attacked by the immune system.
Cell Protection Solutions
Cell Protection Solutions intend to safeguard insulin-producing cells from the body’s autoimmune attack. Currently, there are three notable research approaches: Encapsulation, Gene-Edited Cells, and Immune System Modification. Some of these approach branches overlap and are increasingly explored in concert with Cell Supply Solutions.
1. Encapsulation:
The protection of insulin-producing cells from the autoimmune attack by placing the cells inside a physical barrier, such as a gel, device, or pouch. There are macro-encapsulation approaches which hold many cells in one protection product, and micro-encapsulation approaches which provide a barrier for each individual cell.
The main obstacle to this pathway is ensuring that cells are shielded sufficiently from the immune system’s attack while still being permeable enough to receive oxygen, respond to changes in blood glucose, and release insulin to the body.
2. Gene-Edited Cells:
In this research approach, implanted cells are genetically modified to avoid triggering an autoimmune attack. A high-profile example of this is CRISPR Therapeutics, a biotech company investigating two cell lines: CTX-211, stem cell-derived cells gene edited with CRISPR Cas9, and a collaboration with Vertex Pharmaceuticals to develop gene-edited hypo-immune cells (in development). There are many additional companies and academic centers conducting research in this pathway.
3. Immune System Modification:
Immune system modification entails modifying the body’s immune system internally to stop attacking insulin-producing beta cells. This could be done with an oral drug, retraining the body’s DNA to alter the beta cell immune response, and other methods.
Currently, the only successful method available to stop the autoimmune attack is lifelong, full-body immunosuppression, which compromises the immune system’s overall health and is not feasible for the majority of the T1D community.
Advanced Insulin Delivery Solutions
The Advanced Insulin Delivery Solutions pathway consists of intelligent systems that automate the insulin delivery process. The two research branches in this pathway are Glucose Responsive Insulin and Advanced Artificial Pancreas. Different from an insulin pump, these treatments would require little-to-no monitoring and be capable of fully regulating the balance of insulin and glucose.
1. Glucose Responsive Insulin:
Insulin that is automatically released in response to the body’s natural rise in blood glucose and stops once it normalizes. Theoretically, a single daily injection would satisfy the needs of a person with T1D without the measured dosing and frequent monitoring required today. This branch is still in the research and development stage. To be successful, this ‘smart insulin’ must be sensitive enough to respond quickly to changes in glucose levels and have the accuracy to maintain a healthy TIR without falling into high or low blood sugars. To date, this pathway has posted few positive results.
2. Advanced Artificial Pancreas:
A wearable device that acts as a fully functioning, healthy pancreas by automatically adjusting glucose levels and insulin in the body. This device must include a CGM, a reservoir for both insulin and glucagon, and an advanced control algorithm to determine the correct dosage to quickly bring blood glucose to a healthy level. When surveyed, 88% of people said this method would qualify as a Practical Cure if it is small enough to “generally forget you are wearing it” and essentially be “set and forget.”
