2016 Pathway Visionary Awardee Andrew M. Scharenberg, MD

Editing genes involved in type 1 diabetes

Project title: Regulatory T-cell stabilization via gene editing as novel therapy for Type I diabetes
Institution: Seattle Children's Hospital
Pathway project publications: 1
Transitioning to Chief Scientific Officer of Casebia Therapeutics effective July 1, 2017

Major accomplishments:

Several lines of evidence suggest that dysfunction of a type of immune cell, known as a thymic regulatory T-cell (tTreg), leads to a breakdown of normal protection from the immune system in insulin-producing beta cells. When the tTreg cells fail, the immune system begins to attack and destroy the body's own beta cells, leading to type 1 diabetes. This project seeks to apply an innovative approach for "editing" genes in tTreg cells to preserve their function and protect the beta cells from autoimmune attack, potentially preventing or reversing type 1 diabetes.To date, we have established a mechanism  for enforced FOXP3 stabilization in inflammatory T-cell populations, and demonstrated that these cells exhibit regulatory T-cell properties, including similar surface marker profile, capacity to suppress expansion of other cells in vitro, and capacity to suppress in vivo using a xenogeneic GvHD model. We have performed transcriptomic analyses of the engineered cell populations, and determined that their transcriptomes are highly similar to those of natural regulatory T-cells.  Current efforts are aimed at developing processes for consistent large scale manufacturing of clinical grade cell populations.

Impact statement:

My Pathway award has been central to my having the opportunity to develop gene editing approaches to engineering regulatory-phenotype T-cells.  It is my hope that such cells could impact patients with type I diabetes by allowing restoration of immune tolerance to beta cells before exhaustion of the beta cell regenerative capacity.  The award has allowed me to establish a research program in immune tolerance, that I hope in the next year I will be able to take forward into clinical translation. I will assume the role of Chief Scientific Officer at Casebia Therapeutics in July 2017, where I hope to continue working on translation of gene edited cell therapeutics for a variety of indications, including type 1 diabetes.