Protector of beta cells
While Erica Cai, PhD, began her career in the cancer field, she moved over to diabetes when she was studying for her master’s degree. It was a mitochondrial uncoupling protein that was responsible for the development of type 2 diabetes that attracted her attention. As she continued her investigation into beta cells, she shifted her focus to type 1 diabetes (T1D).
Today, Cai and her lab team are exploring ways to protect beta cells for three reasons.
- Protecting beta cells means preventing T1D.
- Beta cells are the only cells that secret insulin to circulation.
- They have a limited ability to regenerate.
Cai has used CRISPR screening to find new targets that could help beta cells better protect themselves from immune system attacks. She has already found that deleting a protein coding gene (RNLS – Renalase, FAD Dependent Amine Oxidase) made beta cells resistant to autoimmune killing. This finding was published in nature metabolism (“Genome-scale in vivo CRISPR screen identifies RNLS as a target for beta cell protection in type 1 diabetes,” July 27, 2020).
Now, Cai is investigating another target – a transcription factor (TF). Preliminary data is showing that if this TF is removed the beta cell could better resist an immune attack. However, Cai and her team want to ensure that removing one protein doesn’t have downstream consequences. Cai hopes that her work will lead to a new drug therapy that can halt T1D progression.
Passion to prevent type 1 diabetes
When Li Zhang, MD, PhD, was a practicing physician in China, many of her patients were living with diabetes. She observed that her type 2 diabetes patients could have a mostly normal life with prescription medication and insulin. However, her type 1 diabetes (T1D) patients could not. T1D patients tend to have more severe life-threatening complications such as heart disease, stroke or kidney disease and have a significantly shorter life span. It was this experience that drove her to research a way to improve the life for T1D patients and eventually prevent the disease.
Dr. Zhang already has established an antibody therapy that can protect mice from getting diabetes that was published in mAbs (“A monoclonal antibody with broad specificity for the ligands of insulin B:9-23 reactive T cells prevents spontaneous type 1 diabetes in mice,” Nov. 5, 2020). The success in diabetic mice encouraged Dr. Zhang to translate this antibody therapy into human studies.
Today, she has successfully identified a lead antibody targeting a human T1D antigen. She is actively testing the protection of these antibodies in humanized mice to understand if these antibodies can protect humanized mice from getting diabetes. Zhang notes, “If we can prevent diabetes in humanized mice with this antigen, this suggests we can prevent diabetes in humans.”
T1D is a complicated autoimmune disease characterized by unwanted immune cells damaging self-islets. Another innovative approach to reduce the onset of T1D is to balance the immune system by supplying protective immune cells. Dr. Zhang already has discovered that engineered immune T cells can delay the approach of T1D in mice, supported by a National Institutes of Health grant. She recently received a $340,000 federal grant to explore engineered protective regulatory T cells (Tregs) that target a T1D self-antigen related to HLA-DQ8, which is part of a gene class that is responsible for causing T1D in 60 percent of individuals living with the disease.
Using the Fab Phage Display Library, a capability made available to the IBRI by Eli Lilly and Company, Dr. Zhang and her team have identified human antigen-specific antibodies. Dr. Zhang’s perspective is that the antigen-specific antibody and regulatory T cell therapies, alone or in combination, have great potential for clinical application to reduce T1D effectively and safely.