Current Research

Translating disease hypotheses into potential therapies

Four scientists working in the Cai Lab
Induced pluripotent stem cells
Two scientists working in the Zhang Lab

Science translated, hope realized

What began as a scientific interest for D. Wade Clapp, MD, chair of the Department of Pediatrics at the Indiana University (IU) School of Medicine, has grown into a life-altering passion.

Dr. Clapp is a neonatologist who started in hematology, so pediatric sarcomas and genetic cancers are not his natural area of acumen. Yet, as he continued his research and began meeting patients and their families, the physician in him took over.

Dr. Clapp, who is focused on two rare genetic disorders called Neurofibromatosis type 1 (NF1) and Neurofibromatosis 2 (NF2), noted that almost a quarter million people ages 18 to 24 years old live with NF1 and 25,000 more individuals have NF2. However, NF2-linked tumors account for approximately 3 percent of all nervous system related tumors. Dr. Clapp and his colleagues have worked on NF1 for nearly 20 years and now have three drugs in clinical trials and one that is FDA approved. Their work in NF2 has begun much more recently.

NF2 is characterized by benign tumors of the nerves that transmit balance and sound impulses from the inner ears to the brain, leading to deafness, vertigo, facial muscle weakness and chronic neuropathic pain.

“The primary way to treat NF2,” Dr. Clapp said recently, “hasn’t changed since I was in medical school. These kids, who live in our community, deserve more.” He went on to say, “Surgery carries significant risks, yet no long-term effective therapies exist for these highly debilitating tumors. This is why it’s so important to me to work to develop pharmaceutical approaches to halt or reverse the progression of tumor growth in patients.”

Dr. Clapp has worked with Steve Angus, PhD, assistant professor of pediatrics at the IU School of Medicine, to develop a series of genetically engineered mice with NF2 that develop tumors just like humans with NF2. These mice serve as vital surrogates, since there are so few young people living with NF2. Dr. Clapp and team have seen some initial successes with three potential drugs; however, it is his collaboration with the IBRI that will take his research to the next level.

In collaboration with the IBRI, Dr. Clapp and his colleagues are pursuing detailed screening combinations, with the goal of identifying drugs or drug combinations that could immediately proceed to Phase I/II clinical trials. “The IBRI offers us high-throughput screening capabilities and the ability to create induced pluripotent stem cells (iPSCs),” said Dr. Clapp. “Plus, the IBRI has tremendous chemistry expertise that opens us to novel compounds, drug combinations and chemical matter. We’re especially looking forward to the IBRI bringing its chemistry lab online in the fall.”

Dr. Clapp had been working with the IBRI’s Mary Mader, PhD, to explore PROTACs (proteolysis targeting chimera), which blocks both the activation of the kinase and inhibits its interaction with other proteins. For NF2 tumors, Dr. Clapp has been looking at a particular kinase that has the potential to suppress tumors.

Dr. Clapp and Mader are exploring the sensitivity of the kinase – taking it from micromolar to nanomolar. A kinase typically can inhibit the growth of a tumor but doesn’t kill it. “If we are able to use a kinase at such a low level with higher targeting, we might be able to kill the tumor,” said Dr. Clapp.

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.

  1. Protecting beta cells means preventing T1D.
  2. Beta cells are the only cells that secret insulin to circulation.
  3. 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.