The future of gene therapy for a rare pediatric autoimmune disease

Rosa Wand is an associate professor of pediatrics at Stanford University. His goal as a doctor-scientist is to use modern technologies in the laboratory to find cures for incurable pediatric diseases. Wand’s main focus was on the rare autoimmune disease IPEX syndrome, short for immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. In this disorder, a mutation in the forkhead box P3 critical transcription factor gene (FOXP3) causes regulatory T-cell dysfunction. The result is a collection of unwanted immune reactions that appear in childhood against a person’s own tissues.

A little later the researchers identified the connection between FOXP3, regulatory T cells, and IPEX syndrome, Wand has begun treating the disorder with allogeneic stem cell transplants using donor cells. Twenty years later, he innovates IPEX treatments using mutant-editing gene therapy strategies FOXP3 in patients they possess immune and stem cells.

What prompted you to become a doctor-scientist?

Medicine and research have always been linked for me; I loved pediatrics and was interested in immunology. As a physician, I understand the frustration of giving a drug that can cure symptoms but not cause disease. This is what led me to the search. Working in pediatrics, I have seen many patients with rare diseases. We need to understand the mechanisms of these mutations, show that mutations can lead to devastating diseases, and find treatments for them.

What is the clinical outlook for patients with IPEX syndrome and what treatment options currently exist?

These children are born with severe autoimmune diseases that affect many areas including the intestines, skin, pancreas, nervous system, kidneys and blood. This disease greatly affects the quality of life of patients because they need continuous care and their symptoms worsen over the years.

A common treatment for symptoms but not the cause is drug immunosuppression. This treatment suppresses the unwanted immune reaction against one’s own tissues, but also suppresses the immune reaction against pathogens. In the long run, these drugs have many side effects, lead to chronic infections, and aren’t strong enough to prevent the disease from getting worse. The alternative is to completely replace the immune system. This is done through the transplantation of hematopoietic stem cells with cells from an allogeneic donor. While proven to be curative, this strategy has many problems, including the need for compatibility between the donor and the recipient. The patient has to take many drugs to clear their cells before the transplant, after which there is a possibility of rejection due to graft versus host disease.

You’re working on two new treatments for IPEX that use patient cells instead of donor cells. How do these therapies work?

Regulatory T cell therapy is similar to the strategy used in CAR T cell therapy for cancer. Let’s take a patient’s lymphocytes and add a normal FOXP3 gene under a constitutive promoter so that these cells become regulatory T cells. After growing a population of these cells, we give them back to the patient. I think this could be a great alternative to pharmacological immunosuppression. We have a clinical trial for this autologous gene therapy and have already treated two patients.

The ideal therapy is to correct the genetic mutation in the patient’s stem cells, rather than existing lymphocytes. The modified stem cells can then continuously generate new immune cells, including regulatory T cells, within the patient. A couple of years ago, Matthew Porteus, my colleague at Stanford University, and I published a paper on the feasibility of using CRISPR gene editing to fix the FOXP3 mutation in cells from IPEX patients. In the regulatory T cell approach, the corrected gene is always highly expressed. In stem cells, we need to preserve the complex regulation of the transcription factor FOXP3 so that when different immune cells are formed, each has the correct gene expression depending on the cell type and the activation state of the immune system. I hope what we are working on right now is the ideal strategy to treat these patients.

What is your perspective on using CRISPR to modify stem cells for gene therapy?

The fact that we can edit a precise site within a gene makes CRISPR an extremely attractive and promising technology, and new techniques are emerging that can improve it even further. For example, being able to modify without making a double-stranded DNA break will help prevent the potential introduction of new mutations into modified cells.

When it comes to gene therapy, what we learn from one disease can be applied to others, but then again each situation is specific. Each gene and its mechanism of action should be considered when developing gene therapy. That is why a gene therapy should be developed by scientists who know the gene and the disease very well.

This interview has been condensed and edited for clarity.