Caroline Le Poole talks to colleagues in a lab

Immunologist Caroline Le Poole (centre) is co-founder of Temprian Therapeutics.Credit: Northwestern University

Temprian Therapeutics is a spin-off from Northwestern University in Chicago, Illinois.

Vitiligo is an autoimmune disease that affects an estimated 50 million people worldwide. It isn’t life-threatening, but its conspicuous characteristic — the loss of pigment from the skin — can be a psychological burden for some people.

Decades have passed since any new treatments reached the market. But a gene-based therapy under development could offer hope for people seeking treatment. Caroline Le Poole, an immunologist at Northwestern University in Chicago, Illinois, is co-founder of Temprian Therapeutics, a start-up that is moving the therapy towards clinical trials.

The strategy emerged from Le Poole’s research into how the immune system turns against pigmented skin cells called melanocytes. The change in pigmentation of the skin is the result of melanocytes being attacked by the immune system’s T cells. This is often preceded by physical skin trauma such as sunburn, or by emotional stress. Le Poole’s team found that one molecule, called inducible heat-shock protein 70 (HSP70i), has an outsize role in the progression of symptoms. HSP70i ordinarily prevents melanocytes from self-destructing when they’re under stress. But in people with vitiligo this process is disrupted. Melanocytes respond to stress by ejecting HSP70i. When this happens, the protein activates the immune system’s dendritic cells, which draws in T cells (see ‘Vanquishing vitiligo’).

Le Poole and her colleagues found that by switching just one amino acid in the HSP70i sequence, they could prevent the protein from unleashing an autoimmune reaction. The mutated HSP70i does not activate dendritic cells and the T cells stay away, allowing the skin to retain its pigmentation.

Reprogramming melanocytes to make the mutated protein involves genetic engineering. Researchers put a copy of the protein’s altered gene sequence into a plasmid, a small, hoop-shaped DNA molecule, and, using a DNA-delivery applicator, inject the protein-coding plasmid into skin cells. From inside the cell, the modified gene overrides its normal counterpart and starts making the mutant protein.

In 2013, Le Poole’s team reported striking results from this gene-based technique in a mouse model of vitiligo. The loss of pigmentation gave the mice salt-and-pepper grey fur1. After the treatment, some of the black pigmentation returned. “By making that one small change in the protein, we were able to reverse the depigmentation process,” Le Poole says, adding that she was “shocked and awed by the result”.

Then, in 2018, her team reported follow-up results in pigs bred for melanoma research2. This type of pig has a strong immune response to its cancer. And as the pigs’ T cells attack tumours, they also kill melanocytes, causing vitiligo lesions. But after the gene-based treatment, the lesions shrank steadily for six months, even in areas where the therapy hadn’t been applied. Le Poole suspects that dendritic cells draining into lymph nodes near application sites instruct T cells throughout the body to avoid melanocytes wherever they’re located.

Sparking excitement

Prashiela Manga, a molecular biologist who specializes in vitiligo at New York University Langone Health in New York City, says Le Poole’s approach to treating vitiligo has sparked a lot of excitement in the field. “It suggests the potential for a systemic response, which is pretty amazing,” she says.

Conventional therapies for the condition — corticosteroids and exposure to ultraviolet B light — haven’t changed much for 30 years, and cost more than US$25,000 per patient. These treatments are also highly disruptive. ”You have to go to a dermatologist’s office three times a week to get the UVB treatment, which for many patients is impractical,” says John Harris, a dermatologist at the University of Massachusetts Medical School in Worcester who is advising Temprian as a consultant. Harris is leading a promising study of inhibitors of JAK enzymes for vitiligo; the research is now moving into phase III clinical trials. The inhibitors block cytokines that normally promote immune activity, and have the effect of “putting T cells to sleep”, Harris says. “But as soon as you stop treatment, the disease relapses,” he adds. People would have to take the drugs for years, which raises concerns about the consequences of broad-based, long-term immune suppression.

Harris notes that the gene-based approach isn’t as simple to administer as an oral medication or a topical cream. Le Poole treated pigs with a needle-free jet applicator that injects DNA in solution, and she plans to use the same device for people, in doses given during four weekly visits to a clinic. The approach can also be used for a selective “homeostatic reset” that diverts T cells from attacking melanocytes in the first place, Harris says. “So instead of apprehending criminals one at a time, you enhance the police force so the criminals don’t come out at all,” he says. Ideally, one course of gene-based treatment will induce long-term repigmentation of vitiligo lesions across the body.

“Of course, some individuals with vitiligo choose not to treat it, which is a very personal decision,” says Harris. “We as physicians and scientists are working hard to develop better options for those who seek them, while at the same time we celebrate with those who do not.”

Spun off from Northwestern University in 2018, Temprian opened its offices at a health-care start-up incubator in Chicago. The company completed a pre-investigational new drug meeting with the US Food and Drug Administration in November 2019, and is now raising seed money to start phase I human safety studies with an anticipated budget of $3 million. In May, the company received notice of approval of a US patent covering key aspects of its therapeutic approach. “We’re seeing a lot of activity in this space,” says chief executive Kettil Cedercreutz. “We’re looking to take this forward as a front-line therapy for vitiligo, and then move into other conditions building on what we know about the biology.”

The market for a vitiligo treatment is uncertain. Vitiligo tends to be a low-priority condition for global health, Manga says, despite its potential psychological impact. Children with the condition are often bullied, and adults with vitiligo can be stigmatized and discriminated against. It can cause low self-esteem, self-consciousness and depression. The Temprian therapy could provide relief for some people with this condition.