Genetic studies lead to alopecia areata breakthrough

Trolling nearly 1 million polymorphic SNP markers in an alopecia areata genome-wide association study (GWAS) revealed genes shared with three other autoimmune diseases — type 1 diabetes, rheumatoid arthritis, and celiac disease. This discovery holds the promise that emerging therapies for those other diseases will prove effective in treating alopecia areata.

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Angela M. Christiano, PhD: ‘Our studies demonstrate proof-of-concept that these drugs may also have efficacy in alopecia areata.’

Angela M. Christiano, PhD: ‘Our studies demonstrate proof-of-concept that these drugs may also have efficacy in alopecia areata.’

Angela M. Christiano, PhD: ‘Our studies demonstrate proof-of-concept that these drugs may also have efficacy in alopecia areata.’

Prominent alopecia areata investigator Angela M. Christiano, PhD, presented the results of this research during her presentation, “Basepairs to Bedside: Genetics and Immunology in Alopecia Areata,” at the Plenary session Friday. She collaborated with Columbia University immunologist Raphael Clynes, MD, PhD, in this research endeavor. Dr. Christiano is the Richard & Mildred Rhodebeck Professor in the departments of dermatology and genetics & development; vice chair and director of basic science research, department of dermatology; and director, Center for Human Genetics, Columbia University, New York.

“By our GWAS findings aligning with these other diseases, we were able to piggyback on the many studies that had already been done,” she said. “That enabled us to think of ways to interfere with the autoimmune process involved in alopecia areata.”

The process she referred to was the faulty upregulation of an immune signal that mistakes the hair follicle for an infected or dying cell, and therefore launches the release of cytotoxic T cells that attack the end organ. A key source for fueling those particular killer T cells in an autoimmune response is IL-15, and therefore, therapies could be aimed at blocking the IL-15 signal that sustains those killer T cells. Two FDA-approved small molecule drugs that interfere downstream in these signaling pathways include ruxolitimib, a JAK1/2 inhibitor, approved to treat the blood disorder myelofibrosis, and tofacitinib, a JAK3 inhibitor approved for the treatment of rheumatoid arthritis.

Drs. Christiano and Clynes conducted studies of ruxolitinib and tofacitinib in a mouse model of alopecia areata, even though neither of those drugs was developed for autoimmune disease of the skin. The research team studied the response of the C3H/HeJ mouse, a well-defined model for alopecia areata, by grafting affected tissue from the CeH/HeJ donor mouse and grafting it onto a group of recipient mice. Investigators then administered both drugs as a prevention strategy to one group of C3H/HeJ mice, and as a topical treatment of established disease in another group of C3H/HeJ mice that had lost their hair from the alopecia areata-grafted tissue. The preventively treated mice never lost their hair, and the topically treated mice with established disease experienced a regrowth of hair.

“We were very excited to find that both drugs restore hair growth in mice with established disease,” Dr. Christiano said. “Several drug companies are developing JAK inhibitors for a wide range of other disease indications. Our studies demonstrate proof-of-concept that these drugs may also have efficacy in alopecia areata.”

The investigators came to this point in their research after recent extensive GWAS research and earlier work with candidate-gene approach studies. Dr. Christiano began her research 15 years ago as part of the National Alopecia Areata Registry that collected DNA samples from among the 10,000 alopecia areata participants in the registry. With the earlier candidate gene approach, investigators sought genes from other related autoimmune diseases to determine whether those were relevant to alopecia areata. This approach proved to be mostly confirmatory of established genes in other autoimmune disorders.

However, the more advanced and unbiased GWAS investigation led to a promising discovery. In this study, the whole genome was blanketed with polymorphic SNP markers that cover all chromosomes and did not pre-select them on the basis of their roles in other diseases.

“We were essentially letting the genome tell us where the genes lie, rather than us trying to guess where the genes are,” Dr. Christiano said. “When we do that across a large enough number of markers, we cover the genome very densely with markers, allowing the truly significant ones to rise above the noise.”

The investigators compared a group of more than 1,000 alopecia areata patient samples with a group of more than 3,000 control individuals. Any commonalities shared equally between the two groups were discarded. It was the genes whose SNPs were differentially over-represented in alopecia areata versus controls that captured the investigators’ attention. Investigators discovered eight susceptibility genes that appeared to contribute to alopecia areata. Seven genes were unexpected and new, and one was a confirmatory HLA gene cluster. Through the GWAS studies, a trend clearly emerged, revealing significant overlap of susceptibility genes with the three other autoimmune diseases — type 1 diabetes, rheumatoid arthritis, and celiac disease.

“We are excited by this work because our first GWAS study using only 1,000 samples uncovered our first key eight genes. Based on comparisons with other complex genetic disease research, this is a very high yield for such a small number of starting samples. Yet despite the small sample, we have already hit upon three existing FDA-approved drugs that could potentially be used to treat alopecia areata,” Dr. Christiano said. “We have been guided by our genetic findings in a relatively short amount of time to lead us to selecting drugs that were not developed for alopecia, but are nevertheless showing impressive results in our pre-clinical studies.”

For Dr. Christiano, herself a patient with alopecia areata, these findings represent the first milestone of human genetics and personalized medicine in transforming the future of patient care in this disease.

 

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