The search for the next “isotretinoin”

When presenting the Marion B. Sulzberger, MD Memorial Award and Lectureship on Sunday, Diane Thiboutot, MD, recognized Dr. Sulzberger’s strong influence in allergy, immunology, and dermatology, including his personal connection to acne.

Diane Thiboutot, MD

“I didn’t know Marion Sulzberger, but I think I would have liked him,” Dr. Thiboutot said as she shared her work in search of the next isotretinoin to treat acne. “Dr. Sulzberger passed away in 1983 at the age of 90, just at the time the first clinical trials for isotretinoin were being conducted. Marion Sulzberger never had the chance to treat his acne patients with isotretinoin. I am sure that he, like me, would have wondered how it worked.”

Dr. Sulzberger served in World War I and II and began his medical studies in 1920 in Geneva, Switzerland. He continued his education at the University of Zurich. During World War II, he was decorated by both the United States and France for outstanding research and study of the treatment of dermatoses caused by poison gases, burns, and tropical skin diseases.

Professor and chairman at New York University-Bellevue Medical Center, and later professor of clinical dermatology at the University of California in San Francisco, Dr. Sulzberger was also adviser to the U.S. government, founder of the Society for Investigative Dermatology, and president of the American Dermatological Association.

Dr. Sulzburger learned about acne through his sister, who suffered from severe cystic acne. This first-hand experience inspired his well-known quote, “There is no single disease which causes more psychic trauma and more maladjustment between parents and children, more general insecurity and feelings of inferiority, and greater sums of psychic assessment than does acne vulgaris.’’

Understanding acne and its treatment

Although acne is the most common skin condition and the benefits of isotretinoin are clear, understanding the complexities of the pathogenesis of acne and the mechanisms by which isotretinoin interrupts this process continues.

Discovered by accident, isotretinoin is considered the cure for acne. It didn’t follow the traditional path of rational drug design — aiming at a known target, Dr. Thiboutot said. By understanding the mechanisms by which the drug dramatically reduces sebum production, reverses follicular hyperkeratinization, arrests inflammation, and improves acne, it’s possible to develop a safer alternative, she said. Isotretinoin’s primary side effect is tied to birth defects.

“We don’t know what isotretinoin is targeting. No animal gets acne lesions. The lipid composition of human sebum is unique, and Cutibacterium acnes (formerly P. acnes) can’t colonize animal skin,” she said. “Different components of the pathogenesis of acne can be modeled using rodents and human cell culture (like keratinocytes, sebocytes, and immune cells).”

Early laboratory studies to find a safer alternative have focused on identifying the factors that regulate lipid production in the sebaceous gland using a human sebocyte model. Researchers were able to identify activity of a variety of enzymes involved in the production of hormones and lipids within the sebaceous gland.

“The idea was that if we could identify inhibitors of these enzymes, we might be able to reduce sebum production to the same extent as isotretinoin. In other words, we were looking for a specific target — as is done in traditional drug discovery,” Dr. Thiboutot said.

New advances bring promise

Acne is a multifactorial disease, Dr. Thiboutot said. Unfortunately, until now, researchers lacked the tools and model systems to examine the disease using a multifactorial approach. Today, however, tremendous advances have been made with regard to the immunology of acne, differences in C. acnes strains, changes in microbiome in health and disease, as well as the metabolomics of the interaction between humans as hosts and the community of bacteria, fungi, and viruses living on our skin. Whole genome sequencing and metabolomics allow researchers to examine the genes and proteins expressed in skin and to understand the relationships between humans and the microbiome in health and disease.

“The field of informatics, computational biology, and artificial intelligence has exploded,” Dr. Thiboutot said. “Libraries of compounds have been developed whose effects on gene expression in various cell lines have been catalogued. Algorithms have been developed to find patterns in these large datasets to match a drug signature with a disease signature to accelerate drug discovery through drug repurposing or drug repositioning.”

In 2014, Dr. Thiboutot participated in a multidisciplinary discussion of the important areas of research in acne. Her research gathered patient samples to develop the acne disease signature and to identify the isotretinoin signature both on cultured cells and in patients using the latest technologies.

To date, Dr. Thiboutot’s research has sampled 18 subjects before and during isotretinoin therapy. Nine of these subjects returned six months after finishing treatment to provide additional samples. Whole genome sequencing was completed on the blood, the skin from the back, and the microbiome obtained from a cyanoacrylate sample of the follicles on the face. Researchers analyzed serum cytokines. Data analysis is still in progress. Dr. Thiboutot will publish her data and submit it to the Geo database.

Maximizing expertise

“In research using large datasets, it’s important for dermatologists to contribute their expertise to assure that the right types of data are being collected and that the data is collected in the right way to assure the validity of the findings,” Dr. Thiboutot said. “There is still a lot to learn about acne. Additional patient data with different genetic backgrounds and across the lifespan are needed to address our unanswered questions, including those Marion Sulzberger wondered about at age 80.”

These questions include why acne usually starts and stops at certain ages, how it cures itself, why some patients have excess sebum and little acne, and others are the reverse, why some blackheads and whiteheads initiate inflammation and suppuration and others don’t, and why cysts or scars form in some patients and not in others.

“Maybe by the time I’m 80, we’ll know! Let’s hope so,” Dr. Thiboutot said.