Degrading CARD14 to Treat Psoriasis
Principal Investigator: Anne Bowcock, Ph.D.
Institution: Icahn School of Medicine at Mount Sinai
Grant Mechanism: Translational Research Grant
Funding Amount: $200,000
Project Start Date: August 1, 2024
Project End Date: July 31, 2026
Status: Active
Keywords: Psoriasis, Animal Models, Drug Therapy, Cell Signaling
Project Summary:
Although biologics have been spectacularly successful they need to be injected and may have long-term effects. We propose a novel approach to psoriasis. We will focus on a protein we identified a few years ago (CARD14) that is central to early alterations arising in psoriatic skin. We will target activated CARD14 for degradation via a novel technology (Bridged-PROTAC). We have identified 29 degraders and will identify additional compounds. We will evaluate their sensitivity and specificity in cell-based systems and animals. We will ultimately evaluate these compounds in animal models of psoriasis, with the long-term goal of taking this to the clinic. This approach could also be applicable to other alterations that arise in psoriasis.
How will your project help improve the lives of the 125 million affected by psoriatic disease?
We are researching a novel way of treating psoriasis, and possibly psoriatic arthritis. Although biologics targeting immune components circulating in the blood have had remarkable success, we wish to target the altered molecular pathway leading to psoriasis in keratinocytes. We will develop small molecules that disrupt the pathway, thereby leading the cell to revert to a non-psoriatic state. Specifically, we will target activated CARD14, encoded by a gene that we have shown is critical to the development of psoriasis in patients with rare variants in this gene, and which also plays a critical role in the psoriasiform response in “classic” psoriasis. These small molecule CARD14 degraders will have high sensitivity and specificity for the pathway activated in psoriatic disease. We will ultimately take these CARD14 degraders to the clinic, for treatment of psoriasis and possibly psoriatic arthritis. This will be a novel paradigm for psoriasis treatment.
Why is psoriatic disease research important to you, personally? What role will this award play in your research efforts or career development?
I have worked on trying to understand and ultimately treat psoriatic disease for over 30 years. I am committed to this research and have made significant findings in both understanding molecular alterations leading to psoriasis, and in the identification of gene (CARD14) which is mutated in rare forms of inherited psoriasis, and which also plays a role in classic psoriasis. This award will allow me to continue with my research efforts to understand and treat psoriatic disease.
Researcher Profile:
Anne Bowcock, Ph.D., is Professor of Dermatology, Oncological Sciences and Genetics & Genomics, at Icahn School of Medicine at Mount Sinai, and the Norman Orentreich M.D., Professor of Dermatological Research. She has held academic positions at Imperial College, London (UK), Washington University in St. Louis, and UT Southwestern Medical Center at Dallas. She has researched the genetic basis of psoriasis for over 30 years. She obtained her Ph.D. from the University of Witwatersrand, Johannesburg, South Africa, and was a postdoctoral fellow, in the Department of Genetics at Stanford University. She will be joined by Jian Jin, Ph.D., Professor in the Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, the Mount Sinai Endowed Professor in Therapeutics Discovery, and Director of the Mount Sinai Center for Therapeutics Discovery at ISMMS. Dr. Jin is an internationally recognized medicinal chemist and chemical biologist with over years of experience in small-molecule drug discovery.