Research Profile: Christiane J. Ferran, MD, PhD
Christiane J. Ferran, MD, PhD
Lewis Thomas Professor of Surgery, Harvard Medical School
Cleide Angolano, PhD
Mauricio Contreras, MD
John Gigioli, MD
Anant Shah, PhD
Maryam Shamloo, PhD
Jacqueline Wade, MD
My laboratory focuses on:
- Defining the molecular signature of what “return to homeostasis” entails in the face of injury, whether inflammatory, immune, infectious, metabolic, or mechanical, i.e. the “molecular basis of health”
- Identifying the culprits that hinder “return to homeostasis” and thus result in pathology
- Validating signature molecules in animal models of human disease for clinical translation as diagnostic, prognostic, and most importantly, therapeutic tools
This line of research was triggered by our seminal discovery that up-regulation of the ubiquitin-modulatory protein A20, AKA, TNFAIP3 or the anti-apoptotic Bcl members, A1, Bcl-2 and Bcl-xL in endothelial cells in response to inflammatory stimuli, serves a general “protective” function by shutting down inflammation through inhibition of the transcription factor NF-κB (JBC 1996;271:18068). Subsequent studies confirmed A20 as one of humans’ most potent and ubiquitous physiologic anti-inflammatory molecules. A20 not only goes to the NF-κB heart of inflammation, but also beyond to control Interferonγ and α/β signaling, and modulate cell survival and proliferation, with return to homeostasis as the ultimate goal. We established the therapeutic benefits of A20-based therapies in a number of disease models that share inflammation as a central pathogenic component, focusing on the three fields below.
Our data qualifies A20 as a potent “atheroprotective” and “modulator of angiogenesis” molecule, as evidenced in animal models of:
- Neointimal hyperplasia post-balloon angioplasty
- Transplant arteriosclerosis, the pathognomonic feature of chronic allograft rejection
- Accelerated atherosclerosis of diabetes
- Vein graft and prosthetic arterial graft failure
- Proliferative retinopathies, and blinding eye diseases
Liver Regeneration and Repair
We have extensively documented a potent “hepatoprotective” role for A20 in the liver, stemming from combined anti-inflammatory, anti-apoptotic, and pro-proliferative functions of A20 in hepatocytes. Accordingly, A20-based therapies protect mice from lethality in models of acute toxic hepatitis, lethal radical hepatectomy where 90% of the liver is resected, prolonged warm liver ischemia, and orthotopic liver transplantation using marginal grafts.
We uncovered an unsuspected phenotype in A20 heterozygous mice, whereby a benign 2/3 hepatectomy caused a staggering 50% lethality. These data imply that single nucleotide polymorphisms that negatively impact A20 expression and/or function could inform the risk of extensive liver resections for donation or tumor.
We lately discovered that A20 regulates lipid metabolism in a way that improves fatty liver disease in a mouse model of human non-alcoholic fatty liver disease.
Current pre-translational studies in pigs using clinically safe gene therapy platforms to induce A20 expression in the liver are promising and prelude clinical implementation in transplantation and xenotransplantation.
Treatment of diabetes
Islet transplantation: A20 retained its anti-apoptotic and anti-inflammatory functions in β-cells, thus was an ideal candidate to genetically engineer islet grafts for the treatment of diabetes.
Insulin alternatives: We discovered a novel anti-diabetic function of A20, whereby a single injection of a hepatotropic A20 gene therapy vector restored glycemic control in a mouse model of type I diabetes. Remarkably, this effect was long-lasting and insulin independent. We are exploring clinical translation of this finding into a first-in-class anti-diabetic modality.
- Elected member and Subcommittee on Climate Change member: HMS Faculty Council
- Member: Committee for Senior Appointment, BIDMC
- Member: Promotion and Reappointment Committee, Department of Surgery, BIDMC
- Member: Search Committee for Director of the Cancer Center, BIDMC, HMS
- Member: Search Committee for Director of the Cell and Gene Therapy Center, BWH, HMS
- Member: Executive Committee, Center for Vascular Biology Research, BIDMC
Scientific Review Boards
- Reviewer: NIH SBIR/STTR CVRS (10) Small Business: Cardiovascular Sciences Activities SEP study section
- Reviewer: NIH Surgery Anesthesia Traumatology study section
- Reviewer: NIH T32 Training Grants study section
Invited Presentations and Visiting Professorships
- A20 Gene Therapy for Diabetes and its Vascular Complications 1.0 to 2.0: A Tale of Discovery and Translation. Lecture, annual retreat, Center for Vascular Biology Research, BIDMC, and the BWH Vascular Biology Center, HMS; Boston, MA
- A20: A Homeo-Dynamic Regulator of Allografts Fate. Lecture, eGenesis Bio; Cambridge, MA
- A20: A Tale of a Versatile Allograft Shield. Visiting Professor, MGH Transplantation grand rounds
- Christiane Ferran, MD, PhD, received one of five (5/87) inaugural Blavatnik Therapeutics Challenge Awards from HMS, which are aimed at accelerating clinical translation of promising scientific projects.
- Cleide Angolano, PhD, was the recipient of a multi-PI Trailblazer Award from the NIH.
Novel Therapies to Achieve Glycemic Control. International publication of docket number: WIPO PCT WO2018/035121 A1. Inventors: Christiane Ferran MD, PhD, Cleide da Silva/Angolano, PhD, Alessandra Mele, MD
Teaching, Training, and Education
For the past 22 years I have been training postdoctoral research fellows, surgical residents, undergraduate, graduate, and medical students, and research associates who rotate in my laboratory. I also mentor junior faculty in the Department of Surgery and the CVBR. Reflecting my commitment to teaching/mentoring, I serve on three NIH-funded T32, one K12, and one T35 training grants as:
- Co-Principal Investigator, Longwood-Harvard T32 in Vascular Surgery (Multi-PI: Frank LoGerfo, MD, Leena Pradhan-Nabzdyk, PhD, MBA, BIDMC)
- Faculty mentor, renal T32 (Director: Martin Pollak, MD, BIDMC)
- Faculty mentor, transplantation biology T32 (Director: Joren Madsen, MD, MGH)
- Faculty mentor, vascular surgery T35 (Directors: Frank LoGerfo, MD, Leena Pradhan-Nabzdyk, PhD, MBA, BIDMC)
- Faculty, translational glycobiology K12 program (Director: Robert Sackstein, MD, BWH)
Selected Research Support
- Novel Therapies to Achieve Glycemic Control. Juvenile Diabetes Research Foundation, 2016-2020; PI: Christiane Ferran, MD, PhD (Co-I: Cleide Angolano, PhD)
- Bioengineering of Vein Graft to Resist Intimal Hyperplasia. NIH, 2018-2021; PI: Christiane Ferran, MD, PhD (Co-I: Mauricio Contreras, MD)
- Mechanisms of Prosthetic Arterial Graft Failure. NIH, 1987-2022; Multi-PIs: Christiane Ferran, MD, PhD; Frank LoGerfo, MD, David Mooney, PhD
- Genetic Engineering of Vein Bypass Grafts in Vascular and Cardiovascular Surgery. NIH, 2007-2023; Multi-PIs: Christiane Ferran, MD, PhD, Frank LoGerfo, MD, Manoj Bhasin, PhD
- Novel Insulin-Independent Therapy to Treat Type I Diabetes. Blavatnik Foundation/Harvard Medical School BTCA, 2021-2023. PI: Christiane Ferran, MD, PhD
- Understanding the Relationships Between FUS-BBB Opening, Neuroinflammation and the Neurovascular Response. NIH, 2020-2023; Multi-PIs: Cleide Angolano, PhD; Nicholas Todd, PhD
Todd N, Angolano C, Ferran C, Devor A, Borsook D, N McDannold. Secondary effects on brain physiology caused by focused ultrasound-mediated disruption of the blood-brain barrier. J Control Release 2020;324:450-459.
Kipper FC, Angolano C, Vissapragada R, Contreras MA, Moore J, Bhasin M, Ferran C,* Thomas AJ.* Embryonic periventricular endothelial cells demonstrate a unique pro-neurodevelopment and anti-inflammatory gene signature. Scientific Reports 2020;10:20393. *co-last authors
Haque O*, Cloonan D*, McIntosh E, Ferran C. Xenotransplantation 1.0 to 2.0. In: Hakim N, Haberal M, Maluf D, editors. Transplantation surgery, 2nd ed. Springer; 2020. Chapter 18, p. 279-304. *equal contributors
Angolano C, Kaczmarek E, Essayagh S, Daniel S, Choi L, Tung B, Sauvage G, Lee A, Arvelo MB, Moll HP, Ferran C. A20/TNFAIP3 increases eNOS expression in a KLF2 dependent manner to support endothelial cell health in the face of inflammation. Front Cardiovasc Med 2021; revision submitted.
Breitenecker C, Lang V, Mohrherr J, Horrvath J, Moritsch S, Eferl R, Stoiber D, Moriggl R, Bilban M, Ferran C, Dome B, Laszlo V, Györffy B, Deszo K, Moldvay J, Casanova E, Moll HP. Downregulation of A20 promotes immune escape of lung adenocarcinomas. Sci Transl Med 2021; revision submitted.