Genetic testing for nephrotic syndrome and FSGS
Our researchers, together with collaborators, have identified multiple genetic mutations associated with segmental glomerulosclerosis (FSGS), a devastating form of nephrotic syndrome that is the second leading cause of kidney failure in children. Based on this research, we now offer a diagnostic test panel for nephrotic syndrome and FSGS that covers more than two dozen genes.
Our team is also using the genetic information to develop better treatments for FSGS and nephrotic syndrome. For example, a study in the lab of our division chief Friedhelm Hildebrandt, MD, identified genetic mutations that involve Coenzyme Q-10. A clinical trial led by Ankana Daga, MBBS, will give Coenzyme Q-10 to children with nephrotic syndrome to see if it improves their disease course.
Understanding kidney self-repair
End-stage kidney disease often begins with injury to podocytes, highly specialized cells that intermingle with the capillaries and filter the blood, maintaining the proper water and salt balance. The lab of Jordan Kreidberg, MD, PhD, has been trying to understand how kidneys and podocytes naturally maintain themselves. The team recently identified a master genetic program and a key regulator called WT-1 that appears to orchestrate podocytes’ innate injury-repair response. Kreidberg and his colleagues continue to study WT1 and other genetic factors in podocyte injury to better understand the repair process and identify potential treatments for FSGS and kidney failure due to diabetes or hypertension.
Improving outcomes following kidney transplantation
Dr. David Briscoe and faculty within the Transplant Research Program are conducting a variety of studies to improve the longevity of transplanted organs and better identify patients at risk for complications. The Briscoe Lab studies the processes of inflammation resolution and the discovery of receptor ligand interactions that both promote and inhibit alloimmunity and the rejection process. Research studies are in three broad areas including:
- How events within the intragraft microenvironment promote, sustain or inhibit T cell activation and allorecognition
- How discrete signals and molecular interactions in select populations of T cells promote immunoregulation
- The application of these discoveries into the development of biomarkers and new therapeutics to transform clinical care and improve outcomes following transplantation
Dr. Soumitro Pal and members of his laboratory study molecular mechanisms of cancer growth in patients following organ transplantation using in vitro cell culture models as well as a sophisticated murine model. Dr. Pal's research also aims to identify molecular targets and novel therapeutics for the treatments of renal inflammation and renal cancer.
Dr. Johannes Wedel uses bioinformatic tools and sophisticated immunological techniques to study the identification of novel cell types and signaling pathways that regulate T cell-dependent immune responses following transplantation.
Kidney stone genetics and prevention
Recent research by Friedhelm Hildebrandt, MD, found that a surprising 21 percent of children with kidney stones have a causative single-gene mutation. Knowing the mutation can often change therapy. For example, certain stone-causing mutations have been associated with other treatable medical complications that clinicians can screen for, such as eye problems or hearing loss.
Michelle Baum, MD, co-director of the Kidney Stone Program, hopes that care for kidney stone disease will one day be focused on preventing stone formation, rather dealing with its consequences. She is helping to launch clinical trials of new medications to treat primary hyperoxaluria (PH), one of the rarest, most devastating causes of kidney stones as well as other organ complications. For many years, PH could only be treated by kidney-liver transplant. Dr. Baum is a primary investigator in a multicenter clinical study that aims to correct the genetic error in metabolism that causes PH using RNA inhibitor therapy.
Using applied genomics to treat nephrotic syndrome
In partnership with patients, physicians, and researchers around the globe, the Sampson Lab, headed by Principal Investigator Matt Sampson, MD, MS, seeks to improve the health of children with the protein-spilling kidney disease nephrotic syndrome using the tools of modern genomics. We integrate sequencing technologies, computer science, biostatistics, epidemiology, and functional experiments to bring an “applied genomics” approach to nephrotic syndrome research. Our goal is to translate these genomic discoveries to genomic medicine; bringing a Precision Medicine approach to inform us on the causes, prognoses, and treatments for patients with nephrotic syndrome.
Our research seeks to:
- Discover and/or characterize new and established nephrotic syndrome-associated genetic variants
- Illuminate the mechanisms linking these genetic changes with nephrotic syndrome, towards development of targeted treatments and cures
- Uncover the clinical consequences for patients carrying disease-associated genetic variants
- Identify strategies to improve genomic literacy about kidney diseases for nephrologists and patients and their families
Gene regulation and kidney disease
Dongwon Lee, PhD’s laboratory aims to understand how gene regulation contributes to the development and progression of human diseases, specifically focusing on kidney diseases. We use a combination of single-cell multiomics data, genetic data from disease cohorts, functional assays, and machine-learning approaches to address these complex problems. In addition, we work closely with clinicians and experimental biologists to validate and verify our models and predictions. We are dedicated to developing new genomic computational tools and making them accessible to the research community.
Specific goals:
- Building gene regulatory networks in a cell-type-specific manner to understand the molecular basis of kidney diseases
- Developing machine-learning models to identify regulatory variants and estimate their impact on human traits and diseases
- Validating predictions using high-throughput sequencing technologies in collaboration with experimental biologists
Genetic basis of pediatric kidney disease
Amar Majmundar, MD, PhD, is currently an attending pediatric nephrologist at Boston Children's Hospital and an Assistant Professor of Pediatrics at Harvard Medical School. Dr. Majmundar's research explores the genetic basis of pediatric kidney diseases, with a focus on Mendelian genetic forms of nephrotic syndrome and kidney stone disease.
Active projects in his laboratory include:
- Discovering novel Mendelian genetic causes of pediatric kidney stone diseases using human genomics
- Investigating biological mechanisms by human variants in actin regulatory gene NOS1AP cause a pediatric glomerulopathy using cellular and mouse models
- dissecting the biological mechanisms by which de novo variants in TRIM8 cause a syndrome of epilepsy and nephrotic syndrome in humans using cellular and mouse models.
To learn more, please visit the Majmundar Lab website.
Clinical relevance of ABCB5
Markus Frank, MD's laboratory defined a novel function for ABCB5 in cancer stem cell maintenance and tumor growth, and investigates the therapeutic efficacy of ABCB5 targeting in melanoma and additional ABCB5-expressing human malignancies.
Research in the Markus Frank Lab focuses on the physiological and pathological roles of the P-glycoprotein family of ATP-binding cassette (ABC) multidrug resistance transporters. His laboratory cloned and characterized the third member of this human gene family, ABCB5, which marks progenitor subpopulations in human skin and cancer stem cells in human malignant melanoma.
The group showed that ABCB5 functions as a drug-resistance mediator in human melanoma. They also demonstrated that specific targeting of ABCB5 can sensitize melanoma cells to chemotherapy. In subsequent work, they discovered that ABCB5 expression identifies malignant melanoma-initiating cells (MMICs) that correlate with tumorigenic growth in vivo, and that ABCB5 is more abundant in human malignant melanoma than in benign melanocytic nevi in human patients.
The Frank Laboratory demonstrated that ABCB5-positive MMICs can be specifically targeted to inhibit tumor growth, providing proof-of-principle for the potential therapeutic utility of the cancer stem cell concept.
Further, they provided evidence for immunomodulatory functions of human cancer stem cells. Although MMICs with a key role in tumor formation and growth can be immunologically targeted to inhibit tumor development, they also express biomolecules that are immunoprotective. Thus, MMICs serve specific roles in evasion of antitumor immunity and melanoma immunotherapeutic resistance.
In tandem with fundamental approaches to further dissect the functional roles of ABCB5 in physiological and cancer stem cells, Dr. Frank's laboratory explores the clinical relevance of ABCB5 as a biomarker of melanoma progression, prognosis, and outcome, and investigates the therapeutic efficacy of ABCB5 targeting in human malignant melanoma.