U01HL167036

"Real Answers" (Registry Expansion Analyses to Learn) - Sickle Cell Disease (SCD) is an inherited disorder of human adult hemoglobin, which primarily afflicts Americans of African descent. The mutant hemoglobin, HB S, polymerizes upon deoxygenation, leading to impaired red blood cell rheology, microvascular occlusion, chronic inflammatory state, and chronic hemolytic anemia, culminating in chronic organ damage and a shortened life expectancy.

SCD is an orphan disease, with an estimated ~110,000 patients in the U.S. who suffer from disparities and discrimination and increased health care utilization. Until recently, the management of the disease has been largely confined to symptom control, with pain management and transfusions. In 1998, the U.S. FDA approved hydroxyurea (HU) as the first disease modifying therapy for SCD. Subsequent studies in children and adults with SCD has confirmed the beneficial effects of HU, with prevention of organ damage and decrease in mortality.

In the past five years, three additional disease modifying drugs (L-glutamine, voxelotor, and crizanlizumab) targeting different mechanisms in disease pathophysiology have been approved by the FDA, broadening the available therapeutic armamentarium for SCD. Although this is a welcomed development, knowledge gaps exist on the choice of the most effective disease modifying therapy or combinations, based on a spectrum of sub-phenotypes of the disease.

This gap is unlikely to be filled by knowledge gained from randomized clinical trials involving the use of FDA approved therapies. This application seeks to meet this unmet need by taking advantage of the infrastructure (prospective registry of 2400 SCD patients) provided by the NHLBI funded Sickle Cell Disease Implementation Consortium (2016-2022) consisting of eight centers throughout U.S.

We propose to approach this problem by enrolling 1200 patients (150 patients from each center) by applying the following specific aims:

1) Compare the effect of novel disease modifying therapies (L-glutamine, voxelotor, and crizanlizumab) on clinical outcomes in individuals with SCD. We will follow these individuals prospectively for 5 years, emulating data collection protocols and eligibility from key, interventional phase III SCD trials, and monitor organ injury NT-proBNP for heart and lung injury, urine albumin/creatinine ratio for kidney function, hemolysis score for blood, as well as symptom burden (ASCQ-ME).

2) Identify genetic and genomic predictors of response to disease modifying therapies, by a) whole exome sequencing and b) RNA seq (mononuclear cells, retics, platelets); and

3) Integrate study data into the CureSCi metadata catalog to enhance future cross study analyses.

Icahn School Of Medicine At Mount Sinai

THE DIVISION OF BLOOD DISEASES AND RESOURCES SUPPORTS RESEARCH AND RESEARCH TRAINING ON THE PATHOPHYSIOLOGY, DIAGNOSIS, TREATMENT, AND PREVENTION OF NON-MALIGNANT BLOOD DISEASES, INCLUDING ANEMIAS, SICKLE CELL DISEASE, THALASSEMIA, LEUKOCYTE BIOLOGY, PRE-MALIGNANT PROCESSES SUCH AS MYELODYSPLASIA AND MYELOPROLIFERATIVE DISORDERS, HEMOPHILIA AND OTHER ABNORMALITIES OF HEMOSTASIS AND THROMBOSIS, AND IMMUNE DYSFUNCTION. FUNDING ENCOMPASSES A BROAD SPECTRUM OF HEMATOLOGIC INQUIRY, RANGING FROM STEM CELL BIOLOGY TO MEDICAL MANAGEMENT OF BLOOD DISEASES AND TO ASSURING THE ADEQUACY AND SAFETY OF THE NATION'S BLOOD SUPPLY. PROGRAMS ALSO SUPPORT THE DEVELOPMENT OF NOVEL CELL-BASED THERAPIES TO BRING THE EXPERTISE OF TRANSFUSION MEDICINE AND STEM CELL TECHNOLOGY TO THE REPAIR AND REGENERATION OF HUMAN TISSUES AND ORGANS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

New York, New York 100296504 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 187% from $2,567,678 to $7,362,213.