# "REAL Answers" (Registry Expansion Analyses to Learn)

> **NIH NIH U01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $2,389,467

## Abstract

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.

## Key facts

- **NIH application ID:** 10908994
- **Project number:** 5U01HL167036-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Jeffrey Avins Glassberg
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $2,389,467
- **Award type:** 5
- **Project period:** 2023-08-20 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10908994

## Citation

> US National Institutes of Health, RePORTER application 10908994, "REAL Answers" (Registry Expansion Analyses to Learn) (5U01HL167036-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10908994. Licensed CC0.

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