Dr. Traci Mondoro

Working Together as
a Community

The Cure Sickle Cell Initiative includes people from various scientific disciplines—basic and clinical researchers, statisticians, data scientists, geneticists, clinical trialists, and others who are actively involved in various sub-committees and working groups. An important element of the Initiative is working together as a community to accelerate research by avoiding duplication of efforts, leveraging evolving knowledge, and integrating best practices from government, academia, and industry.

Current efforts focus on six key priorities: creating biological and clinical endpoints, developing data resources, enhancing existing bio resources, engaging patients through outreach, designing a regulatory interface, and enabling and accelerating clinical trials.

Gene therapy could be life-changing for patients with sickle cell disease and give them a whole new way of living and way to think about life.

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NHLBI AND GENE THERAPY RESEARCH

PROJECTS FUNDED BY THE
INITIATIVE UNDER OTA-19-005

This project uses genome editing technology (CRISPR/Cas9) to develop a treatment that corrects the change, or mutation, in the hemoglobin gene (β-globin; HBB), that is responsible for the sickling of red blood cells. The goals of this project include optimizing and validating new tests that increase the safety of genome editing for patients.

This project is using genome editing technology (CRISPR/Cas9) to increase the production of fetal hemoglobin (HbF) in the red blood cells of individuals with sickle cell disease. Shortly after birth (around 3-6 months), babies usually stop producing HbF, and switch over to the adult form of hemoglobin. This treatment approach would provide protection against sickling by preventing this switch. The goal of this project is to complete the IND-enabling studies for approval to conduct the first-in-human clinical trials with this genome edited cell therapy product in patients with sickle cell disease.

As part of the effort to improve resources for scientific researchers developing therapies for sickle cell disease, this project aims to collect plexiform-mobilized peripheral blood stem cells from volunteers with sickle cell disease. These cells will be delivered to the NHLBI BioLINCC Data and Biospecimen Repository Program that will store these biological samples, and make them available upon request, to qualified researchers.

This project uses genome editing technology (CRISPR/Cas9) to develop a treatment that corrects the change, or mutation, in the hemoglobin gene (β-globin; HBB), using a non-infectious viral particle as a vehicle to deliver the therapy to the correct stem cells. The goal of this project is to produce a key tool to be used in IND-enabling studies for approval to conduct the first-in-human clinical trials with this genome edited cell therapy product in patients with sickle cell disease.

Currently, curative treatments for sickle cell disease involve undergoing a stem cell transplant. For a patient to receive a transplant, their bone marrow needs to be “conditioned” to remove the diseased cells, and accept new, healthy cells. Current conditioning regimens use harsh chemotherapy agents that have several severe side effects. The goal of this project is to develop a new conditioning regimen that reduces the toxicities of chemotherapy conditioning using an antibody (a type of protein) that recognizes a molecule on the surface of stem cells and leads to their elimination, creating space for new cells to be received.

This project uses genome editing technology (CRISPR/Cas9) to develop a treatment that corrects the change, or mutation, in the hemoglobin gene (β-globin; HBB), by delivering the treatment using a method called electroporation. Electroporation uses high-voltage electric pulses to introduce DNA into cells outside of the body. These corrected cells are then reintroduced into the patient’s bone marrow. The goal of this project is to complete the IND-enabling studies for approval to conduct the first-in-human clinical trials with this genome edited cell therapy product in patients with sickle cell disease.

PROJECTS FUNDED BY THE
INITIATIVE UNDER OTA-19-007

This project is developing new tests, or assays, to characterize the severity of sickle cell disease in patients. This panel of assays detects biological molecules, or biomarkers, that will be evaluated to determine if they can indicate how well a patient is responding to a potential curative genetic-based therapy for sickle cell disease. The biomarkers being detected in this assay – circulating endothelial cells and microvesicles (microscopic cellular particles which are naturally released from cells) – are correlated to increased inflammation, which is a common symptom of sickle cell disease.

This project is validating and standardizing new tests, or assays, to characterize changes in red blood cells (RBCs). This panel of assays detects biological molecules, or biomarkers, that will be evaluated to determine if they can indicate how well a patient responds to a potential curative genetic-based therapy for sickle cell disease. The biomarkers being detected in this assay are direct indicators of physical changes in RBCs including: (1) RBC adhesion, (2) RBC deformability, (3) RBC density and hemoglobin composition, and (4) blood quality (rheology) using Microfluidic BioChip Assays developed by the investigative team. These biomarkers would be measured as a patient undergoes a potential curative treatment for sickle cell disease. The goal of the project is to determine if the tests correlate with clinical improvement, allowing for easier monitoring of patient health after undergoing curative therapies for SCD.

This project is validating and standardizing new tests, or assays, to characterize the blood quality, or rheology, of patients with sickle cell disease. This panel of assays detects, changes in the properties of red blood cells to ultimately determine how well a patient responds to a potential curative genetic-based therapy for sickle cell disease. It is not known what level of sickle hemoglobin (HbS) correction or fetal hemoglobin (HbF) expression is needed to achieve a cure through a genetic-based therapy. This project aims to validate rheological characteristics in patients with sickle cell disease in order to tell the difference between normal (HbAA), trait (HbAS), and sickle (HbSS). The goal of the project is to determine if these tests correlate with clinical improvement, allowing for easier monitoring of patient health after undergoing curative therapies for SCD.