Precision Approach for Sickle Cell Disease Could Offer a Perfect Donor Match

By Lauren Ingeno

Children’s Hospital of Philadelphia researchers are developing a precision medicine approach to better match patients with sickle cell disease with compatible blood donors. The research, funded by the National Heart, Lung, and Blood Institute, aims to improve blood transfusion outcomes.

“We want to develop an algorithm and low-cost precision medicine test for blood typing, so that any hospital or clinic throughout the country could take the sequencing results of the donor and patient and easily interpret them to find the best match,” said Stella Chou, MD, principal investigator of the study and Chief of the Division of Transfusion Medicine at CHOP. 

Sickle cell disease is a group of inherited blood disorders that affect about 100,000 people in the United States, more than 90% of whom are African American. Patients with these disorders have a gene mutation that causes hemoglobin molecules to stick together, hardening red blood cells into C-shaped “sickles,” which can clog blood vessels and lead to intense pain and other complications, including stroke.

A primary method for managing many complications of sickle cell disease is blood transfusions, in which a patient receives healthy red blood cells from a donor. However, 30% of patients with sickle cell disease who receive a transfusion will eventually have an immune response to the therapy, called red blood cell alloimmunization. That happens when, despite careful donor matching, patients develop antibodies against the donated blood because the body recognizes it as foreign.

This can lead to delays in care, increased healthcare costs, and makes transfusion therapy unsafe and impossible in some cases, according to Dr. Chou.

“It can cause you to break down the transfused red cells, which can worsen your clinical scenario, and then transfusion may no longer be an option,” she said.

The two best-known blood groups are ABO and Rh. Within each group, cells carry surface markers, or antigens, which tell your body whether a foreign substance “belongs” or is an invader. For example, patients with an AB blood type carry both the A and B antigen. If your blood type is “positive”, such as O+, then your blood cells have the RhD antigen; if you’re negative, then your blood cells lack the RhD antigen. A patient’s blood type is compatible with a donor’s if their immune system does not recognize any of the antigens in donated blood as foreign.

Studies performed by Dr. Chou and colleagues have shown that patients with sickle cell disease and African Americans — who are a critical donor population — have significant genetic variation in their Rh blood system. This genetic variance is difficult to identify during the typical donor screening process and can be a major risk factor for alloimmunization. 

To overcome this genetic variability, Dr. Chou and a research team are developing a precision medicine approach that aims to link patients with sickle cell disease with their “perfect match.”

In a pilot study led by Dr. Chou, researchers demonstrated the feasibility of identifying and transfusing more than 300 RH genotype-matched donor units to chronically transfused patients with sickle cell disease.

Now, the research team is developing a low-cost, higher-throughput method to test donors for RH variants, which Dr. Chou said she hopes would facilitate the widespread implementation of RH genotype matching.

First, the researchers will transfuse RH genotype-matched red cells to chronically transfused patients with sickle cell disease to determine whether the approach lessens the occurrence of alloimmunization. In addition, the researchers plan to genetically engineer induced pluripotent stem cells to generate “designer” red cells that express variant Rh proteins for precise antibody identification. Finally, the team will apply new, next-generation sequencing approaches and data analysis pipelines to identify a low-cost method to accurately identify the complex RH genotypes in African American donors and patients.   

“We think this can be feasible and will ultimately improve transfusion outcomes for patients with sickle cell disease,” Dr. Chou said.