ISAC Award Program Application Concept

Evaluation of RBC mtDNA as a biomarker in Sickle Cell Disease
Angela Rivers   (San Francisco, CA)
Individuals with Sickle Cell Disease (SCD) often begin showing symptoms in the first year of life and suffer from painful swelling of the hands and experience sudden attacks of severe pain. SCD is caused by a mutation of the ß-globin gene resulting in the polymerization of sickle hemoglobin (HbS) when deoxygenated. In adulthood, patients continue to have chronic hemolytic anemia, painful crises, multisystem organ damage and a shorter lifespan. Two major sources of complications are the sickling of the red blood cell (RBC) and oxidative stress. 100,000 Americans have SCD, and the incidence is more frequent among those whose ancestors originated from sub-Saharan Africa and Spanish speaking countries in the Western hemisphere, occurring in 1 out of every 365 African American births and 1 out of every 16,300 Hispanic American births. Currently, hemorheological biomarkers serve as an important metric for analyzing the overall quality of the treatment; however, they have limitation in their availability and association with disease severity. The purpose of this proposal is to develop mitochondrial DNA (mtDNA) as an additional biomarker for SCD. Our lab made the innovative discovery that RBCs in SCD abnormally retain mitochondria. Mitochondria are normally eliminated from RBCs in a process called mitophagy. In addition, we demonstrated that retained mitochondria is an important contributor to oxidative stress. The abnormal retention of mitochondria in the sickle RBC has been confirmed by other groups. In addition, recent publications suggest that the unusual exposure of the endosomal Toll-like receptor TLR9, which recognizes mtDNA, on the surface of the RBC and the presence of cell-free mtDNA in circulation, a potentially proinflammatory damage-associated-molecular-pattern (DAMP) signal. Unfortunately, the literature can be confusing and misleading since it is often inferred that the qPCR quantification of mtDNA obtained from multiple methods and multiple sample types diagnosed the retention of mitochondria in the sickle RBC. Genomic DNA, which is not found in RBCs, and cell-free DNA are often used as a reference standard in those measurements. We propose to clarify and improve these procedures so that they can be used in diagnostic testing. Figure 1 demonstrates the possible locations of mtDNA in a patient with SCD. Each of these scenarios could be a cause of different groups of pathological problems; therefore, when considering mtDNA as parameters for SCD complications these different patterns must be evaluated. This work has been innovative since our original publication in 2018. There are now 4 additional publications indicating erythrocyte mitochondria in SCD and one publication about erythrocyte mitochondrial retention in systemic lupus erythematosus (SLE). As we continue to expand the therapeutic and curative treatment options for SCD, reproducible assays that have a strong association with SCD-related clinical complications should also be incorporated into clinical trials to ensure a complete picture of the effects of the novel therapies. We hope that mtDNA will revolutionize SCD similar to HbA1c. It will be a diagnostic test that can potentially evaluate disease severity and alloimmunization.
Data for this report has not yet been released.

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