Mouse models of sickle cell disease: Imperfect and yet very informative

Abstract

The root cause of sickle cell disease (SCD) has been known for nearly a century, however, few therapies to treat the disease are available. Over several decades of work, with advances in gene editing technology and after several iterations of mice with differing genotype/phenotype relationships, researchers have developed humanized SCD mouse models. However, while a large body of preclinical studies has led to huge gains in basic science knowledge about SCD in mice, this knowledge has not led to the development of effective therapies to treat SCD-related complications in humans, thus leading to frustration with the paucity of translational progress in the SCD field. The use of mouse models to study human diseases is based on the genetic and phenotypic similarities between mouse and humans (face validity). The Berkeley and Townes SCD mice express only human globin chains and no mouse hemoglobin. With this genetic composition, these models present many phenotypic similarities, but also significant discrepancies that should be considered when interpreting preclinical studies results. Reviewing genetic and phenotypic similarities and discrepancies and examining studies that have translated to humans and those that have not, offer a better perspective of construct, face, and predictive validities of humanized SCD mouse models.

Keywords: Anemia; Genotype; Mouse model; Phenotype; Sickle cell; Validity.

Figure 1.

Phenotypic similarities and discrepancies between humans with sickle cell disease (SCD) and humanized SCD mouse models. CNS represents central nervous system, MCV mean corpuscular volume, MCH mean corpuscular hemoglobin, and MCHC mean corpuscular hemoglobin concentration. Created with Biorender.com

Figure 2.

Representative transmission electron microscopy images of blood from sickle Townes mice (HbSS, A and B) and control mice (HbAA, C and D). The arrows indicate retained mitochondria in red blood cells.

Figure 3.

From bench to bedside and back, reverse translation of clinical studies to preclinical humanized mouse models of sickle cell disease. PK represents pyruvate kinase. Created with Biorender.com