The Han Lab is located within the Gene and Cell Therapy program at the Herman B Wells Center for Pediatric Research.
Development of gene editing therapies for DMD and cardiovascular diseases
In the last several years, the Han Lab has made seminal contributions to the development of gene editing therapies for genetic diseases. Han's laboratory pioneered the CRISPR-genome editing therapeutic strategy for treating Duchenne muscular dystrophy (DMD) and demonstrated that this strategy functionally restored dystrophin expression in live mdx mice, a widely used mouse model of DMD (Xu et al., Mol Ther, 2015; Xu et al., Nucleic Acids Res, 2016; El Refaey et al., Circ Res, 2017; Xu et al., Mol Ther, 2019). More recently, his group rationally designed an improved base editor for adeno-associated virus (AAV)-mediated in vivo delivery, and demonstrated that AAV9-delivered base editing rescued dystrophin in over 95% cardiomyocytes in adult dystrophic mice (Xu et al., Nat Commun, 2021). The Han Lab is now developing spatially and temporally controllable system for safer therapeutic gene editing in vivo to treat Duchenne muscular dystrophy, Atherosclerotic cardiovascular disease and others.
Dissect the molecular pathogenesis of LGMDs
Defects in a number of genes such as ANO5, POPDC1, 2 and 3 can cause various forms of limb girdle muscular dystrophy (LGMD) with or without cardiac involvement. To understand the molecular functions of these genes and their products in striated muscles, the Han lab has generated animal models with the loss of function mutations in these genes and employed AAV gene transfer approaches. The molecular pathogenesis mechanisms are now being investigated in the lab.
Disease modeling and therapeutic development using genome edited rabbits and hiPSC-derived cardiac organoids
It is frequently observed that the mouse models do not faithfully recapitulate the human diseases. For example, the mdx mice (which is widely used as a model for DMD) does not develop cardiomyopathy and live to near normal lifespan, in contrast to DMD patients. Similarly, disruption of Ano5 in mice as mentioned above does not produce overt muscular dystrophy as in patients with ANO5 mutations. Thus, there is a need to develop alternative animal models for better modelling human diseases so that the findings in these animals can have higher translational potential. The Han Lab has generated mutant rabbits to model DMD and Ano5-related muscular dystrophy. They have demonstrated that these animals faithfully recapitulate the corresponding human diseases. The lab is currently utilizing these novel rabbit models to test the therapeutic efficacy and testing of clinical-stage compound in alleviating DMD cardiomyopathy in collaboration with pharmaceutic companies such as Stealth BioTherapeutics.
Moreover, the gene editing therapeutic strategy is highly personalized precision medicine, requiring the safety and efficacy testing in human cells before proceeding to clinical trials. The Han Lab is currently employing the cardiac organoids to design and optimize base editing strategies for skipping different exons of human DMD gene to rescue the dystrophin expression and function.