ABOUT THE GRANT

Infantile Krabbe disease (KD) is rapidly progressive and fatal if untreated. The current treatment is hematopoietic stem cell
transplant (HSCT), which involves ablating diseased immune cells and replacing them with healthy donor cells. When
administered to patients in the first few months of age before symptom onset, HSCT improves neurologic symptoms and extends
survival; however, many patients continue to experience severe neurologic deficits and eventually succumb to disease. As such,
there is a great need for more effective therapies.

A prevailing hypothesis is that HSCT works by cross-correction, whereby donor immune cells infiltrate the brain and transfer
missing enzyme to diseased host cells. To what extent it mediates the therapeutic effects of HSCT remains unclear and
whether boosting it improves immunotherapies is underexplored. Here, we propose pairing cell engineering with new immune
cell transplant tools to address these knowledge gaps. Insights from this proposal will directly inform several ongoing and future
therapeutic efforts that leverage cross-correction and lead to more effective immunotherapies for patients with KD and possibly
other lysosomal storage disorders.

Sai Chaluvadi is an MD/PhD candidate at the University of Pennsylvania in the Neuroscience Graduate Group. Sai is conducting his thesis work in Dr. Frederick “Chris” Bennett’s lab, studying cross-correction – a process by which healthy donor cells transfer functional enzymes to deficient host cells. This process is thought to underlie the therapeutic effects of bone marrow transplant in Krabbe patients, whereby healthy donor cells infiltrate the central nervous system and transfer galactosylceramidase to deficient host cells, fixing the diseased host cells and delaying disease progression.

Yet, the extent to which cross-correction naturally occurs and whether this process can be synthetically boosted remains unclear. Through support from the Rosenau Family Research Foundation, Sai aims to 1) uncover the extent to which cross-correction underlies the therapeutic effects of bone marrow transplant in models of Krabbe disease and 2) use advanced cellular engineering strategies to boost cross-correction for improvement of existing cell therapies. This project will advance therapy development for Krabbe disease by elucidating how existing therapies work and by enhancing them. through synthetic biology.