Engineered Memory T cells as a Platform to Treat Enzymopathies

ABSTRACT We aim to significantly improve outcomes for patients suffering from diseases resulting from missing or defective enzymes, called enzymopathies, by developing a superior and novel cell-based therapeutic approach. Our proof-of-concept studies have focused first on Mucopolysaccharidosis type I (MPS I), an autosomal recessive lysosomal disease caused by deficiency of alpha-L-iduronidase (IDUA) enzyme, resulting in accumulation of glycosaminoglycans (GAGs). Affected individuals suffer from multi-systemic disease, including hepatosplenomegaly, corneal clouding, skeletal dysplasias, cardiopulmonary obstruction. In the severe form of MPS I called Hurler syndrome, there is progressive neurologic impairment and pre-adolescent death. Current treatments for MPS I include hematopoietic stem cell transplant (HSCT) and/or enzyme replacement therapy (ERT). Even in the best case, these treatments fail to stop the development of significant disease burden, resulting in a low quality of life. Further, these treatments are incredibly costly, and HSCT itself is associated with many serious risks, including death. Using a mouse model of MPS I, we have produced provocative preliminary data demonstrating that levels of enzymatically active IDUA can be significantly increased and disseminated widely throughout the body, through administration of primary human memory T cells engineered to overexpress IDUA. As memory T cells can be long lived and distribute widely throughout tissues, including the central nervous system (CNS), and because their manufacture and clinically safety is well established, they are an attractive candidate for a cell-based therapeutic approach to enzyme replacement. Here, we propose to build on our preliminary data by first optimizing manufacturing methods by utilizing an efficient and cost-effective non-viral transposon system called TcBuster (TcB), of which our team has extensive experience, including GMP manufacture for clinical use. Next, we will use the NSG-MPS I mouse model to further evaluate the safety and efficacy of this cell-based treatment approach, by testing neurocognitive behaviors in treated versus untreated MPS I mice, and performing a rigorous safety evaluation, including histopathological analysis. Thus, the studies proposed in this STTR application are to continue development of a novel cell-based therapy for MPS I that we hypothesize will provide increased safety and efficacy compared to current HSCT and ERT therapies, yielding increased and more sustained enzyme levels, and increased distribution to the CNS. Though we are focusing first on the treatment of MPS I, this approach is amenable for development as a platform therapy, capable of being tailored for the treatment of a variety of diseases.