Engineering cell-based micropharmacies for in vivo protein replacement therapy

Abstract

The treatment of many chronic and genetic disorders depends on the consistent delivery of therapeutic proteins to correct underlying deficiencies or modulate disease progression. However, conventional methods, such as enzyme replacement therapy (ERT) and cancer immunotherapies, often require frequent infusions, suffer from limited tissue distribution, or pose a significant burden to patients and caretakers. To overcome these limitations, cell-based micropharmacies have emerged as a promising platform for continuous therapeutic protein expression and targeted delivery in vivo. Utilizing the innate properties of specific cell subsets, such as T cells, B cells, and hematopoietic stem cells, these engineered cells can stably produce and secrete therapeutic proteins. This thesis explores the development of T cell-based micropharmacies for enzyme replacement in Mucopolysaccharidosis type I (MPS I), a lysosomal storage disorder resulting from a deficiency in alpha-L-iduronidase (IDUA). Current treatments, including ERT and hematopoietic stem cell transplantation (HSCT) have improved patient outcomes but they leave significant gaps in addressing manifestations and early mortality. To address these challenges, we engineered primary human T cells to stably express and secrete IDUA. Preclinical studies in an MPS I mouse model demonstrated that engineered T cells are able to secrete functional IDUA and significantly reduce glycosaminoglycan (GAG) accumulation. Furthermore, patient-derived MPS I T cells were engineered to express IDUA, validating the feasibility of autologous cell therapy for personalized treatment. These findings establish T cell-based micropharmacies as a viable platform for long-term, systemic enzyme delivery, addressing critical limitations of current therapies and setting the stage for broader applications across lysosomal storage disorders (LSDs) and other enzyme-deficiency diseases.