Engineering Memory T Cells as a platform for Long-Term Enzyme Replacement Therapy in Lysosomal Storage Disorders

Area of Science:

• Biomedical Science
• Genetics
• Immunology

Background:

• Mucopolysaccharidosis type I (MPS I) is a rare genetic disorder caused by alpha-L-iduronidase (IDUA) deficiency, leading to toxic glycosaminoglycan (GAG) accumulation.
• Current treatments for MPS I offer limited efficacy, particularly for skeletal and central nervous system (CNS) manifestations.

Approach:

• Genetically engineered human memory T cells (Tm) to express IDUA.
• Administered engineered Tm as a cellular therapy in an immunodeficient mouse model of MPS I.

Key Points:

• A single dose of engineered Tm resulted in detectable IDUA enzyme levels in circulation for up to 22 weeks.
• Reduced urinary GAG excretion and GAG levels in multiple tissues, including the heart, lung, liver, spleen, kidney, bone marrow, and CNS.
• Engineered Tm successfully engrafted in various tissues, providing sustained IDUA production and metabolic correction.

Conclusions:

• Genetically engineered Tm represent a viable platform for cellular-based enzyme replacement therapy for MPS I.
• This approach shows potential for treating other enzymopathies and protein deficiencies.