Engineering memory T cells as a platform for long-term enzyme replacement therapy in lysosomal storage disorders

Area of Science:

• Biochemistry
• Genetics
• Immunology

Background:

• Mucopolysaccharidosis type I (MPS I) is a rare genetic disorder caused by alpha-L-iduronidase (IDUA) deficiency.
• Accumulation of glycosaminoglycans (GAGs) leads to severe skeletal and central nervous system (CNS) damage.
• Current treatments for MPS I offer insufficient relief.

Purpose of the Study:

• To evaluate engineered human memory T (Tm) cells expressing IDUA as a cellular therapy for MPS I.
• To assess the biodistribution, enzyme activity, and therapeutic efficacy of these engineered Tm cells in a mouse model.

Main Methods:

• Genetically engineered Tm cells to express functional IDUA.
• Administered a single dose of engineered Tm cells to immunodeficient MPS I mice.
• Monitored IDUA levels, GAG excretion, tissue distribution, and metabolic correction.

Main Results:

• Detectable IDUA enzyme levels in blood for up to 22 weeks post-treatment.
• Significant reduction in urinary GAG excretion.
• Engineered Tm cells distributed to multiple tissues, including the CNS, correcting GAG levels and demonstrating metabolic correction.

Conclusions:

• Engineered Tm cells represent a promising platform for cellular-based enzyme replacement therapy for MPS I.
• This approach holds potential for treating other enzymopathies and protein deficiencies.
• Further research may explore cognitive improvements and long-term efficacy.