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Sustained long-term disease correction in a murine model of MPSII following stem cell gene therapy
Stuart Ellison1, Aiyin Liao1, Hélène F E Gleitz1
1Stem Cell & Neurotherapies Group, University of Manchester, Manchester M13 9PT, UK.
Abstract:
Mucopolysaccharidosis type II (MPSII) is a pediatric lysosomal storage disease caused by deficiencies in the IDS (iduronate-2-sulfatase) gene resulting in accumulation of glycosaminoglycans, multisystem disease, and profound neurodegeneration in severe forms. Although enzyme replacement therapy is available for somatic forms of disease, the inability of native IDS to pass the blood-brain barrier renders it ineffective for the brain. We previously demonstrated the short-term efficacy of a brain-targeted hematopoietic stem cell gene therapy approach to treat MPSII mice using lentiviral IDS fused to the blood-brain-barrier-crossing peptide ApoEII (IDS.ApoEII) in comparison with a lentivirus expressing native IDS and an unmanipulated bone marrow transplant. Here we evaluated the longevity of disease correction for 12-16 months following treatment. We observed sustained IDS enzyme activity in organs of long-term IDS.ApoEII-treated MPSII mice, similar to those analyzed 6 months post-treatment, with continued clearance of storage material in the brain and peripheral organs, maintained correction of astrogliosis, microgliosis, and correction of altered cytokines and chemokines. IDS.ApoEII also significantly reduced retinal atrophy, characteristic of MPSII. Overall, IDS.ApoEII resulted in systemic prevention of the MPSII phenotype, with no observed toxicity following treatment. This provides evidence of the sustained efficacy and safety of this treatment ahead of a recently opened clinical trial.
Insights
Hematopoietic stem cell gene therapy using IDS.ApoEII provides sustained correction for Mucopolysaccharidosis type II (MPSII) in mice. This brain-targeted approach effectively clears storage material and prevents neurodegeneration, showing long-term safety and efficacy.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Mucopolysaccharidosis type II (MPSII) is a genetic lysosomal storage disease impacting multiple organs and causing neurodegeneration.
- Current enzyme replacement therapy cannot cross the blood-brain barrier, limiting its effectiveness for brain-related MPSII symptoms.
- Hematopoietic stem cell gene therapy offers a potential solution for delivering therapeutic enzymes to the brain.
Purpose of the Study:
- To evaluate the long-term efficacy and safety of a brain-targeted gene therapy for MPSII in a mouse model.
- To assess the sustained enzyme activity, storage material clearance, and neuropathology correction following treatment.
- To determine the potential of IDS.ApoEII gene therapy for systemic and central nervous system disease manifestations.
Main Methods:
- Treatment of MPSII mice with lentiviral IDS fused to the ApoEII peptide (IDS.ApoEII) via hematopoietic stem cell gene therapy.
- Comparison with lentivirus expressing native IDS and unmanipulated bone marrow transplant.
- Long-term evaluation (12-16 months) of enzyme activity, glycosaminoglycan storage, neuroinflammation markers (astrogliosis, microgliosis), cytokine/chemokine levels, and retinal health.
Main Results:
- Sustained IDS enzyme activity observed in organs of IDS.ApoEII-treated mice up to 16 months post-treatment.
- Continued clearance of storage material in both the brain and peripheral organs.
- Maintained correction of neuroinflammation, altered cytokines/chemokines, and significant reduction in retinal atrophy.
Conclusions:
- Brain-targeted hematopoietic stem cell gene therapy with IDS.ApoEII demonstrates sustained efficacy in preventing the systemic and neurological phenotype of MPSII in mice.
- The treatment shows long-term safety with no observed toxicity.
- These findings support the potential of IDS.ApoEII gene therapy for clinical application in MPSII patients, including those with severe neurological involvement.
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