Study to Evaluate Gene-Edited Cell Therapy for MPSII


The LV-HSCGT therapy has demonstrated efficacy in preclinical studies in mouse models.

A phase 1/2 study will evaluate a gene-edited cell therapy (LV-HSCGT) for the potential treatment of neuronopathic mucopolysaccharidosis type 2 (nMPSII, Hunter syndrome).

The study design was presented at the 18th Annual WORLDSymposium, February 7-11, 2022, by Claire Horgan, MD, Royal Manchester Children’s Hospital. Horgan and colleagues have developed a novel lentiviral-mediated hematopoietic cell therapy (LV-HSCGT) to address unmet needs in MPSII.

“Enzyme replacement therapy is the only clinically approved treatment option for MPSII and its efficacy is limited both by its inability to cross the blood-brain barrier (BBB) and the formation of neutralizingallo-antibodies. Allogeneic stem cell transplantation modifies the disease phenotype, but its utility is limited by treatment-related morbidity and mortality, including graft versus host disease, and by the requirement for matched donors, and early diagnosis since transplant better prevents progression of disease than it does reverse established disease manifestations,” Horgan and colleagues wrote.

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The phase 1/2 study will evaluate cryopreserved autologous CD34+ hematopoietic stem cells, transduced ex vivo with CD11b lentiviral vector, in order to produce functional human iduronate-2-sulphatase (IDS)ApoEIIlacking in MPSII. The study will enroll pediatric patients aged 3 to 24 months with nMPS2 and preserved neurodevelopmental status (DQ ≥70).

Hematopoietic stem cells will be mobilized, collected, and transduced with the lentiviral vector. Patients will be infused with the cell therapy after myeloablative busulfan conditioning. The study will primarily evaluate the safety, tolerability and biological efficacy of the therapy,including engraftment and toxicities.It will also evaluate efficacy via IDS enzyme activity, vector copy numbers, and heparan sulfate reductions.

LV-HSCGT has shown efficacy in mouse models in preclinical studies. Investigators found that the therapy corrected the native IDS enzyme and achieved partial neurological correction. It yielded supraphysiological levels of IDS in transduced HSCs with similar vector copy numbers in vitro

“The LV-HSCGT approach can bypass the BBB, providing life-long enzyme delivery to treated patients. Here we present proof of principle data for MPSII LV-HSCGT and proposed clinical trial design. The trial is in set-up and has not yet received regulatory approval,” Horgan and colleagues wrote.

Horgan C, Jones S, Holley R, et al. Ex-vivo autologous stem cell gene therapy for MPSII (Hunter syndrome). Presented at: 18th Annual WORLDSymposium, February 7-11, 2022. Poster 125.
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