Hunter Syndrome Gene Therapy Clinical Trial Cleared to Begin in the UK


In a mouse model of MPS II, IDS.ApoEII effected completely normalized brain pathology and behavior.

A clinical trial application for AVROBIO’s AVR-RD-05, an investigational autologous hematopoietic stem cell (HSC) gene therapy intended for the treatment of neuronopathic mucopolysaccharidosis type II (nMPS-II; Hunter syndrome) being developed in a collaboration with University of Manchester (UoM), has been approved by the UK Medicines and Healthcare Products Regulatory Agency (MHRA), Research Ethics Committee (REC), and Health Research Authority (HRA).1

AVR-RD-05 is intended to transduce HSC’s ex-vivo lentiviral vector that encodes brain-targeted iduronate-2-sulfatase (IDS) enzyme, the disease-targeted protein. A preclinical study provided proof of concept of a brain-targeting approach using lentiviral IDS fused to ApoEII (IDS.ApoEII).2 In a mouse model of MPS II, IDS.ApoEII effected completely normalized brain pathology and behavior, while a normal bone marrow transplant provided no brain correction, and a lentivirus expressing normal IDS, which cannot cross the blood-brain barrier, provided incomplete brain correction.

"We are thrilled to collaborate with the team at UoM to bring to infants and families living with Hunter syndrome a potential one-time therapy for this devastating disease,” Geoff MacKay, president and chief executive officer, AVROBIO, said in a statement.1 “Hunter syndrome causes complications throughout the body, including severe neurological, cardiac and respiratory dysfunction, skeletal malformations and hearing impairment. This investigational HSC gene therapy which includes CNS-targeted gene expression has been designed to express supra-physiological levels of the IDS enzyme in transduced HSCs, with the intent to correct both the systemic and neurological manifestations of this disease."

An open-label, nonrandomized phase 1/2 clinical trial is planned to begin treating patients in the first half of 2023. The study will enroll up to 5 male children between the ages of 3 months and 12 months (inclusive) who have been diagnosed with nMPS-II. It will evaluate safety, efficacy, and pharmacodynamics.

“It's incredibly exciting to have the opportunity to test our investigational brain-targeted HSC gene therapy in boys with Hunter disease," Brian Bigger, PhD, professor of Cell and Gene Therapy at The University of Manchester, who will help oversee the study, added to the statement.1 "There are currently no available treatments that target the brain in this devastating disorder, so the approach of tagging the IDS enzyme with a blood-brain-barrier crossing peptide will enable us to see if this approach can improve outcomes for patients."

AVR-RD-05 previously received rare pediatric disease designation from the FDA in November 2021 and orphan drug designation from the FDA in July 2022.3,4 Several other companies are also currently pursuing new treatments for MPS subtypes. REGENXBIO’s RGX-121, an investigational gene therapy for MPS II, recently demonstrated promising safety and efficacy in interim data from an ongoing phase 1/2/3 clinical trial. Meanwhile in July 2022, Lysogene announced that LYS-SAF302, an investigational gene therapy intended for the treatment of mucopolysaccharidosis type IIIA (MPS IIIA), had generated promising preliminary data in a phase 2/3 clinical trial.

1. AVROBIO announces neuronopathic mucopolysaccharidosis type II (nmps-ii) or hunter syndrome clinical trial application (CTA) accepted by U.K. Regulatory agency to initiate pediatric phase 1/2 gene therapy trial. News release. AVROBIO, Inc. September 14, 2022. 
2. Gleitz HF, Liao AY, Cook JR, et al. Brain‐targeted stem cell gene therapy corrects mucopolysaccharidosis type II via multiple mechanisms. EMBO Mol Med. 2018;10(7).
3. AVROBIO receives rare pediatric disease designation from the U.S. FDA for AVR-RD-05, a gene therapy for mucopolysaccharidosis type II (MPSII) or hunter syndrome. News release. AVROBIO, Inc. November 3, 2021. 
4. AVROBIO receives orphan drug designation from the U.S. Food and drug administration for AVR-RD-05, a gene therapy for mucopolysaccharidosis type II (MPSII) or hunter syndrome. News release. AVROBIO, Inc. July 13, 2022. 
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