The University of Manchester (UoM) has initiated recruitment activities for a phase 1/2 clinical trial (NCT05665166) evaluating 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).1
UoM was previously collaborating on the development of AVR-RD-05 with AVROBIO, but regained the license to the HSC gene therapy following the company’s cessation of development on all programs.1,2 The trial, which was cleared for initiation by the United Kingdom’s Medicines and Healthcare Products Regulatory Agency, Research Ethics Committee, and Health Research Authority over a year ago, in September 2022, will take place at Royal Manchester Children’s Hospital.1,3
The study will seek to enroll up to 5 male children between the ages of 3 months and 12 months (inclusive) who have been diagnosed with nMPS-II and who have not yet experienced developmental decline.3 The patients may be receiving enzyme replacement therapy (ERT), the standard of care treatment for nMPS-II, at the beginning of the trial. Although, UoM stated that a goal of the treatment will be to allow patients to cease use of ERT. The single-arm, open-label trial is expected to take place over the course of 24 months, with an estimated primary completion date in August 2026 and an estimated completion date in December 2026.
- The University of Manchester has initiated a phase 1/2 clinical trial for AVR-RD-05, an investigational gene therapy for neuronopathic mucopolysaccharidosis type II (Hunter syndrome).
- The trial aims to enroll up to 5 male children between 3 to 12 months of age with Hunter syndrome, some of whom may be receiving enzyme replacement therapy.
- The gene therapy approach involves the use of an autologous hematopoietic stem cell (HSC) gene therapy, designed to introduce the iduronate-2-sulfatase (IDS) enzyme into the brain more efficiently, potentially normalizing brain pathology.
“This is a next generation stem cell gene therapy approach, which allows transit of the iduronate-2-sulfatase (IDS) enzyme into the brain,” Brian Bigger, PhD, the professor of cell and gene therapy at UoM who worked on the development of the therapy, said in a statement.1 “The newly inserted IDS gene produces an IDS enzyme that contains a proprietary ApoEII-tagged sequence, which can bind to ApoE-dependent receptors on the blood brain barrier, and move enzyme into the brain more efficiently, thus potentially normalizing brain pathology. This should speed up delivery of enzyme to the brain, where it is most needed as we can leverage all the enzyme produced by the blood to do this rather than just relying on the engraftment of monocyte cells from the blood into the brain.”
A preclinical study provided proof of concept of a brain-targeting approach using lentiviral IDS fused to ApoEII (IDS.ApoEII).4 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.
AVROBIO’s strategic decision to end its development activities was announced in July 2023.1,2 The company cited a need to evaluate its strategic options for the future, which it noted may include seeking an acquisition, merger, business combination, or another type of transaction. The announcement came just a month after AVROBIO sold its cystinosis HSC gene therapy program to Novartis.4 In addition to AVR-RD-05, AVROBIO had also been developing HSC gene therapies for indications including Gaucher disease type 1 and type 3 and Pompe disease.
“This ground-breaking trial initiated by The University of Manchester offers the possibility of new treatment options in the future for patients with the severest form of nMPS-II,” Bob Stevens, chief executive of the MPS society, added to the statement.1 “We look forward to hearing the outcome of this trial, with cautious optimism and hope that science will offer the chance of a ‘Rare Life Lived Better’.”
1. Groundbreaking gene therapy trial for Hunter syndrome opens. News release. The University of Manchester. October 30, 2023. Accessed November 3, 2023. https://www.manchester.ac.uk/discover/news/groundbreaking-gene-therapy-trial-for-hunter-syndrome-opens/?utm_source=miragenews&utm_medium=miragenews&utm_campaign=news
2. AVROBIO to explore strategic alternatives. News release. AVROBIO, Inc. July 12, 2023. Accessed November 3, 2023. https://investors.avrobio.com/news-releases/news-release-details/avrobio-explore-strategic-alternatives
3. 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. Accessed November 3, 2023. https://investors.avrobio.com/news-releases/news-release-details/avrobio-announces-neuronopathic-mucopolysaccharidosis-type-ii
4. 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). Doi.org/10.15252/emmm.201708730
5. AVROBIO completes sale of cystinosis gene therapy program for $87.5 million. News release. AVROBIO, Inc. June 12, 2023.Accessed November 3, 2023. https://investors.avrobio.com/news-releases/news-release-details/avrobio-completes-sale-cystinosis-gene-therapy-program-875