The technology, developed in Professor Brian Bigger’s laboratory and recently published in the journal Brain, involves the use of a high-titre lentiviral vector to drive the expression of a codon-optimised α-N-acetylglucosaminidase (NAGLU) gene under the control of the myeloid-specific CD11b promoter (LV.CD11b.NAGLU).
MPS-IIIB is a rare neurodegenerative inherited lysosomal storage disease caused by mutations in the NAGLU gene.
The disease, which affects children as early as 2 years of age, results in severe and rapidly progressive brain disease and neurological symptoms. There is currently no effective treatment option for MPS-IIIB.
This programme in MPS-IIIB complements the existing collaboration programme between Orchard, The University of Manchester and Manchester University NHS Foundation Trust in MPS-IIIA.
Autologous ex-vivo lentiviral haematopoietic stem cell gene therapy is anticipated to correct neurological manifestations through the engraftment of subpopulations of haematopoietic stem cells in the central nervous system, thereby providing supranormal and widespread enzyme expression throughout the brain.
In both MPS-IIIA and MPS-IIIB, preclinical studies have produced encouraging results showing a normalisation of heparan sulphate levels in the brain and peripheral organs, as well as neurological disease correction.
Dr Jesus Garcia-Segovia, Orchard’s VP Clinical Development, CNS and Metabolic Disorders, said: “The incorporation of MPS-IIIB into our development pipeline is a significant milestone in the consolidation of our neurometabolic franchise, which is currently focused on the development of autologous ex-vivo haematopoietic stem-cell gene therapy for children suffering from MPS-IIIA.”
“We are very excited at the possibility of bringing effective treatments capable of addressing the high unmet medical need in children suffering from these devastating conditions.”
Professor Brian Bigger, Professor of Cell and Gene Therapy in the Faculty of Biology, Medicine and Health, The University of Manchester, said: “It is incredibly exciting for us to work with our trusted partner Orchard Therapeutics to translate another autologous ex-vivo gene therapy that has demonstrated efficacy in a preclinical mouse model of MPS-IIIB into clinical development and scale-up.”
Dr Andrea Spezzi, Orchard’s Chief Medical Officer, said: “MPS-IIIA and MPS-IIIB are devastating diseases. Orchard and its collaborators are highly motivated to develop gene therapies to address the root cause of these disorders and will work tirelessly to make treatments available to patients as soon as possible. We are now focussing all our efforts on completing the preclinical activities required to enable the start of clinical studies in MPS-IIIA towards the end of 2018 and thereafter in MPS-IIIB.”
Orchard’s development pipeline of autologous ex-vivo gene therapies includes novel treatments for primary immune deficiencies and inherited metabolic disorders including other undisclosed early and late-stage programmes.
