New research is hoping to provide a cure to Hunter Syndrome where many other therapies have failed
Mucopolysaccharidosis type II (MPSII) is an X-linked, paediatric lysosomal storage disease caused by mutations in the IDS gene, leading to deficiency of iduronate-2-sulfatase (IDS).
Deficiency of IDS leads to a build-up of heparan sulfate and dermatan sulfate throughout the body and occurs at an incidence of 1.3 per 100,000 live births. MPSII is classified as either attenuated or severe. Both classifications include skeletal abnormalities, stiff joints, short stature, hepatosplenomegaly and cardiorespiratory problems; additionally, patients with severe MPSII (two thirds of patients, Hunter Syndrome) display progressive neurodegeneration.
Hunter patients manifest with cognitive symptoms, which cannot be treated with enzyme replacement therapy, as native IDS does not cross the blood–brain barrier.
Other lysosomal disease gene therapies (MPSIIIA, B and C) are in clinical development with partners using a similar approach (all licenced from The University of Manchester) and are expected to reach significant peak sale values (£100m, £50m and £20m respectively).
In a recent proof-of-concept study the team compared a brain‐targeted hematopoietic stem cell gene therapy approach using lentiviral IDS fused to ApoEII to cross the blood-brain-barrier (IDS.ApoEII LV), compared to a lentivirus expressing normal IDS or a normal bone marrow transplant.
In MPSII mice, all treatments corrected peripheral disease, but only IDS.ApoEII mediated normalisation of brain pathology and behaviour, providing significantly enhanced correction compared to unmodified IDS. A normal bone marrow transplant achieved no brain correction.
Whilst corrected macrophages traffic to the brain, secreting IDS/IDS.ApoEII enzyme for cross‐correction, IDS.ApoEII was more active in plasma and was taken up and transcytosed across brain endothelia significantly better than IDS via both heparan sulfate/ApoE‐dependent receptors and mannose‐6‐phosphate receptors.
The team are currently in the process of fundraising to take this technology into a clinical proof of concept study.