Brain‐targeted stem cell gene therapy corrects mucopolysaccharidosis type II via multiple mechanisms

Abstract

The pediatric lysosomal storage disorder mucopolysaccharidosis type II is caused by mutations in IDS, resulting in accumulation of heparan and dermatan sulfate, causing severe neurodegeneration, skeletal disease, and cardiorespiratory disease. Most patients manifest with cognitive symptoms, which cannot be treated with enzyme replacement therapy, as native IDS does not cross the blood–brain barrier. We tested a brain‐targeted hematopoietic stem cell gene therapy approach using lentiviral IDS fused to ApoEII (IDS.ApoEII) compared to a lentivirus expressing normal IDS or a normal bone marrow transplant. In mucopolysaccharidosis II mice, all treatments corrected peripheral disease, but only IDS.ApoEII mediated complete normalization of brain pathology and behavior, providing significantly enhanced correction compared to 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 additionally 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. Brain‐targeted hematopoietic stem cell gene therapy provides a promising therapy for MPS II patients.

The role of innate immunity in mucopolysaccharide diseases

“…A similar HS sulphation pattern was observed in a mouse model of MPSII (Gleitz et al . ). These HS disaccharides may contribute to the initiation of various signalling pathways in MPS; especially if these highly sulphated disaccharides have the potential to act as endogenous DAMPs (Archer et al .…”

Mucopolysaccharidosis Type II: One Hundred Years of Research, Diagnosis, and Treatment

“…They have reported a disorganized neuronal pattern in the brain, an increase in glial apoptotic cells preceding neuronal death together with a reduced number of PDGFR-α-positive glial progenitors [208], and an acute inflammatory state in 8-day-old mice, and progressive astrogliosis and microgliosis (up to 8 months) [209]. Additionally, 8-month-old mice showed extensive neuroinflammation, demonstrated by elevated cytokines levels [223]. An on-tissue high spatial resolution MALDI IMS analysis, followed by GM3-immunohistochemistry, was able to detect GM2 and GM3 ganglioside accumulation throughout 16 brain regions, with a distribution similar to GAG Alcian blue staining [224].…”

“…Among these are different dosages and routes of administration of ERT [103,125,222,229,[231][232][233][234][235], microcapsules enclosing myoblasts over-expressing IDS [183], different gene-therapy approaches [164][165][166]171,172,223,236], genistein [188], brain-penetrating IgG-Iduronate 2-sulphatase fusion protein [134], HSCT [234,237,238], ZFN-mediated in vivo genome editing [239], engineered nanoparticles for IDS enzyme brain-targeting [184,185], anti-human transferrin receptor antibody fusion protein [135], and chloroquine [230]. They were also useful for testing new methods of GAG analysis, aimed at improving their use as biomarkers in pre-clinical studies and successively in patients [125,223,240,241]. In particular, the RP-HPLC method [242] was applied to analyse the total relative amount of HS and its disaccharide composition [223], while another HPLC-based approach, founded on an analysis of the 2-sulfoiduronic acid derived from the non-reducing end of GAGs, allowed clear discrimination between Ids-ko and wild-type mice in the liver and brain [240].…”

“…They were also useful for testing new methods of GAG analysis, aimed at improving their use as biomarkers in pre-clinical studies and successively in patients [125,223,240,241]. In particular, the RP-HPLC method [242] was applied to analyse the total relative amount of HS and its disaccharide composition [223], while another HPLC-based approach, founded on an analysis of the 2-sulfoiduronic acid derived from the non-reducing end of GAGs, allowed clear discrimination between Ids-ko and wild-type mice in the liver and brain [240]. Recently, two different studies reported the use of mass spectrometry for GAG analysis in MPS II mice.…”

GM2 Gangliosidoses: Clinical Features, Pathophysiological Aspects, and Current Therapies

“…Allogenic HSC transplantation (HSCT) can be performed from bone marrow (BM), umbilical cordon (UC), or peripheral blood after a myeloablative regimen [ 108 ]. This strategy has been successfully performed in other LSDs such as MPS I [ 109 , 110 ], MPS II [ 111 ], and Gaucher type 1 and 2 [ 112 ].…”