Normalization and Improvement of CNS Deficits in Mice With Hurler Syndrome After Long-term Peripheral Delivery of BBB-targeted Iduronidase

Abstract

Mucopolysaccharidosis type I (MPS I) is a progressive lysosomal storage disorder with systemic and central nervous system (CNS) involvement due to deficiency of α-L-iduronidase (IDUA). We previously identified a receptor-binding peptide from apolipoprotein E (e) that facilitated a widespread delivery of IDUAe fusion protein into CNS. In this study, we evaluated the long-term CNS biodistribution, dose-correlation, and therapeutic benefits of IDUAe after systemic, sustained delivery via hematopoietic stem cell (HSC)-mediated gene therapy with expression restricted to erythroid/megakaryocyte lineages. Compared to the highest dosage group treated by nontargeted control IDUAc (165 U/ml), physiological levels of IDUAe in the circulation (12 U/ml) led to better CNS benefits in MPS I mice as demonstrated in glycosaminoglycan accumulation, histopathology analysis, and neurological behavior. Long-term brain metabolic correction and normalization of exploratory behavior deficits in MPS I mice were observed by peripheral enzyme therapy with physiological levels of IDUAe derived from clinically attainable levels of HSC transduction efficiency (0.1). Importantly, these levels of IDUAe proved to be more beneficial on correction of cerebrum pathology and behavioral deficits in MPS I mice than wild-type HSCs fully engrafted in MPS I chimeras. These results provide compelling evidence for CNS efficacy of IDUAe and its prospective translation to clinical application.

Getting the Most: Enhancing Efficacy by Promoting Erythropoiesis and Thrombopoiesis after Gene Therapy in Mice with Hurler Syndrome

“…Brain GAG levels reduced significantly in GT-treated mice with over 3% efficiencies, and they did not normalize in the highest dose group (200% GT), which is consistent with previous observations in similar experimental settings. 29 Comparable levels of brain GAGs were detected between unstressed and stressed mice within all gene-dose groups (data not shown). Without stress bleeding, complete normalization of GAGs was observed in all peripheral organs tested at the highest dose group (MPS/GT 200%) and in MPS/WT treatment controls.…”

“… 14 Replacing strong viral enhancers and promoters with housekeeping gene promoters in SIN-RV or LV seems to reduce catastrophic genetic events. However, therapeutic efficacy in LSD treatment has been highly correlated with enzyme doses achieved in animal models 29 , 42 or clinical experience, including gene therapy clinical trials and HSC transplantation with the choice of donors (healthy versus carriers). 8 , 43 To compensate for utilizing relatively weak cellular promoters (such as the PGK promoter), above-normal enzyme levels needed for significant clinical efficacy would require multiple proviral insertions in each HSC that present a higher risk of oncogenesis in all offspring of transduced HSCs.…”

“…The results also defined the minimum effective dose (MED) for long-term phenotypic correction in peripheral organs, while the correlation of transgene doses with CNS phenotypic improvement has been reported previously in a similar setting. 29 This work provides a proof of concept that manipulating erythropoiesis and thrombopoiesis can further improve therapeutic benefits in HSC-mediated gene therapy of MPS I, a repeatable and reversible approach to enhance clinical efficacy of gene therapy.…”

Pre-clinical Mouse Models of Neurodegenerative Lysosomal Storage Diseases

“…Knockout MPS I mice (Idua -/-) exhibit cognitive and motor defects with storage of GAGs in Purkinje cells (Baldo et al, 2012). Systemic delivery of apoE-fused IDUA protein produced from erythroid/megakaryocytic cells via LVmediated HSCGT successfully corrected metabolic and behavioral deficits in MPS I mice (El-Amouri et al, 2014). Furthermore, efforts to directly edit the genome and correct mutations are currently underway.…”

Regression of ventriculomegaly following medical management of a patient with Hurler syndrome

“…2,6,8 Following HSCT, reversal of periventricular changes may have additional effects on ventricular size. 4,7,12 A limitation to this case is that only one follow-up MRI study was obtained, 1 year after starting ERT and 7 months post-HSCT. Takahashi et al demonstrated a transient increase in ventricular size in a Hurler patient post-HSCT with no overall net change in ventricular size.…”