Phenotypic Correction of Murine Mucopolysaccharidosis Type II by Engraftment of Ex Vivo Lentiviral Vector-Transduced Hematopoietic Stem and Progenitor Cells

Abstract

Mucopolysaccharidosis type II (MPS II, Hunter syndrome) is an X-linked recessive lysosomal disease caused by deficiency of iduronate-2-sulfatase (IDS). The absence of IDS results in the accumulation of the glycosaminoglycans (GAGs) heparan sulfate and dermatan sulfate. Currently, the only approved treatment option for MPS II is enzyme replacement therapy (ERT), Elaprase. However, ERT is demanding for the patient and does not ameliorate neurological manifestations of the disease. Using an IDS-deficient mouse model that phenocopies the human disease, we evaluated hematopoietic stem and progenitor cells (HSPCs) transduced with a lentiviral vector (LVV) carrying a codon-optimized human IDS coding sequence regulated by a ubiquitous MNDU3 promoter (MNDU3-IDS). Mice treated with MNDU3-IDS LVV-transduced cells showed supraphysiological levels of IDS enzyme activity in plasma, peripheral blood mononuclear cells, and in most analyzed tissues. These enzyme levels were sufficient to normalize GAG storage in analyzed tissues. Importantly, IDS levels in the brains of MNDU3-IDS-engrafted animals were restored to 10–20% than that of wild-type mice, sufficient to normalize GAG content and prevent emergence of cognitive deficit as evaluated by neurobehavioral testing. These results demonstrate the potential effectiveness of ex vivo MNDU3-IDS LVV-transduced HSPCs for treatment of MPS II.

Lentiviral Gene Therapy for Mucopolysaccharidosis II with Tagged Iduronate 2-Sulfatase Prevents Life-Threatening Pathology in Peripheral Tissues But Fails to Correct Cartilage

“… 28–31 This suggests that delivery of recombinant lysosomal enzymes to HV when administrated intravenously is inefficient. 32 In this study, we showed that HSPC-LVGT effectively treats Alcian Blue reactivity as well as lysosomal pathology of HV, as previously shown, 33 independently of the tag used. IDS immunoreactivity was detected as strong signal in the endothelial layer of the HV leaflet, while the rest of the valve tissue was devoid of IDS protein.…”

Tagged IDS causes efficient and engraftment-independent prevention of brain pathology during lentiviral gene therapy for Mucopolysaccharidosis type II

“…In most cases, codon-optimized human IDS was placed under the control of the MND (myeloproliferative sarcoma virus enhancer, negative control region deleted, dl587rev primer-binding site substituted)-derived MCU3 promoter, a strong ubiquitous promoter that resulted in an increase of IDS activity in bone marrow and plasma of 30- to 296-fold above activity in wild-type (WT) animals. 20 , 21 , 22 Nevertheless, the use of unmodified IDS in these studies caused only a partial reduction of GAG levels and pathology in the CNS. To improve the efficacy in brain, Gleitz and co-workers used human IDS-tagged C-terminally with ApoE2, an epitope tag derived from apolipoprotein E and able to undergo transcytosis across the BBB.…”

Engineering Memory T Cells as a platform for Long-Term Enzyme Replacement Therapy in Lysosomal Storage Disorders

“…73 Various in vivo rAAV delivery strategies are under exploration for therapeutic protein delivery as well. [74][75][76] rAAV has been used to deliver transgenes for treatment of MPS I and MPS II into the central nervous system and currently there is an ongoing clinical trial using rAAV9 to deliver IDUA into the central nervous system of patients (NCT03580083). 39,77 However, metaanalysis of 255 rAAV clinical trials calls into question the cost, durability, immunogenicity, and toxicity of various in vivo rAAV gene therapies.…”