Gene therapy augments the efficacy of hematopoietic cell transplantation and fully corrects mucopolysaccharidosis type I phenotype in the mouse model

Abstract

Type I mucopolysaccharidosis (MPS I) IntroductionType I mucopolysaccharidosis (MPS I) is one of the most frequent lysosomal storage disorders (LSDs) and is due to the inherited deficiency of ␣-L-iduronidase (IDUA) activity, which results in the accumulation of its unprocessed substrates (glycosaminoglycans; GAGs) in many organs. 1 The disorder is systemic and clinically heterogeneous. Clinical manifestations include skeletal dysplasia, joint stiffness, visual and auditory defects, cardiac insufficiency, hepatosplenomegaly, and mental retardation. The clinical spectrum ranges from the severe Hurler syndrome (MPS I-H) to the attenuated Scheie syndrome. Mental retardation is distinctive only of MPS I-H, which is fatal in childhood if untreated, thus representing the variant with the most urgent need for new therapies. Enzyme replacement therapy (ie, parenteral administration of exogenous enzyme that can be internalized by tissue cells via the mannosium-6-phosphate receptor) is recommended only for MPS I patients without primary neurologic disease, due to the inability of the enzyme to efficiently cross the blood-brain barrier; moreover, neutralizing antibodies can attenuate its efficacy. 2 When performed at early ages, hematopoietic stem cell (HSC) transplantation (HCT) from healthy donors alleviates most disease manifestations in MPS I-H patients, likely by migration of the transplant-derived leukocytes into organs, where they can clear the storage and secrete the functional enzyme for correction of the metabolic defect in resident cells. 3 However, despite recent improvements in the outcome of HCT, the morbidity and mortality associated with the procedure are still not negligible, mostly due to rejection and graft-versus-host disease. Moreover, the amount of enzyme that transplantation can provide to the organism can be limiting, especially since donors are often heterozygous siblings. Indeed, a relationship between circulating enzyme levels after transplant and urinary GAGs has been shown 4 : the low enzyme levels achieved with heterozygote donor transplant lead to less adequate reduction in GAG levels. Likely due to partial metabolic correction at disease sites, the impact of HCT on central nervous system (CNS) and skeletal disease, despite being substantial in ameliorating patients' phenotype, could still benefit from further improvement. 5 The benefits of different gene therapy approaches were established in MPS I animal models. Intravenous delivery of viral vectors, which can establish a tissue source for systemic enzyme distribution, was effective in controlling disease manifestations in The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on May 10, 2018. by guest www.bloodjournal.org From MPS I animal models upon neonatal treatment. [6][7][8][9] However, residu...

Lentiviral Vector Gene Therapy Protects XCGD Mice From Acute Staphylococcus aureus Pneumonia and Inflammatory Response

“…34 Our study included a wide distribution of VCN (ranging from 0.3 to 9.8). While these VCNs are in line with previous studies from our group and others [36][37][38] it is expected that lower VCNs would be observed in the clinical application based on our previous studies in human CD34+ cells, 23 and clinical trials in other therapeutic areas. 34,39 Unfortunately, no published data is available regarding the protection from the infections in clinical trials with lentiviral vectors encoding for gp91phox.…”

Lentiviral Hematopoietic Stem Cell Gene Therapy in Inherited Immune and Lysoso- mal Enzyme Deficiencies

“…Using a codon optimized IDUA gene driven by a cellular promoter in a lentiviral vector to transduce hematopoietic stem cells, we demonstrated long-term expression in the hematopoietic system resulting in full correction of the Hurler phenotype (unpublished) without any severe adverse effects. Similar results and a further safety analysis were obtained in a parallel study [43,44], completing the preclinical analysis enabling an initial clinical trial in selected patients.…”

Long-Term Functional Outcomes of Children with Hurler Syndrome Treated with Unrelated Umbilical Cord Blood Transplantation

“…To circumvent the blood-brain barrier, intrathecal ERT is currently being studied; however, the long-term safety and efficacy remain unclear (Tolar et al 2009). Transplantation of HSCs genetically modified to express supranormal levels of IDUA showed promising results in MPS I mice (Visigalli et al 2010). Whether this therapy represents an effective and safe therapeutic option for human patients in the future warrants further clinical studies.…”