Long‐term follow‐up following bone marrow transplantation for Hunter disease

Vellodi, Ashok; Young, Elisabeth; Cooper, Alan; Lidchi, Victoria; Winchester, Bryan; Wraith, J. E.

doi:10.1023/a:1005525931994

Cited by 151 publications

(58 citation statements)

References 22 publications

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“…BMT has lessened the clinical manifestations of MPS VII in mice (reviewed in ref. 9), and MPS in large animals (24)(25)(26) and humans (27)(28)(29), but has substantial risks for patients and a compatible donor is often not Synovial fluid was aspirated from the knee joint at 6 -8 months after birth for normal (N; n ϭ 7), 6 -8 months for affected (A; n ϭ 6), 6 -8 months for RV-treated (RV; n ϭ 7 because of inclusion of fluid from both knees in some animals), and 10 months for HGF͞RV-treated (HGF͞RV; n ϭ 1) dogs. The averages Ϯ SEM are shown.…”

Section: Discussionmentioning

confidence: 99%

“…Our gene therapy approach almost completely prevented cardiovascular disease, a major cause of death in patients with MPS, and corneal clouding was markedly reduced. In contrast, some animals and patients that receive ERT or BMT have only partial reductions in cardiovascular disease and corneal clouding (13,(24)(25)(26)(27)(28)(29)44), which may be due in part to the later age of treatment. Two RV-treated dogs had low (1.5% of normal) GUSB enzyme activity and reductions in cytoplasmic vaculation in the brain at 6 months (K.P.P.…”

Section: Discussionmentioning

confidence: 99%

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Therapeutic neonatal hepatic gene therapy in mucopolysaccharidosis VII dogs

Ponder

Melniczek

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

160

132

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Dogs with mucopolysaccharidosis VII (MPS VII)were injected intravenously at 2-3 days of age with a retroviral vector (RV) expressing canine ␤-glucuronidase (cGUSB). Five animals received RV alone, and two dogs received hepatocyte growth factor (HGF) before RV in an attempt to increase transduction efficiency. Transduced hepatocytes expanded clonally during normal liver growth and secreted enzyme with mannose 6-phosphate. Serum GUSB activity was stable for up to 14 months at normal levels for the RV-treated dogs, and for 17 months at 67-fold normal for the HGF͞RV-treated dog. GUSB activity in other organs was 1.5-60% of normal at 6 months for two RV-treated dogs, which was likely because of uptake of enzyme from blood by the mannose 6-phosphate receptor. The body weights of untreated MPS VII dogs are 50% of normal at 6 months. MPS VII dogs cannot walk or stand after 6 months, and progressively develop eye and heart disease. RV-and HGF͞RV-treated MPS VII dogs achieved 87% and 84% of normal body weight, respectively. Treated animals could run at all times of evaluation for 6 -17 months because of improvements in bone and joint abnormalities, and had little or no corneal clouding and no mitral valve thickening. Despite higher GUSB expression, the clinical improvements in the HGF͞RV-treated dog were similar to those in the RV-treated animals. This is the first successful application of gene therapy in preventing the clinical manifestations of a lysosomal storage disease in a large animal.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Therapeutic neonatal hepatic gene therapy in mucopolysaccharidosis VII dogs

Ponder

Melniczek

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

160

132

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“…HSCT of MPS patients improves their QOL, but the therapeutic effect on bone lesions remains limited [23]. The musculoskeletal manifestations still deteriorate and impact the QOL in most transplanted patients with MPSs [24].…”

Section: Introductionmentioning

confidence: 99%

Therapies for the bone in mucopolysaccharidoses

Tomatsu

Alméciga-Díaz

Montaño

et al. 2015

Molecular Genetics and Metabolism

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Patients with mucopolysaccharidoses (MPS) have accumulation of glycosaminoglycans in multiple tissues which may cause coarse facial features, mental retardation, recurrent ear and nose infections, inguinal and umbilical hernias, hepatosplenomegaly, and skeletal deformities. Clinical features related to bone lesions may include marked short stature, cervical stenosis, pectus carinatum, small lungs, joint rigidity (but laxity for MPS IV), kyphoscoliosis, lumbar gibbus, and genu valgum. Patients with MPS are often wheelchair-bound and physical handicaps increase with age as a result of progressive skeletal dysplasia, abnormal joint mobility, and osteoarthritis, leading to 1) stenosis of the upper cervical region, 2) restrictive small lung, 3) hip dysplasia, 4) restriction of joint movement, and 5) surgical complications. Patients often need multiple orthopedic procedures including cervical decompression and fusion, carpal tunnel release, hip reconstruction and replacement, and femoral or tibial osteotomy through their lifetime. Current measures to intervene in bone disease progression are not perfect and palliative, and improved therapies are urgently required. Enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT), and gene therapy are available or in development for some types of MPS. Delivery of sufficient enzyme to bone, especially avascular cartilage, to prevent or ameliorate the devastating skeletal dysplasias remains an unmet challenge. The use of an anti-inflammatory drug is also under clinical study. Therapies should start at a very early stage prior to irreversible bone lesion, and damage since the severity of skeletal dysplasia is associated with level of activity during daily life. This review illustrates a current overview of therapies and their impact for bone lesions in MPS including ERT, HSCT, gene therapy, and anti-inflammatory drugs.

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“…The outcome is largely contingent on the type and stage of the disease. In general, this procedure is relatively effective in alleviating visceral symptoms and in stabilizing bone lesions, provided that it is performed before the occurrence of major neurological damage [31, 32, 33]. However, diseases that have an early onset and involve predominantly the CNS respond poorly or not at all to BMT, albeit some variations in outcomes have been observed among disease subtypes [32, 34].…”

Section: Therapy For Lysosomal Storage Diseasesmentioning

confidence: 99%

Gene Transfer Strategies for Correction of Lysosomal Storage Disorders

d’Azzo¹

2003

Acta Haematol

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Lysosomal storage diseases (LSDs) represent a large group of monogenic disorders of metabolism, which affect approximately 1 in 5,000 live births. LSDs result from a single or multiple deficiency of specific lysosomal hydrolases, the enzymes responsible for the luminal catabolization of macromolecular substrates. The consequent accumulation of undigested metabolites in lysosomes leads to polysystemic dysfunction, including progressive neurologic deterioration, mental retardation, visceromegaly, blindness, and early death. In general, the residual amount of functional enzyme in lysosomes determines the severity and age at onset of the clinical symptoms, implying that even modest increases in enzyme activity might affect a cure. A key feature on which therapy for LSDs is based is the ability of soluble enzyme precursors to be secreted by one cell type and reinternalize by neighboring cells via receptor-mediated endocytosis and routed to lysosomes, where they function normally. In principle, somatic gene therapy could be the preferred treatment for LSDs if the patient’s own cells could be genetically modified in vitro or in vivo to constitutively express high levels of the correcting enzyme and become the source of the enzyme in the patient. Both ex vivo and in vivo gene transfer methods have been experimented with for gene therapy of lysosomal disorders. Several of these methods have proved efficient for the transfer of genetic material into deficient cells in culture and reconstitution of enzyme activity. However, the same methods applied to humans or animal models have been giving inconsistent results, the bases of which are not fully understood. A broader knowledge of disease pathogenesis, facilitated by available, faithful animal models of LSDs, coupled to the development of better gene transfer systems as well as the understanding of vector host interactions will make somatic gene therapy for these devastating and complex diseases the most suitable therapeutic approach.

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Long‐term follow‐up following bone marrow transplantation for Hunter disease

Cited by 151 publications

References 22 publications

Therapeutic neonatal hepatic gene therapy in mucopolysaccharidosis VII dogs

Therapeutic neonatal hepatic gene therapy in mucopolysaccharidosis VII dogs

Therapies for the bone in mucopolysaccharidoses

Gene Transfer Strategies for Correction of Lysosomal Storage Disorders

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