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Lentiviral gene therapy using cellular promoters cures type 1 Gaucher disease in mice.

ABSTRACT: Gaucher disease is caused by an inherited deficiency of the enzyme glucosylceramidase. Due to the lack of a fully functional enzyme, there is progressive build-up of the lipid component glucosylceramide. Insufficient glucosylceramidase activity results in hepatosplenomegaly, cytopenias, and bone disease in patients. Gene therapy represents a future therapeutic option for patients unresponsive to enzyme replacement therapy and lacking a suitable bone marrow donor. By proof-of-principle experiments, we have previously demonstrated a reversal of symptoms in a murine disease model of type 1 Gaucher disease, using gammaretroviral vectors harboring strong viral promoters to drive glucosidase ?-acid (GBA) gene expression. To investigate whether safer vectors can correct the enzyme deficiency, we utilized self-inactivating lentiviral vectors (SIN LVs) with the GBA gene under the control of human phosphoglycerate kinase (PGK) and CD68 promoter, respectively. Here, we report prevention of, as well as reversal of, manifest disease symptoms after lentiviral gene transfer. Glucosylceramidase activity above levels required for clearance of glucosylceramide from tissues resulted in reversal of splenomegaly, reduced Gaucher cell infiltration and a restoration of hematological parameters. These findings support the use of SIN-LVs with cellular promoters in future clinical gene therapy protocols for type 1 Gaucher disease.

SUBMITTER: Dahl M

PROVIDER: S-EPMC4427872 | biostudies-other | 2015 May

REPOSITORIES: biostudies-other

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Lentiviral gene therapy using cellular promoters cures type 1 Gaucher disease in mice.

Dahl Maria M Doyle Alexander A Olsson Karin K Månsson Jan-Eric JE Marques André R A ARA Mirzaian Mina M Aerts Johannes M JM Ehinger Mats M Rothe Michael M Modlich Ute U Schambach Axel A Karlsson Stefan S

Molecular therapy : the journal of the American Society of Gene Therapy 20150206 5

Gaucher disease is caused by an inherited deficiency of the enzyme glucosylceramidase. Due to the lack of a fully functional enzyme, there is progressive build-up of the lipid component glucosylceramide. Insufficient glucosylceramidase activity results in hepatosplenomegaly, cytopenias, and bone disease in patients. Gene therapy represents a future therapeutic option for patients unresponsive to enzyme replacement therapy and lacking a suitable bone marrow donor. By proof-of-principle experiment ...[more]

PMID: 25655314

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Project description:OBJECTIVE: To evaluate the cost-effectiveness of enzyme replacement therapy (ERT) compared to standard medical care without ERT in the Dutch cohort of patients with type 1 Gaucher disease (GD I). DESIGN: Cost-effectiveness analysis was performed using a life-time state-transition model of the disease's natural course. Transition probabilities, effectiveness data and costs were derived from retrospective data and prospective follow-up of the Dutch study cohort. SETTING: The tertiary referral center for Gaucher disease in the Netherlands. PARTICIPANTS: The Dutch cohort of patients with GD I. INTERVENTION: ERT versus standard medical care without ERT in symptomatic patients. MAIN OUTCOME MEASURES: Years free of end organ damage (YFEOD) (splenectomy, bone complication, malignancy, multiple complications), quality adjusted life years (QALY), and costs. RESULTS: Over an 85 year lifetime, an untreated GD I patient will generate 48.9 YFEOD and 55.86 QALYs. Starting ERT in a symptomatic patient increases the YFEOD by 12.8 years, while the number of QALYs gained increases by 6.27. The average yearly ERT medication costs range between € 124,000 and € 258,000 per patient. The lifetime costs of ERT starting in the symptomatic stage are € 5,716,473 against € 171,780 without ERT, a difference of € 5,544,693. Consequently, the extra costs per additional YFEOD or per additional QALY are € 434,416 and € 884,994 respectively. After discounting effects by 1.5% and costs by 4% and under a reasonable scenario of ERT unit cost reduction by 25%, these incremental cost-effectiveness ratios could decrease to € 149,857 and € 324,812 respectively. DISCUSSION: ERT is a highly potential drug for GD I with substantial health gains. The conservatively estimated incremental cost-effectiveness ratios are substantially lower than for Pompe and Fabry disease. We suggest that the high effectiveness has contributed importantly to acceptance of reimbursement of ERT for GD I. The present study may further support discussions on acceptable price limits for ultra-orphan products.

Project description:BACKGROUND:Gaucher disease (GD) is a lysosomal disorder caused by biallelic pathogenic mutations in the GBA1 gene that encodes beta-glucosidase (GCase), and more rarely, by a deficiency in the GCase activator, saposin C. Clinically, GD manifests with heterogeneous multiorgan involvement mainly affecting hematological, hepatic and neurological axes. This disorder is divided into three types, based on the absence (type I) or presence and severity (types II and III) of involvement of the central nervous system. At the cellular level, deficiency of GBA1 disturbs lysosomal storage with buildup of glucocerebroside. The consequences of disturbed lysosomal metabolism on biochemical pathways that require lysosomal processing are unknown. Abnormal systemic markers of cobalamin (Cbl, B12) metabolism have been reported in patients with GD, suggesting impairments in lysosomal handling of Cbl or in its downstream utilization events. METHODS:Cultured skin fibroblasts from control humans (n = 3), from patients with GD types I (n = 1), II (n = 1) and III (n = 1) and an asymptomatic carrier of GD were examined for their GCase enzymatic activity and lysosomal compartment intactness. Control human and GD fibroblasts were cultured in growth medium with and without 500 nM hydroxocobalamin supplementation. Cellular cobalamin status was examined via determination of metabolomic markers in cell lysate (intracellular) and conditioned culture medium (extracellular). The presence of transcobalamin (TC) in whole cell lysates was examined by Western blot. RESULTS:Cultured skin fibroblasts from GD patients exhibited reduced GCase activity compared to healthy individuals and an asymptomatic carrier of GD, demonstrating a preserved disease phenotype in this cell type. The concentrations of total homocysteine (tHcy), methylmalonic acid (MMA), cysteine (Cys) and methionine (Met) in GD cells were comparable to control levels, except in one patient with GD III. The response of these metabolomic markers to supplementation with hydroxocobalamin (HOCbl) yielded variable results. The content of transcobalamin in whole cell lysates was comparable in control human and GD patients. CONCLUSIONS:Our results indicate that cobalamin transport and cellular processing pathways are overall protected from lysosomal storage damage in GD fibroblasts. Extending these studies to hepatocytes, macrophages and plasma will shed light on cell- and compartment-specific vitamin B12 metabolism in Gaucher disease.

Project description:Type 1 Gaucher disease (GD1), a glycosphingolipid storage disorder caused by deficient activity of lysosomal glucocerebrosidase, is classically considered non-neuronopathic. However, current evidence challenges this view. Multiple studies show that mutations in GBA1 gene and decreased glucocerebrosidase activity are associated with increased risk for Parkinson disease. We tested the hypothesis that subjects with GD1 will show neurochemical abnormalities consistent with cerebral involvement. We performed Magnetic Resonance Spectroscopy at 7 T to quantify neurochemical profiles in participants with GD1 (n = 12) who are on stable therapy. Age and gender matched healthy participants served as controls (n = 13). Neurochemical profiles were obtained from parietal white matter (PWM), posterior cingulate cortex (PCC), and putamen. Further, in the GD1 group, the neurochemical profiles were compared between individuals with and without a single L444P allele. We observed significantly lower levels of key neuronal markers, N-acetylaspartate, γ-aminobutyric acid, glutamate and glutamate-to-glutamine ratio in PCC of participants with GD1 compared to healthy controls (P < .015). Glutamate concentration was also lower in the putamen in GD1 (P = .01). Glucose + taurine concentration was significantly higher in PWM (P = .04). Interestingly, individuals without L444P had significantly lower aspartate and N-acetylaspartylglutamate in PCC (both P < .001), although this group was 7 years younger than those with an L444P allele. This study demonstrates neurochemical abnormalities in individuals with GD1, for which clinical and prognostic significance remains to be determined. Further studies in a larger cohort are required to confirm an association of neurochemical levels with mutation status and glucocerebrosidase structure and function. SYNOPSIS: Ultrahigh field magnetic resonance spectroscopy reveals abnormalities in neurochemical profiles in patients with GD1 compared to matched healthy controls.

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Lentiviral gene therapy using cellular promoters cures type 1 Gaucher disease in mice.

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Lentiviral gene therapy using cellular promoters cures type 1 Gaucher disease in mice.

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