Treatment Of Gaucher Disease Research Articles

The effect of N-octyl-β-valienamine on β-glucosidase activity in tissues of normal mice

Gaucher disease (GD), mainly caused by a defect of acid β-glucosidase (β-Glu), is the most common sphingolipidosis. We have previously shown that a carbohydrate mimic N-octyl-β-valienamine (NOV), an inhibitor of β-Glu, could increase the protein level and enzyme activity of various mutant β-Glu in cultured GD fibroblasts, suggesting that NOV acted as a pharmacological chaperone to accelerate transport and maturation of this mutant enzymes. In the present study, the NOV effect was evaluated for β-Glu activity, tissue distribution and adverse effects in normal mice. We measured the β-Glu activity in tissues of normal mice which received water containing increasing concentrations of NOV ad libitum for 1 week. Fluid intake and body weight were measured periodically throughout the study. Measurement of tissue NOV concentration, blood chemistry and urinalysis were performed at the end of the study. The results showed that NOV had no impact on the body weight but fluid intake in the 10 mM NOV group mice decreased and there was a moderate increase in blood urea nitrogen (BUN). No other adverse effect was observed during this experiment. Tissue NOV concentration increased in all tissues examined with increasing NOV doses. No inhibitory effect of NOV on β-Glu was observed. Furthermore, NOV increased the β-Glu activity in the liver, spleen, muscle and cerebellum of the mice significantly. This study on NOV showed its oral availability and wide tissue distribution, including the brain and its lack of acute toxicity. These characteristics of NOV would make it a potential therapeutic chaperone in the treatment of GD with neurological manifestations and selected mutations.

The pharmacological chaperone effect of N-octyl -β -valienamine on human mutant acid β-glucosidases

Gaucher's disease (GD), mainly caused by a defect of acid β-glucosidase (β-Glu), is the most common form of sphingolipidosis. We have previously shown that the carbohydrate mimic and inhibitor of β-Glu, N-octyl -β -valienamine (NOV), could increase the protein level and enzyme activity of various mutant β-Glus in cultured GD fibroblasts and in COS cells, suggesting that NOV acts as a pharmacological chaperone to accelerate transport and maturation of these mutant enzymes. In present study, we continued to investigate the chaperone characteristics of NOV. More importantly, chaperone activities of NOV were evaluated in COS cells transiently expressing ten new, recombinant β-Glu mutants with mutations located in domain I, II and III. NOV was only effective on the T369M mutation, located in domain III. As we suggested in a previous study, domain III may be a prerequisite for pharmacological rescue of the mutant β-Glu by NOV. These characteristics of NOV could provide potential therapeutic chaperone properties that would be useful in the treatment of GD with neurological manifestations due to gene mutations in β-Glu.

A new surrogate marker for CNS pathology in Niemann–Pick disease type C?

Over the past 20 years there has been unprecedented progressin the development of treatments for lysosomal storage diseases(LSDs) [1]. Enzyme replacement therapy (ERT) continues to expandwith clinical programmes in Niemann–Pick type B, MPS IV andmetachromatic leucodystrophy. One small molecule drug (miglu-stat) is approved for type 1 Gaucher disease and other substratereduction therapy (SRT) and chaperone approaches are in the pipe-line [2]. Indeed, it is possible that in the future physicians treatingGaucher disease may be able to choose from three different en-zyme preparations, two inhibitors of glucosyl ceramide synthesisand a chaperone.However, these treatments are not all equally efficacious. Onemajor obstacle is that there is no means of delivering significantamounts of enzyme across the blood–brain barrier. This meansthat whilst ERT canbe highlyeffective against the visceralmanifes-tations of LSDs, patients in whom CNS involvement is the majorfeature do not benefit. For the majority of LSDs, which involve stor-age and pathology in the brain, ERT is not currently a realisticoption.Considerable research activity is therefore currently focused ondeveloping strategies to target brain disease in these disorders,either using small molecules, gene therapy or methods to deliverenzymes across the blood–brain barrier.One major obstacle in designingclinical trialsis the definitionofsuitable clinical endpoints. Regulatory authorities demand con-trolled trials, which demonstrate statistically significant changesin quantifiable variables. Pharmaceutical companies want trialsto be completed in months rather than years. Unfortunately, theseare rare, neurodegenerative diseases, which show variable andunpredictable progression over long periods. We do not knowwhich aspects of CNS pathology may be stabilised or improvedby treatment and it is very difficult to decide which clinical mani-festations should be measured or to know how long it may take tosee a significant change.The situation would be greatly improved if there were validatedsurrogate markers of brain disease that could be monitored as sec-ondaryclinical endpoints. These wouldpotentiallyprovidean earlyindicator of efficacy, prior to significant changes in clinicalsymptoms.The utility of surrogate markers in the storage disease field isbest exemplified by type 1 Gaucher disease [3]. This is a visceralstorage disorder with the Gaucher macrophage being the centralcell type in the pathogenic cascade [4]. These cells secrete a num-ber of factors that can be measured in peripheral blood and used assurrogate markers to estimate the total storage cell burden in un-treated patients and measure the degree of improvement followingthe initiation of ERT or SRT [5].However, currentlythere are no equivalent markersfor measur-ing storage in the brain. The Holy Grail in this field would be toidentify a non-invasive method that could be performed in mosthospitals where the parameter being measured was closely linkedto the primary pathological events occurring in the brain. It wouldneed to correlate with disease severity and be altered by diseasemodifying therapies.Miglustat, a small molecule inhibitor of glucosylceramide syn-thesis, does cross the blood–brain barrier and has shown benefitwhen used for SRT in a number of mouse models of CNS glyco-sphingolipid storage diseases [6], including Niemann–Pick type C

Diagnostic and Disease Management Algorithms for Gaucher Disease: A Guide for Haematologists

In Gaucher disease (GD), inherited deficiency in lysosomal acid beta-glucocerebrosidase leads to the widespread accumulation of glycolipid-laden macrophages in tissues and consequent multisystemic disease. The presenting symptoms of type 1 (non neuronopathic) Gaucher disease commonly reflect the haematologic components of the disease, i.e., splenomegaly, thrombocytopenia, anaemia, and bleeding tendency. Consequently the majority of patients are referred to haematologists for diagnosis and management. However, the remarkable heterogeneity of the disease compounded by its rarity presents a diagnostic challenge. Only around 20% of haematologists consider GD in differential diagnosis even though all classic manifestations of the disease may be present. Haematologic malignancy is the most often considered diagnosis in such patients. Lack of awareness of GD and its protean manifestations renders individuals with Gaucher disease vulnerable to misdiagnosis, diagnostic delays and risk of irreversible complications that are otherwise preventable by timely therapy. Missed diagnosis may place individuals at risk of bleeding even in the presence of mild thrombocytopenia, irreversible skeletal complications leading to disability and impaired growth, and an increased risk of malignancy, especially multiple myeloma. Imiglucerase (Cerezyme) enzyme replacement therapy is effective in reversing haematological, visceral and some skeletal manifestations of the disease. In a minority of patients in whom imiglucerase is not suitable, Miglustat substrate reduction therapy (Zavesca) is an alternative. An international group of physicians met to harness their respective experience of managing the diverse phenotypes of Gaucher disease in order to raise awareness of GD and to determine under which circumstances GD should be given greater priority in differential diagnosis. As a result of their discussions, simple diagnostic algorithms have been devised, which focus on splenomegaly as the most prevalent presenting manifestation of GD in individuals of both Ashkenazi Jewish and non Ashkenazi Jewish background. Given the prevalence of GD in Ashkenazim, a possible diagnosis of GD is prioritised in the presence of splenomegaly in this population. When challenged by differential diagnosis of splenomegaly, GD can be confirmed or eliminated by a straightforward assay for beta glucocerebrosidase activity. Diagnostic algorithms are accompanied by disease management algorithms, which reflect published therapeutic goals and monitoring guidelines, to simplify decision making in the evaluation, treatment and ongoing monitoring of GD in response to therapy.

Isofagomine Induced Stabilization of Glucocerebrosidase

Structurally destabilizing mutations in acid beta-glucosidase (GCase) can result in Gaucher disease (GD). The iminosugar isofagomine (IFG), a competitive inhibitor and a potential pharmacological chaperone of GCase, is currently undergoing clinical evaluation for the treatment of GD. An X-ray crystallographic study of the GCase-IFG complex revealed a hydrogen bonding network between IFG and certain active site residues. It was suggested that this network may translate into greater global stability. Here it is demonstrated that IFG does increase the global stability of wild-type GCase, shifting its melting curve by approximately 15 degrees C and that it enhances mutant GCase activity in pre-treated N370S/N370S and F213I/L444P patient fibroblasts. Additionally, amide hydrogen/deuterium exchange mass spectroscopy (H/D-Ex) was employed to identify regions within GCase that undergo stabilization upon IFG-binding. H/D-Ex data indicate that the binding of IFG not only restricts the local protein dynamics of the active site, but also propagates this effect into surrounding regions.

Treatment perspectives for the lysosomal storage diseases

Background: The therapy of the lysosomal storage diseases (LSDs) was developed by supplying adequate amounts of the needed enzyme to affected individuals. This approach in Gaucher disease provided a prototype for the basic and clinical sciences, and the economic foundation for other ultra-orphan diseases. Objective: Using the success of enzyme therapy for Gaucher disease, the challenges are highlighted for alternative bioproduction systems, and substrate reduction and molecular chaperone approaches for treatment of Gaucher disease and other ultra-orphan diseases. Methods: Literature review provided insight into the current status of enzyme therapies for LSDs, the proposed mechanisms of alternative approaches to therapy, and the obstacles in a competitive marketplace for treatment of ultra-rare diseases. Results/conclusions: These developments are placed in the contexts of finding rare patients with LSDs, their marked phenotypic spectrum, potential markets, and new orphan drug costs. The confluence of these challenges has led to a competitive environment with the potential for multiple, alternative, expensive treatments for orphan diseases.

No justification for very high‐dose enzyme therapy for patients with type III Gaucher disease

Journal of Inherited Metabolic DiseaseVolume 30, Issue 6 p. 843-844 EditorialFree Access No justification for very high-dose enzyme therapy for patients with type III Gaucher disease Ari Zimran, Ari Zimran Gaucher Clinic, Shaare Zedek Medical Center, Jerusalem, 91031 IsraelSearch for more papers by this authorDeborah Elstein, Corresponding Author Deborah Elstein [email protected] Gaucher Clinic, Shaare Zedek Medical Center, Jerusalem, 91031 Israel [email protected]Search for more papers by this author Ari Zimran, Ari Zimran Gaucher Clinic, Shaare Zedek Medical Center, Jerusalem, 91031 IsraelSearch for more papers by this authorDeborah Elstein, Corresponding Author Deborah Elstein [email protected] Gaucher Clinic, Shaare Zedek Medical Center, Jerusalem, 91031 Israel [email protected]Search for more papers by this author First published: 19 November 2007 https://doi.org/10.1007/s10545-007-0783-8Citations: 18AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References Altarescu G, Brooks B, Margalioth E, Eldar Geva T, Levy-Lahad E, Renbaum P (2007) Simultaneous preimplantation genetic diagnosis for Tay–Sachs and Gaucher disease. Reprod Biomed Online, 15: 83– 88, . Barton NW, Brady RO, Dambrosia JM, et al (1991) Replacement therapy for inherited enzyme deficiency: macrophage-targeted glucocerebrosidase for Gaucher's disease. N Engl J Med, 324: 1464– 1470, . Beutler E (2006) Lysosomal storage diseases: natural history and ethical and economic aspects. Mol Genet Metab, 88: 208– 215, . Beutler E (2007) Consensus recommendations. Br J Haematol, 138 (6): 673– 675, . Cox T, Lachmann R, Hollak C, et al (2000) Novel oral treatment of Gaucher's disease with N-butyldeoxynojirimycin (OGT 918) to decrease substrate biosynthesis. Lancet, 355: 1481– 1485, . Davies EH, Erikson A, Collin-Histed, et al (2007) Outcome of type 3 Gaucher on enzyme replacement therapy: review of 55 cases J Inherit Metab Dis doi:10.1007/s10545-007-0577-z. Elstein D, Abrahamov A, Zimran A (1998) Ethical considerations for enzyme replacement therapy in neuronopathic Gaucher disease. Clin Genet, 54: 179– 184, . Elstein D, Guedalia J, Doniger GM, et al (2005) Computerized cognitive testing in patients with type I Gaucher disease: effects of enzyme replacement and substrate reduction. Genet Med, 7: 124– 130, . Patterson MC, Horowitz M, Abel RB, et al (1993) Isolated horizontal supranuclear gaze palsy as a marker of severe systemic involvement in Gaucher's disease. Neurology, 43: 1993– 1997. Prows CA, Sanchez N, Daugherty C, Grabowski GA (1997) Gaucher disease: enzyme therapy in the acute neuronopathic variant. Am J Med Genet, 71: 16– 21, . Vellodi A, Bembi B, deVillemeur TB, et al (2001) Management of neuronopathic Gaucher disease: a European consensus. J Inherit Metab Dis, 24: 319– 327, . Weinreb NJ, Charrow J, Andersson HC, et al (2002) Effectiveness of enzyme replacement therapy in 1028 patients with type 1 Gaucher disease after 2 to 5 years of treatment: a report from the Gaucher Registry. Am J Med, 113: 112– 119, . Zimran A, Elstein D, Beutler E (2006) Low-dose therapy trumps high-dose therapy again in the treatment of Gaucher disease. Blood, 108: 802– 803, . Citing Literature Volume30, Issue6November 2007Pages 843-844 ReferencesRelatedInformation

24 Genz-112638: A novel orally available ceramide-based inhibitor of glucosylceramide synthase for treating Gaucher disease

24 Genz-112638: A novel orally available ceramide-based inhibitor of glucosylceramide synthase for treating Gaucher disease

Hypermetabolism in Gaucher disease type I is not associated with altered thyroid hormone levels

Type I Gaucher disease (OMIM 231000) is an inherited storage disorder in which deficiency of the enzyme glucocerebrosidase (EC 32145) leads to accumulation of glucocerebroside in lysosomes of macrophages. These storage cells are present in liver, spleen and bone marrow resulting in hepatosplenomegaly, cytopenia and bone complications. Metabolic abnormalities in Gaucher patients include hypermetabolism, possibly caused by elevated levels of pro-inflammatory cytokines. Nonthyroidal illness (NTI) is a combination of changes in circulating thyroid hormone levels (decreased T(3), elevated rT(3), normal or mildly depressed TSH) present in different illnesses and might be an adaptation to protect the organism from harmful catabolic effects of hypermetabolism. The hypermetabolism and the elevated cytokine levels in Gaucher disease led us to hypothesize that the alterations in thyroid hormone levels as seen in NTI might also occur in Gaucher patients. We studied thyroid hormone levels before and during treatment in 22 adult type I Gaucher patients and resting energy expenditure (REE) and correlations with thyroid hormone levels in 12 patients. Baseline thyroid hormone levels were normal in the majority (17) of patients. No cases of nonthyroidal illness were detected. Baseline REE (kcal/kg per 24 h) was not correlated with circulating levels of T(3), rT(3) or fT(4). Treatment of Gaucher disease with enzyme replacement therapy for several years resulted in a decrease in circulating fT(4) levels. After several months of treatment most patients showed a decrease in REE. There was no correlation between the changes in REE and changes in fT(4) and T(3).

Organisation de la prise en charge de la maladie de Gaucher en France

Gaucher disease management in France is facilitated by CETG (Comitee of Evaluation and Treatment of Gaucher disease). Four hundred and fifty-six patients are enrolled in 2006 in the French Gaucher registry of CETG. Two hundred and thirty patients had treatment. Eighty five % are type 1, 10,5 % type 2 and 5.5 % type 3. Only 1 patient had a saposin C deficiency. Information on CETG is available on www.cetl.net.

Recommendations for the management of the haematological and onco-haematological aspects of Gaucher disease.

Current knowledge of the haematological and onco-haematological complications of type 1 Gaucher disease has been reviewed with the aim of identifying best clinical practice for treatment and disease management. It was concluded that: (i) Awareness of typical patterns of cytopenia can help clinicians distinguish haematological co-morbidities. (ii) Red blood cell studies and complete iron metabolism evaluation at baseline are recommended. (iii) Haemoglobin levels defining anaemia should be raised and used in Gaucher disease treatment and monitoring. (iv) Surgeons should be aware of potential bleeding complications during surgery in Gaucher patients. The higher incidence of multiple myeloma in Gaucher disease suggests that Gaucher patients should have their immunoglobulin profile determined at diagnosis and monitored every 2 years (patients <50 years) or every year (patients >50 years). If monoclonal gammopathy of undetermined significance (MGUS) is found, general MGUS guidelines should be followed. Future studies should focus on the utility of early treatment to prevent immunoglobulin abnormalities and multiple myeloma.

Development of Adamantan-1-yl-methoxy-Functionalized 1-Deoxynojirimycin Derivatives as Selective Inhibitors of Glucosylceramide Metabolism in Man

In this article, we present a straightforward synthesis of adamantan-1-yl-methoxy-functionalized 1-deoxynojirimycin derivatives. The used synthetic routes are flexible and can be used to create a wide variety of lipophilic mono- and difunctionalized 1-deoxynojirimycin derivatives. The compounds reported here are lipophilic iminosugar based on lead compound 4, a potent inhibitor of the three enzymes involved in the metabolism of the glycosphingolipid glucosylceramide. Iminosugar-based inhibitors of glucosylceramide synthase, one of these three enzymes, have attracted increasing interest over the past decade due to the crucial role of this enzyme in glycosphingolipid biosynthesis. Combined with the fact that an increasing number of pathological processes are being linked to excessive glycosphingolipid levels, glucosylceramide synthase becomes a very attractive therapeutic and research target. Our results presented here demonstrate that relocating the lipophilic moiety from the nitrogen atom to other positions on the 1-deoxynojirimycin ring system does not lead to a more potent or selective inhibitor of glucosylceramide synthase. The beta-aza-C-glycoside analogue (17) retained the best inhibitory potency for glucosylceramide synthase and is a more potent inhibitor than the therapeutic agent N-butyl-1-deoxynojirimycin (3), marketed as treatment for Gaucher disease under the commercial name Zavesca.

Designing Protein Therapies: Lessons Learned from Cerezyme® for Gaucher Disease

The development of carbohydrate-modified human glucocerebrosidase (Ceredase® and Cerezyme® [Genzyme Corporation, Cambridge, Massachusetts]) for the treatment of Gaucher disease has transformed the lives of patients and led to the development of enzyme replacement therapies (ERTs) for many other lysosomal storage disorders (LSDs). Gaucher disease and the use of Cerezyme as an ERT serve as a useful model for the design of protein and other therapies for the treatment of LSDs. Like other LSDs, Gaucher disease is a progressive and lethal metabolic disorder that results in irreversible endorgan damage when untreated. Early intervention is key to preventing irreversible complications. Several hundred different mutations have been identified that give rise to Gaucher disease,1 but there is still no reliable correlation between genotype and phenotype. Response to therapy is organ specific; that is, liver and spleen demonstrate a rapid response at a relatively low dose2 but a higher dose, earlier intervention, and long-term therapy are necessary to demonstrate benefit for the skeletal disease. Gaucher disease differs from other LSDs in the low percentage of patients that develop antibodies3; this reflects the fact that many patients produce residual, though inactive or partially active, protein. Cerezyme has an excellent safety and efficacy record, demonstrated over 15 years of clinical use.4 Nevertheless, we have evaluated alternative production methods in an attempt to improve mannose receptor targeting and enzyme delivery to target tissues. To evaluate the effect of increased amounts of terminal mannose residues on the uptake and biodistribution of human glucocerebrosidase, we produced human glucocerebrosidase with mannose chain lengths of 3 to 9 residues.5 Because Cerezyme differs from the human placental enzyme used in the production of Ceredase by 1 amino acid, we also evaluated the effect of that amino acid difference on uptake and biodistribution (even though no clinical difference has been observed between Cerezyme and Ceredase).6 Although terminal mannose is essential for efficient uptake into target cells, more mannose does not alter the uptake or biodistribution of human glucocerebrosidase. More mannose did, however, increase binding to the mannose-binding lectin in vitro, which could have negative consequences on clearance and uptake in vivo. The single amino acid difference between Cerezyme and placental glucocerebrosidase had no effect on half-life, uptake, or tissue targeting.5 In addition to engineering the carbohydrate residues on glucocerebrosidase, it is also possible to engineer the protein backbone to improve biological properties. Although the crystal structure of glucocerebrosidase has been determined,7 it is of little use for predicting how to improve the protein. It does not explain why most mutations cause disease or how the protein is activated by saposin C or phospholipids and is inconsistent with biochemical data. This most likely reflects the fact that the crystal structure is just a static image of a dynamic molecule. The use of competitive inhibitors as chemical chaperones has recently been proposed as a therapeutic strategy.8 This is based on the hypothesis that mutations which cause LSDs result in misfolded proteins, which are degraded by the proteasome, an effect that is likely to be mutation specific. We have studied the effect of chemical chaperones on the uptake and stabilization of Cerezyme as well as recombinantly produced N370S mutant glucocerebrosidase.9 These studies demonstrated that the increased enzyme levels observed are due to lysosomal stabilization. Chaperones, which are competitive inhibitors, remain bound in the lysosome and inhibit enzyme activity, as also demonstrated by Steet et al.10 Because these competitive inhibitors tend to have the same pH optima as the natural substrate—that is, they bind better at low pH—there is likely to be a narrow (if any) therapeutic window. As our results demonstrate, the effects of chaperones on protein levels reported in the literature can be accounted for by reduced lysosomal degradation. Gaucher disease is the first and most effectively treated of the LSDs, and Cerezyme is the gold standard against which to measure future LSD therapies. Alternative manufacturing platforms are unlikely to offer any improvement over Cerezyme. Small molecule chaperones are at best likely to be limited to a few of the several hundred disease-causing mutations. More promising approaches for the future include the development of a secondgeneration substrate inhibition therapy with improved specificity and reduced adverse effects, as well as gene therapy for LSDs with central nervous system involvement. Clinical Therapeutics/Volume 29, Supplement C, 2007

Research Advances: Less Expensive and More Convenient Gaucher's Disease Treatment; Structural Loop Regions: Key to Multidrug-Resistance Transporters?; New Method Identifies Proteins in Old Artwork

Molecular chaperones lead the way to new Gaucher's disease treatment. Researchers determine structure of the multidrug transporter EmrD. Whole egg proteins present in Renaissance art microsamples.

Effective treatment of an elderly patient with Gaucher's disease and Parkinsonism: A case report of 24 months’ oral substrate reduction therapy with miglustat

We report here the results of 24 months’ treatment with oral miglustat of a patient with mild-to-moderate Gaucher's disease (GD) and Parkinsonism. The patient's progressive Parkinsonian tremor, in addition to restricted vascular access, necessitated switching treatment for GD from intravenously infused enzyme replacement therapy (ERT) that had been administered for the previous 7 years. With control of haematological parameters and markers of GD activity improved or maintained and no notable adverse effects, miglustat treatment proved an effective and well-tolerated therapeutic alternative to ERT. Oral miglustat should be considered for the treatment of patients with type I GD and concurrent movement disorders who are unsuitable for ERT.

Therapeutic goals in Gaucher disease

Evidence-based therapeutic goals have been developed by several European and American experts in Gaucher disease in order to attempt to reverse the entire Type 1 Gaucher phenotype, prevent complications, improve quality of life and prevent life-threatening complications. Patients with Gaucher disease will benefit by maximum enzyme replacement treatment (ERT) efficiency if it is given at the optimal time i.e. generally during the asymptomatic phase of the disease. Currently, Cerezyme® is the standard of care for all severities of type 1 Gaucher disease due to its high efficiency at ameliorating bleeding tendencies, reversing organomegaly and part of skeletal damages and eliminating bone crises. ERT has also demonstrated a remarkable safety profile with tolerability at 3 years greater than 99%. Treatment of Gaucher disease is a long-life treatment that the patient should not interrupt without a careful monitoring of the disease evolution.

Therapeutic goals in Gaucher disease

Evidence-based therapeutic goals have been developed by several European and American experts in Gaucher disease in order to attempt to reverse the entire type 1 Gaucher phenotype, prevent complications, improve quality of life and prevent life-threatening complications. Patients with Gaucher disease will benefit by maximum enzyme replacement treatment (ERT) efficiency if it is given at the optimal time i.e. generally during the asymptomatic phase of the disease. Currently, Cerezyme® is the standard of care for all severities of type 1 Gaucher disease due to its high efficiency at ameliorating bleeding tendencies, reversing organomegaly and part of skeletal damages and eliminating bone crises. ERT has also demonstrated a remarkable safety profile with tolerability at 3 years greater than 99 %. Treatment of Gaucher disease is a long-life treatment that the patient should not interrupt without a careful monitoring of the disease evolution.

WITHDRAWN: Satellite Symposium on treating Gaucher disease

WITHDRAWN: Satellite Symposium on treating Gaucher disease

910. AAV8-Mediated Expression of Glucocerebrosidase Ameliorates the Storage Pathology in the D409V/null Gaucher Mouse

Gaucher disease is the most common of the >40 described lysosomal storage disorders. The primary manifestation of Gaucher disease is the accumulation of glucosylceramide (GL-1), predominantly in the macrophages of liver and spleen, due to a genetic defect in the lysosomal hydrolase glucocerebrosidase (GC). A mouse model of Type I Gaucher disease (D409V/null) was used to assess the efficacy of AAV8-mediated gene therapy. This mouse model exhibits only 5% of normal GC activity in visceral tissues resulting in elevated GL-1 levels and the appearance of enlarged macrophages (Gaucher cells) in liver, lung, and spleen at 3 months of age. The AAV vector (AAV8/DC172-hGC) used for these studies contained a hepatocyte-restricted promoter, DC172 (human 1-microglobulin enhancer, human 1-anti-trypsin promoter), to drive the expression of human GC. Intravenous administration of 31011 drp of AAV8/DC172-hGC into 4-week old D409V/null mice (prior to development of disease pathology) generated high levels of GC in the liver and serum, and subsequent uptake by the spleen and lung. Expression was sustained for the duration of the study (6 months) and was effective at preventing both the accumulation of GL-1 in the tissues and the consequent onset of Gaucher disease symptoms. A subsequent study in older mice (4-month old) with established disease pathology showed that administration of a similar dose of AAV8/DC172-hGC was also effective at reversing GL-1 storage in the affected tissues. Furthermore, AAV-treated mice were largely devoid of the lipid-engorged macrophages that were frequently observed in vehicle-treated D409V/null mice. A dose-response study, in which 5-month old mice received 31011, 11011 or 31010 drp of AAV8/DC172-hGC, yielded high and sustained expression of GC in all treatment groups. Three months post-injection, both the 31011 and 11011 drp dosed mice demonstrated a dramatic reduction in GL-1 levels and the number of Gaucher storage cells in liver, lung and spleen. Treatment also corrected the abnormal pathology, cell differentials and MIP-1 levels in the lungs of the D409V/null mice in a dose-dependent manner. Additionally, no antibodies to GC were detected, in accordance with previous AAV gene therapy studies using hepatocyte-restricted promoters. These data demonstrate the effectiveness of AAV-mediated gene therapy at preventing and correcting the biochemical and pathological abnormalities in the mouse model and thus support its continued development in the treatment of Gaucher Disease.

The treatment of Gaucher disease in countries with limited health care resources

The treatment of Gaucher disease in countries with limited health care resources