Results: At baseline, all patients were wheelchair bound. Seventeenrequired respiratory assistance: 9 invasive, 7 non-invasive, 1 combinedinvasive and non-invasive ventilation. Mean age at ERT initiationwas 30.8 ± 14.3 years. Treatment duration ranged from 8 to 75.6months. Ten of 17 patients demonstrated improvements in respiratoryfunction, including a 50% reduction in ventilation for one patient.Motor function improved in 13 of 18 patients and stabilized in theremaining 5 patients; no declines in muscle strength or tone were noted.Most patients (15/16) reported positive improvements in their quality oflife since commencing ERT. Treatment was well-tolerated, with onlyone report of a transient infusion-associated reaction (chills) duringthe first infusions.

Conclusions: Enzyme replacement therapy for juvenile and adultpatients with severe Pompe disease is associated with gains in both respi-ratory and motor function. Intervention earlier in the disease course wasassociated with greater improvement in clinical parameters. Overall,patients were satisfied with their treatment, and reported positive improve-ments in their quality of life regardless of the magnitude of clinical gains orbaseline disease involvement.

doi:10.1016/j.ymgme.2007.10.114

103. Development of an effective and safe hematopoietic stem cell gene

therapy for globoid cell leukodystrophy: The unexpected issue of GALC

toxicity

Ilaria Visigalli a, Martina Cesani a,c, Margherita Neri a,b, Silvia Ungari b,

Laura Tononi d, Sergio Marchesini d, Manuel Grez e, Angela Gritti a, Luigi

Naldini a, Alessandra Biffi a,b, a San Raffaele Telethon Institute for Gene

Therapy, Milan, Italy, b Vita Salute San Raffaele University, Italy,c Experimental Neurology Institute, Italy, d Department of Biomedical

Science and Biotechnology, University of Brescia, Italy, e Georg Speyer-

Haus, Frankfurt, Germany

Globoid cell leukodystrophy (GLD) or Krabbe disease is an inheritedmetabolic leukodystrophy due to the deficiency of the galactocerebrosi-dase (GALC) activity. Pathology is characterized by extensive accumula-tion of non-metabolized lipid substrates leading to severe and widespreaddemyelination in the central (CNS) and peripheral nervous system (PNS).The prognosis is severe leading to death of affected kids, few years afterthe diagnosis. We are testing the efficacy of a gene therapy strategy basedon hematopoietic stem cells (HSC) transplantation (HSCT) and lentiviralvectors (LV) in the murine models of the disease. The high efficiency ofLV-mediated gene transfer and the possibility of multiple vector integra-tion sites in HSC might allow obtaining a massive expression of GALCin cells and tissues, reaching levels that largely exceed the physiologic ones.We first assessed the feasibility and safety of GALC over-expression inHSC and in their progeny. Colony forming cell and TUNEL assaysshowed an overt and significant toxicity of GALC over-expression inHSC, which determined their inability to proliferate and differentiate,and the occurrence of cell apoptosis. Moreover, GALC-transduced HSCtransplanted into lethally conditioned mice failed to repopulate the host.On the contrary, differentiated hematopoietic cells of the myeloid lineage(monocytes and microglia), which constitute the effector population inHSC-based approaches for the treatment of LSD, are not affected byGALC over-expression. In order to overcome this major limitation, weare developing two alternative strategies. First, we are testing macro-phage/microglia specific promoters, such as CD11b and c-Fes, in orderto prevent GALC over-expression within transduced HSC, while obtain-ing high levels of GALC expression within CNS and PNS infiltratinghematopoietic cells. In vitro experiments showed that these promoterstrigger a good expression of the transgene both in monocytic cell linesand primary culture of microglia, while driving low expression in HSC.Preliminary in vivo data confirmed these findings and long-term studiesare currently on going. An alternative strategy could be the use of aHSC-specific microRNA tag in order to de-target vector expression fromHSC while permitting GALC over-expression in differentiated cells. To

this purpose, potential candidate HSC-specific miRNAs have beenrecently identified.

doi:10.1016/j.ymgme.2007.10.115

104. Increased risk of osteopenic fractures in elderly patients with Gaucher

disease

Neal J. Weinreb, Lisa Costantini, University Research Foundation for

Lysosomal Storage Diseases, Coral Springs, FL, USA

Bone mineral density is decreased in 60% of adults with type 1 Gaucherdisease (GD). In elderly patients, BMD that is ‘‘normal’’ for age may notindicate functionally normal bone strength. Here, we report serial dualenergy X-ray absorptiometry (DXA) scores and fracture (Fx) occurrencefor 29 patients age 57–88 treated with imiglucerase, often in conjunctionwith bisphosphonates.

Results: Lumbar (L) spine Z-scores were mostly normal during 9.2–14.9 years on ERT: median �0.50; centiles 10–90: �1.81.

doi:10.1016/j.ymgme.2007.10.116

105. Effect of enzyme replacement therapy with imiglucerase (Cerezyme.)

every 4 weeks in patients with type I Gaucher disease

Neal Weinreb, on behalf of the CZ-011-01 Study InvestigatorsUniversity

Research Foundation for Lysosomal Storage Disorders, Coral Springs, FL,

USA

Introduction: Intravenous imiglucerase (Cerezyme., Genzyme Corpo-ration) is the current standard treatment for type 1 Gaucher disease(GD1). Most patients are infused every 2 weeks. A less frequent, moreconvenient infusion schedule might be equi-effective and improve qualityof life (QOL).

Objective: To assess the safety, efficacy, and impact on QOL of twodosing frequencies of imiglucerase in patients with GD1.

Methods: A phase IV, multicenter, randomized 24-month clinical trialenrolled clinically stable patients who had received imiglucerase for atleast 2 years. Patients were randomized to continue their total 4-week doseas two infusions every 2 weeks (Q2) or one infusion every 4 weeks (Q4).Definitions of clinical success or failure were based upon hemoglobin level,platelet count, liver and spleen volumes, progression of bone disease, andbone crisis.

Results: For the intention-to-treat population (N = 95), interim resultswere available for 29/33 (89.7%) Q2 patients and 52/62 (83.9%) Q4patients who completed to month 12. One patient in the Q2 arm discon-tinued for non-compliance. Discontinuations due to adverse events werelow (one in Q2; three in Q4). No imiglucerase-related serious events werereported. Mean and standard deviation for 4-week doses (U/kg) were66.8 ± 23.66 (range: 37–116) for Q2 and 68.9 ± 21.77 (range: 32–122)for Q4. Q2/Q4 infusion durations (min/4 weeks) were 183.7 ± 62.05(range: 19–321) and 137.0 ± 57.51 (range: 60–310), respectively.

Conclusions: Twenty-four-month efficacy, safety, and QOL data willbe available for presentation in February 2008.

doi:10.1016/j.ymgme.2007.10.117

106. Natural history of Fabry disease: Progression of the nephropathy in a

large series of affected males and heterozygous females

William Wilcox a, Raphael Schiffmann b, Maryam Banikazemi c, Jan

Bultas d, Gabor Linthorst e, Seymour Packman f, Sven Sorensen g, David

Warnock h, Robert Desnick i, a Cedars-Sinai Medical Center, Los Angeles,

CA, USA, b National Instititues of Health, USA, c New York University,

USA, d Charles University Hospital, USA, e Academic Medical Center,

Abstracts / Molecular Genetics and Metabolism 93 (2008) S14–S46 S41

USA, f University of California, San Francisco, USA, g University of

Copenhagen, USA, h University of Alabama at Birmingham, USA, i Mount

Sinai School of Medicine, New York City, NY, USA

Background: Fabry disease is an X-linked lysosomal storage disorderdue to deficient activity of a-galactosidase A causing progressive accumu-lation of glycolipids, organ damage, and early demise. The progression ofrenal, cardiac, and cerebrovascular disease in affected males and femaleshas not been well characterized.

Methods: An epidemiologic chart review of 447 patients (279 males,168 females) with untreated Fabry disease from 27 expert sites in the Uni-ted States and Europe was performed. Prospectively defined study end-points included renal, cardiac, and cerebrovascular disease progression,and/or death.

Results: The mean rate of estimated GFR (eGFR) decline for males(n = 243) and females (n = 152) who did not reach end stage renal diseasewas �2.93 and �1.02 ml/min/1.73 m2/year, respectively. More rapideGFR decline was noted in patients with proteinuria, baseline eGFR val-ues <60 ml/min/1.73 m2, or hypertension. Advanced Fabry nephropathywas more prevalent and occurred earlier among males than females. Car-diac events, mainly arrhythmias, occurred in 44% of patients with avail-able information. Stroke (10%) or transient ischemic attacks (5%) werealso observed.

Conclusions: Proteinuria and/or reduced eGFR at baseline, and hyper-tension were identified as prognostic factors associated with more rapidprogression of the Fabry nephropathy, and can serve as targets for thera-peutic intervention. The progression rate of Fabry nephropathy increasedwith advancing disease.

doi:10.1016/j.ymgme.2007.10.118

107. Syngeneic bone marrow transplantation in a murine model of muco-

polysaccharidosis type I

Daniel A. Wolf a, Kelly M. Podetz-Pedersen a, Jennifer L. Gori a, Walter

C. Low b, Chester B. Whitley c, R. Scott McIvor a, a Department of

Genetics, Cell Biology, and Development, University of Minnesota-Twin

Cities, Minneapolis, MN, USA, b Department of Neurosurgery, University

of Minnesota-Twin Cities, USA, c Department of Pediatrics, University of

Minnesota-Twin Cities, USA

Mucopolysaccharidosis type I (MPS I) is an autosomal recessive inher-ited disease caused by deficiency of the glycosidase a-L-iduronidase(IDUA). IDUA is required for the degradation of the glycosaminoglycans(GAG) heparan sulfate and dermatan sulfate, and deficiency of theenzyme leads to lysosomal storage buildup of these substrates. Specificmutations in the IDUA gene (e.g., W402X, Q70X) lead to the most severephenotype, Hurler syndrome. Manifestations of severe MPS I begin todevelop within the first 2 years of life, including growth delay, hepato-splenomegaly, skeletal deformities, excess urinary GAG, corneal clouding,and neurological defects. Recently, IDUA-deficient mouse models of MPSI have become available, providing a setting for evaluation of therapeuticapproaches for the treatment of this disease. Currently, the standard ofcare for severe MPS I patients involves allogeneic bone marrow transplan-tation (BMT) using a matched donor. However, therapeutic effectivenessof BMT has not yet been systematically studied in the MPS I mousemodel. Our initial goal in these studies is to determine the level of wild-type donor cell engraftment needed to prevent manifestations of the dis-ease in IDUA�/� recipient animals. Previously, our laboratory reportedconditions for varying the level of donor cell engraftment through a com-bination of mild preconditioning and reduced number of donor marrowcells (Blood 2000; 96: 1334–1341). We have engrafted cohorts of 4- to 9-week-old IDUA�/� animals with wild-type donor marrow at both highlevels (90–100%) and reduced levels (�10%). Donor cell engraftment levelsin all animals are being assessed at regular intervals by flow cytometry.Animals are being assessed for plasma IDUA enzyme activity and urinaryGAG levels as a measure of the overall degree of metabolic correction

achieved. Additionally, the animals are to be evaluated histologically todetermine the effect of donor cell engraftment on the accumulation of stor-age materials in different tissues, and are also being subjected to neurolog-ical behavior analysis to determine the clinical effect of donor cellengraftment on the central nervous system. Results from this study willprovide validation for the MPS I mouse as a model for the further devel-opment of cellular therapies in the treatment of this disease, including thedevelopment of genetic therapies involving ex vivo or in vivo transductionof autologous hematopoietic stem cells.

doi:10.1016/j.ymgme.2007.10.119

108. Challenges of LSD treatment: The patient experience

Durhane Wong-Rieger a, Adrian Koning b, a Canadian Organization for

Rare Disorders, Toronto, Ont., Canada, b Canadian Fabry Association,

Canada

Therapies for lysosomal storage disorders offer tremendous hope inreducing symptoms, improving quality of life, and halting disease progres-sion but also present significant challenges in terms of access and manage-ment. As patient groups supporting families, the Canadian Organizationfor Rare Disorders and the Canadian Fabry Association, with the Cana-dian Lysosomal Storage Disease Network, undertook a survey to under-stand the patient experience with these therapies.

Patients and family members were recruited through patient groups,clinics, and companies. Diseases included: Gaucher’s, Fabry’s, MPS I,MPS II, MPS VI, Pompi’s, Tay-Sachs and Neiman Pick. Participants wereinterviewed in person or by phone using a semi-structured format.

Given the relatively limited and short-term experience with these ther-apies, our goal was to document common and unique challenges relevant tofour phases of patient experience: diagnosis, starting treatment; managingtreatment, and discontinuing treatment. Patients were asked about theirdecision to start therapy, impact of therapy on patient and family, and con-cerns about long-term outcomes that affect staying on therapy. There werecommon patterns of response across the various diseases. Key factors influ-encing the starting experience were: eligibility for clinical trials or compas-sionate access, age of diagnosis and disease progression, access to therapy,and relationship to physician. Among factors influencing therapy manage-ment were: proximity to clinic, perceived burden of therapy includingadverse events, and availability of psycho-social support. Finally, discon-tinuation of therapy was a relatively uncommon and unique experience.For all phases, family support was key to management.

doi:10.1016/j.ymgme.2007.10.120

109. Observed changes in behaviour with assessment and procedures in

neurologically affected boys with mucopolysaccharidosis type II undergoing

enzyme replacement therapy

Michelle Wood, Niamh Finnegan, Ashok Vellodi, Great Ormond Street

Hospital London, London, UK

Introduction: Challenging behaviour is a common symptom in MPStype II with neurological symptoms. This can make assessment very diffi-cult. Physiotherapy assessment of function and nursing procedures are avery important part of management of this condition.

We have observed that boys on enzyme replacement have becomemuch more co-operative. It is possible that enzyme replacement therapymay be contributing to this behavioural improvement.

Methods: Three boys with MPS II, of similar age and disease presen-tation, have been closely followed from baseline assessment (pre-enzymetreatment). Assessments and procedures have been graded according toease of interaction, co-operation, participation and tolerance of handling.

Results: At baseline all three boys exhibited challenging behaviour,ranging from aggression, being difficult to direct, non-compliance with

S42 Abstracts / Molecular Genetics and Metabolism 93 (2008) S14–S46