BMN 110 (Recombinant Human GALNS), an Investigational Enzyme Replacement Therapy for Mucopolysaccharidosis Type IVA (MPS IVA Or Morquio Syndrome), Promotes Type II Collagen Synthesis in MPS IVA Patients

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Abstracts / Molecular Genetics and Metabolism 105 (2012) S15–S69

activity was confirmed in EW, and subsequent experiments demonstrated the successful integration of rhNAGLU gene and the promoter elements into a single integration site. rhNAGLU purified from EW using column chromatographic methods demonstrated good uptake into fibroblasts from a patient with MPS IIIB deficiency with correction of enzyme deficiency. Conclusions: SBC-103, a rhNAGLU expressed in EW has properties which allow effective lysosomal targeting to key target cells in contrast to enzyme produced using cell culture. These studies indicate that SBC-103 warrants further investigation as a therapy for patients with Sanfilippo syndrome type B. doi:10.1016/j.ymgme.2011.11.104

BMN 110 (Recombinant Human GALNS), an Investigational Enzyme Replacement Therapy for Mucopolysaccharidosis Type IVA (MPS IVA Or Morquio Syndrome), Promotes Type II Collagen Synthesis in MPS IVA Patients Florence Lorget a, Sungwook Lee a, Kelly Lau a, Laurie Tsuruda a, Chris Hendriksz b, Simon Jones c, Ashok Vellodi d, Sabrina cheng a, Celeste Decker a, Charles O'Neill a, aBioMarin Pharmaceuticals Inc., Novato, CA, USA, bBirmingham Children's Hospita, Birmingham, UK, cCentral Manchester University Hospitals, Manchester, UK, dGreat Ormond Street Hospital, London, UK Mucopolysaccharidosis type IVA (MPS IVA) or Morquio syndrome type A, is a lysosomal storage disorder caused by a deficiency of the enzyme N-acetylgalactosamine-6 sulfatase (GALNS) that results in accumulation of glycosaminoglycan keratan sulfate (KS) in hyaline cartilage, tissue macrophages, heart valves and cornea. KS accumulation in the hyaline cartilage leads to a profound skeletal dysplasia attributed to impaired chondrocyte proliferation and differentiation. During the Dose Escalation Phase 1/2 clinical trial, 20 patients, aged 5 to 16 years old, were administered weekly BMN 110 infusions at the 0.1 mg/kg dose level (Weeks 1 to 12), 1 mg/kg dose level (Weeks 13 to 24), 2 mg/kg dose level (Weeks 25 to 36) and 1 mg/kg dose level (Weeks 37 to 72) during the Continuation Period. Type IIA Collagen N propeptide (PIIANP), a marker of collagen type II formation, was assessed in the serum of the patients prior to dosing at baseline and Weeks 13, 25, 37 and 72. A marked increase in mean PIIANP levels in comparison to baseline levels was measured at Week 25 (+39.8%, p = 0.058), Week 37 (+65.6%, p < 0.001) and Week 72 (+84.5%, p < 0.001). As resting and proliferating chondrocytes are the main source of collagen type II, this data suggests that BMN 110 after intravenous infusions distributes to the cartilage and promotes the chondrocyte function, thus potentially improving the systemic skeletal dysplasia in MPS IVA patients. doi:10.1016/j.ymgme.2011.11.105

Evaluation of Plasma Globotriaosylsphingosine in Patients with Anderson-Fabry Disease in Brazil on Enzyme Replacement Therapy with Agalsidase Alfa Charles Lourenco a, Janice Coelho b, Miguel Moyses Neto a, Osvaldo Merege Vieira Neto a, Wilson MarquesJr. a, c, aUniversity of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil, bFederal University of Rio Grande do Sul, Porto Alegre, Brazil, cUniversity of Sao Paulo, Sao Paulo, Brazil Introduction: Anderson-Fabry disease (AFD) is an inherited disorder due to an enzymatic deficiency of alpha-galactosidase activity, resulting in glycosphingolipid accumulation. As enzyme

replacement therapy (ERT) involving recombinant enzyme has been introduced for this disease, finding a reliable surrogate biomarker for monitoring the therapy is very important for evaluation of benefits and better follow-up of patients on ERT. Material and Methods: We studied 6 Fabry disease patients (four males and two females) over a period of 6 months regarding disease progression and clinical outcome under ERT. Plasma globotriaosylsphingosine (lysoGb3) levels were measured in dried blood spots before and 6 months after treatment with agalsidase alfa. Results: Both male and female patients had elevated levels of lysoGb3; in the males subjects, the increase was impressive before starting treatment. After 6 months, plasma lyso Gb3 were reduced in all patients; in males, plasma lyso Gb3 dropped more dramatically than in the females subjects. Pre-treatment plasma lysoGb3 concentrations of Fabry females were relatively low but remained stable or decrease after ERT. At baseline, only only two patients showed abnormal cardiac findings (mild LVH and mitral valvulopathy, respectively). Brain MRI with angiography was abnormal in two patients (multiple hypersignal loci with arterial tortuosity and periventricular white matter changes). Proteinuria and microalbuminuria were present in all patients; after 6 months under ERT, brain MRI changes remained stable and no further kidney deterioration was seen. Cardiac evaluation still showed no abnormal findings in the other patients and remained unchanged in the other two. Conclusion: Our cohort of Anderson-Fabry disease patients showed reduction of plasma lysoGb3 after ERT introduction. Although it was not possible to evaluate differences in other systems because of the short period of observation, our finding confirms previous studies which show that ERT can correct plasma lysoGb3 in Fabry disease patients even in a short period of 6 months. doi:10.1016/j.ymgme.2011.11.106

Niemann-Pick Type C in Brazil: Natural History and Clinical Course in 42 Patients Charles Lourenco a, Fernanda Timm b, Roberto Giugliani b, Wilson MarquesJr. a, aUniversity of Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil, b Federal University of Rio Grande do Sul, Porto Alegre, Brazil Background: Niemann-Pick type C disease (NPC) is a rentless neurodenerative disorder characterized by a defect in cholesterol trafficking; it is a complex disorder with wide range of clinical phenotypes. Here we describe clinical characteristics and natural history of 42 Brazilian NPC patients. Methods: Retrospective study and review of laboratory/neuroimaging data were carried out in NPC patients diagnosed in the last 6 years. Results: Twenty-six patients were confirmed to have NPC by filipin staining (14 patients required molecular analysis). Regarding clinical form, 7 were perinatal, 16 infantile, 11 juvenile and 8 adults. Prolonged neonatal jaundice was a common feature and five of them were diagnosed with “neonatal hepatitis”. Hepatosplenomegaly was present in all perinatal/infantile patients, but absent in 6 adults. Ocular abnormalities were seen in 38 patients (mostly, vertical supranuclear gaze paralysis). Leukoencephalopathy and progressive cerebral/cerebellar atrophy were the main MRI features. Other systemic manifestations included dystonia, cataplexia, immunodeficiency, dysphagia. At the time of the study, 13 patients were deceased. Conclusions: Onset of neurological disease in NPC patients is extremely variable, even in the same sibship. Better understanding of the natural history of the disease is crucial for evaluation of potential therapeutic approaches in such devastating disorder. doi:10.1016/j.ymgme.2011.11.107