AAVrh10-SGSH intracerebral gene therapy corrects the defect and improves the health status in mucopolysaccharidosis type IIIa

AAVrh10-SGSH intracerebral gene therapy corrects the defect and improves the health status in mucopolysaccharidosis type IIIa

S90 Abstracts / Molecular Genetics and Metabolism 114 (2015) S11–S130 was found between the ECLIA and ELISA Ab titers. A similar enzymatic assay was...

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S90

Abstracts / Molecular Genetics and Metabolism 114 (2015) S11–S130

was found between the ECLIA and ELISA Ab titers. A similar enzymatic assay was used to characterize the neutralizing antibodies at both facilities. Among the 48 samples tested for NAb activity at both facilities, 85% had the same NAb status (NAb+ or NAb−). Thirteen percent were tested as NAb+ by LabCorp and NAb− by the sponsor's test facility. Two percent were tested as NAb+ by the sponsor's test facility and NAb− by LabCorp. In summary, the ECLIA method is considerably more sensitive than the original ELISA method to detect anti-idursulfase antibodies. However, their corresponding anti-idursulfase Ab titers are highly correlated with each other. Because the same enzymatic assay was used with minimal changes, the NAb status and titers are highly comparable between the two testing facilities. This study was funded by Shire.

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doi:10.1016/j.ymgme.2014.12.200

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198 AAVrh10-SGSH intracerebral gene therapy corrects the defect and improves the health status in mucopolysaccharidosis type IIIa Samantha Parker, Michaël Hocquemiller, Alice le Meur, Lysogene, Paris, France

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Mucopolysaccharidosis type IIIA (MPS IIIA) is a lysosomal disorder caused by mutations in N-sulfoglucosamine sulfohydrolase (SGSH), resulting in heparan sulphate (HS) accumulation and progressive neurodegeneration. There is currently no treatment. The main focus of research is the central nervous system (CNS) which is challenging because therapies delivered to the vascular system generally do not cross the blood–brain barrier. Our approach is intracerebral gene therapy. The efficacy of AAV serotype rh.10 carrying the human SGSH cDNA has been demonstrated in the MPS IIIA mouse model. The toxicity has been examined in rats and juvenile dogs. A Phase I/II clinical non-comparative, open-label study in 4 children with MPS IIIA (Protocol No.: P1-SAF-301, EudraCT No.: 2010-019962-10) has been completed with the primary objective to assess the tolerance and safety. A secondary objective was the collection of data to determine potential future efficacy endpoints. The study showed that the treatment was safe and well-tolerated after one year by the four children. All patients showed improvement in behavioural disorders, hyperactivity and sleep disorders (Tardieu et al., 2013, Human Gene Therapy). Furthermore a cognitive enhancement was suggested by neurocognitive evaluation in the youngest child at one year but not sustained at two years post treatment. Lysogene's AAVrh.10-SGSH has an orphan drug status in Europe and the US. A phase II/III multi-centric clinical study in Europe and the USA is planned to start in 2015. The trial will be an open-label, single arm intracerebral administration of AAV serotype rh.10 carrying the human SGSH cDNA in at least 12 patients. The clinical sites and MPS patient/parent associations will implement a specific programme to accompany patients and their families to access the trial from non-trial countries. Our development plan includes the setting up of a multi-centre natural history study in untreated patients with data variables consistent with those used in the clinical development programme. Data access and governance will be designed so that other research groups can use the same core data sets for their treatment development plans in MPS IIIA, thereby avoiding duplication and improving sustainability for long-term collection. The results of these studies will be used to file an application for registration to the regulatory authorities. Reference Tardieu et al (2014). Intracerebral Administration of Adeno-Associated Viral Vector Serotype rh.10 Carrying Human SGSH and SUMF1 cDNAs in Children with Mucopolysaccharidosis Type IIIA Disease: Results of a Phase I/II Trial. Human Gene Therapy 25:1-1.

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doi:10.1016/j.ymgme.2014.12.199

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197 A comparison study of methods for detection and characterization of anti-idursulfase antibodies Luying Pan, Kelly Hilton, Thomas McCauley, Ann Barbier, Yongchang Qiu, Shire, Lexington, MA, USA

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The anti-idursulfase antibodies in patients with Hunter syndrome receiving weekly intravenous infusion of idursulfase (Shire, Lexington, MA, USA) are monitored with an enzyme-linked immunosorbent assay (ELISA)-based tiered approach. Recently, an electrochemiluminescent immunoassay (ECLIA)-based approach with a simpler testing scheme was developed by Shire and validated at a contract research organization (LabCorp) to replace the original ELISA-based assay scheme (performed at the sponsor's testing facility). This study assesses the degree of correlation and agreement between these two methods by comparing their corresponding antiidursulfase antibody (Ab) status, titers, and neutralizing Ab (NAb) status. Samples were collected from patients with Hunter syndrome receiving weekly intravenous infusion of idursulfase and their immunogenicity was monitored with a tiered approach as part of the safety assessment. For this investigation, we used a subset from those samples. Among the 120 samples tested for anti-idursulfase antibodies, the majority (85%) had the same antibody status (Ab+ or Ab−) by both ELISA and ECLIA methods; 14% were confirmed as positive by ECLIA but negative by ELISA; and only 0.8% were confirmed as positive by ELISA but negative by ECLIA. The ECLIA method was estimated to be approximately 200-fold more sensitive than the ELISA method, and the anti-idursulfase Ab titers by ECLIA were considerably higher than their corresponding titers by ELISA. Nevertheless, when compared by the Spearman rank correlation test, a highly significant correlation (correlation coefficient Rs = 0.93)

doi:10.1016/j.ymgme.2014.12.201