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Background The goal of gene therapy for patients with hemophilia A is to safely impart long-term stable factor VIII expression that predictably ameliorates bleeding with the use of the lowest possible vector dose. Methods In this phase 1-2 trial, we infused an investigational adeno-associated viral (AAV) vector (SPK-8011) for hepatocyte expression of factor VIII in 18 men with hemophilia A. Four dose cohorts were enrolled; the lowest-dose cohort received a dose of 5 × 1011 vector genomes (vg) per kilogram of body weight, and the highest-dose cohort received 2 × 1012 vg per kilogram. Some participants received glucocorticoids within 52 weeks after vector administration either to prevent or to treat a presumed AAV capsid immune response. Trial objectives included evaluation of the safety and preliminary efficacy of SPK-8011 and of the expression and durability of factor VIII. Results The median safety observation period was 36.6 months (range, 5.5 to 50.3). A total of 33 treatment-related adverse events occurred in 8 participants; 17 events were vector-related, including 1 serious adverse event, and 16 were glucocorticoid-related. Two participants lost all factor VIII expression because of an anti-AAV capsid cellular immune response that was not sensitive to immune suppression. In the remaining 16 participants, factor VIII expression was maintained; 12 of these participants were followed for more than 2 years, and a one-stage factor VIII assay showed no apparent decrease in factor VIII activity over time (mean [±SD] factor VIII activity, 12.9±6.9% of the normal value at 26 to 52 weeks when the participants were not receiving glucocorticoids vs. 12.0±7.1% of the normal value at >52 weeks after vector administration; 95% confidence interval [CI], -2.4 to 0.6 for the difference between matched pairs). The participants had a 91.5% reduction (95% CI, 88.8 to 94.1) in the annualized bleeding rate (median rate, 8.5 events per year [range, 0 to 43.0] before vector administration vs. 0.3 events per year [range, 0 to 6.5] after vector administration). Conclusions Sustained factor VIII expression in 16 of 18 participants who received SPK-8011 permitted discontinuation of prophylaxis and a reduction in bleeding episodes. No major safety concerns were reported. (Funded by Spark Therapeutics and the National Heart, Lung, and Blood Institute; ClinicalTrials.gov numbers, NCT03003533 and NCT03432520.).

The prevalence of enteric pathogen detection in children in low-income countries climbs rapidly between birth and 6 months of age. Few studies have tested whether improved household environmental and behavioral hygiene conditions protects infants from exposure to enteric pathogens spread via unhygienic human and animal sanitation conditions, especially during this early window of infancy. This cross-sectional study utilized enrollment survey data among households with 6 month old infants in Kisumu, Kenya participating in the Safe Start cluster-randomized controlled trial to estimate associations between household water access and treatment, animal vectors, sanitation access, hand washing practices, supplemental feeding, and flooring, with the outcomes of caregiver-reported 7-day diarrhea prevalence and sum count of different enteric viruses, bacteria, and parasites pathogens in infant stool. Then, we tested whether household environmental hygiene and behavioral practices moderated associations between infant exposure outcomes and latrine access and domestic animal co-habitation. We found that reported handwashing after handling animals and before eating were strongly associated with lower risk of caregiver-reported diarrhea, while owning and co-habitating with animals (versus no animals), living in a household with vinyl covered dirt floors (versus finished floors), and feeding infants cow milk (versus no milk) were strongly associated with pathogen detection in infants. Caregiver handwashing after child or self-defecation moderated the relationship between shared sanitation (vs private) sanitation access and infant exposure to pathogens such that handwashing had the greatest benefit for preventing pathogen exposure of infants in households with private latrines. In the absence of handwashing, access to private sanitation posed no benefits over shared latrines for protecting infants from exposure. Our evidence highlights eliminating animal co-habitation, improving flooring, improving post-defecation and food-related handwashing, and improving safety of cow milk sources and/or safe household storage of milk as interventions to prevent enteric pathogen exposure of infants less than 6 months age.Key QuestionsWhat is already known?The population prevalence of enteric infections and diarrhea climbs rapidly in the first year of life. Risk factors for pediatric infections include unhygienic human and animal sanitary conditions that introduce feces into the environment, as well as intermediate environmental and behavioral exposure pathways. Research examining the mitigating role of improved environmental and behavioral conditions in preventing infant exposure to human and animal sanitary conditions is limited.What are the new findings?Contact with domestic animals and feeding infants cow milk are leading risk factors for exposure to enteric pathogens by 6 months age in Kisumu, while handwashing after animal handling and before eating are protective factors against self-reported diarrhea. The benefits of access to a private improved latrine (versus shared) for protecting infants from pathogen exposure were conditional upon caregivers washing hands after defecation or child-defecation.What do the new findings imply?Interventions that keep animals out of infant living spaces and that improve food-related and post-defecation handwashing may be the most effective strategies for controlling the population prevalence of enteric infections in infants between birth and 6 months age in Kisumu and similar settings.

BackgroundCD20 depletion is a highly-effective treatment for relapsing multiple sclerosis that maintains B cells at low levels through six monthly dosing of 600mg ocrelizumab. This dosing schedule is associated with inhibition of seroconversion following SARS-CoV-2 vaccination, in contrast to the high levels of seroconversion following treatment with alemtuzumab and cladribine tablets. A number of emerging reports suggest that repopulation of 1-3% B cells facilitates seroconversion after CD20-depletion. The frequency of this occurring following repeated ocrelizumab treatment, after other DMT, and after treatment cessation is largely unknown.MethodsRelapse data, lymphocyte and CD19 B cell numbers were extracted from phase II ocrelizumab extension study (NCT00676715) data supplied by the manufacturer via the Vivli Inc, trial data-request portal. Repopulation data of oral cladribine from the phase III CLARITY study (NCT00213135) was supplied by the European Medicines Agency; and the alemtuzumab phase III CARE-MS I (NCT00530348) and CARE-MS II (NCT00548405) trial data were supplied by the manufacturer via the clinicalstudydatarequest.com portal.ResultsOnly 3-5% of people with MS exhibit 1% B cells at 6 months after the last infusion following 3-4 cycles of ocrelizumab, compared to 50-55% at 9 months, and 85-90% at 12 months. During this time relapses occurred at consistent disease breakthrough rates compared to people during standard therapy. In contrast most people (90-100%) exhibited more than 1% B cells during treatment with either cladribine or alemtuzumab.ConclusionsFew people repopulate peripheral B cells with standard ocrelizumab dosing, however an extending the dosing interval by 3-6 months may allow many more people to potentially seroconvert in the relative absence of excess relapse-activity. Most people demonstrate B cell repletion within 3 months of the last treatment of alemtuzumab and cladribine. This may help protect against severe COVID-19.

Objective: To report on safety and effectiveness of subcutaneous cladribine (Litak®) in multiple sclerosis (MS) patients. Methods: Litak® was offered to MS-patients irrespective of disease course. Litak® 10 mg was administered for 3–4 days during week 1. Based on lymphocyte count at week 4, patients received another 0–3 doses at week 5. A second course was administered 11 months later. Follow-up included adverse events, relapses, expanded disability status scale (EDSS), 9-hole-peg and Timed-25-foot-walking tests, no-evidence-of-disease-activity (NEDA), no-evidence-of-progression-or-active-disease (NEPAD), MRI, cerebrospinal fluid (CSF) neurofilament light chain (NfL), and lymphocyte counts. Results: In all, 208 patients received at least one course of treatment. Age at baseline was 44 (17–72) years and EDSS 0–8.5. Cladribine was generally well tolerated. One myocardial infarction, one breast cancer, and three severe skin reactions occurred without long-term sequelae. Two patients died (one pneumonia, one encephalitis). Lymphopenia grade 3 occurred in 5% and grade 4 in 0.5%. In 94 out of 116 pwMS with baseline and follow-up (BaFU) data after two treatment courses, EDSS remained stable or improved. At 18 months, 64% of patients with relapsing MS and BaFU data ( n = 39) had NEDA. At 19 months, 62% of patients with progressive MS and BaFU data ( n = 13) had NEPAD. Of n = 13 patients whose CSF-NfL at baseline was elevated, 77% were normalised within 12 months. Conclusions: Litak® was well tolerated. Effectiveness in relapsing MS appeared similar to cladribine tablets and was encouraging in progressive MS. Our data suggest cladribine may be safe and effective in MS-patients irrespective of their disease stage.

Diarrhoeal disease remains a leading cause of mortality and morbidity worldwide. Cholera alone is estimated to cause 95,000 deaths per year, most of which occur in endemic settings with inadequate water access. Whilst a global strategy to eliminate cholera by 2030 calls for investment in improved drinking water services, there is limited rigorous evidence for the impact of improved water supply on endemic cholera transmission in low-income urban settings. Our protocol is designed to deliver a pragmatic health impact evaluation of a large-scale water supply intervention in Uvira (Democratic Republic of the Congo), a cholera transmission hotspot.A stepped-wedge cluster randomised trial (SW-CRT) was designed to evaluate the impact of a large-scale drinking water supply intervention on cholera incidence among the 280,000 inhabitants of Uvira. The city was divided into 16 clusters, where new community and household taps will be installed following a randomised sequence over a transition period of up to 8 weeks in each cluster. The primary trial outcomes are the monthly incidence of "confirmed" cholera cases (patients testing positive by rapid detection kit) and of "suspected" cholera cases (patients admitted to the cholera treatment centre). Concurrent process and economic evaluations will provide further information on the context, costs, and efficiency of the intervention.In this protocol, we describe a pragmatic approach to conducting rigorous research to assess the impacts of a complex water supply intervention on severe diarrhoeal disease and cholera in an unstable, low-resource setting representative of cholera-affected areas. In particular, we discuss a series of pre-identified risks and linked mitigation strategies as well as the value of combining different data collection methods and preparation of multiple analysis scenarios to account for possible deviations from the protocol. The study described here has the potential to provide robust evidence to support more effective cholera control in challenging, high-burden settings.This trial is registered on clinicaltrials.gov ( NCT02928341 , 10th October 2016) and has received ethics approval from the London School of Hygiene and Tropical Medicine (8913, 10603) and from the Ethics Committee from the School of Public Health, University of Kinshasa, Democratic Republic of the Congo (ESP/CE/088/2015).RESUME (VERSION FRANçAISE): Please note this translation has been generated by the authors and has not been checked against the original, peer-reviewed English version by the Journal. Any discrepancies between the two versions should be raised with the authors. Cette traduction a été préparée par les auteurs et sa conformité avec la version anglaise revue par les pairs n’a pas été vérifiée par le journal. Toute différence entre les deux versions doit être signalée aux auteurs. INTRODUCTION: Les maladies diarrhéiques restent une cause majeure de mortalité et morbidité dans le monde. Le choléra seul cause environ 95’000 morts par an, dont la plupart dans des contextes endémiques où l’accès à l’eau est inadéquat. Tandis qu’une stratégie globale pour l’élimination du choléra d’ici à 2030 appelle des investissements dans l’amélioration des services d’approvisionnement en eau, il y a peu de données probantes et rigoureuses sur l’impact d’un approvisionnement en eau amélioré sur la transmission endémique du choléra dans les contextes urbains à faibles ressources. Notre protocole d’étude est conçu pour livrer une évaluation d’impact épidémiologique pragmatique d’une intervention d’approvisionnement en eau à large échelle à Uvira, République Démocratique du Congo, un point focal de transmission du choléra. MéTHODES/CONCEPTION: Un essai randomisé par grappes par échelons (stepped-wedge cluster randomised trial, SW-CRT) a été conçu pour évaluer l’impact d’une intervention d’approvisionnement en eau potable à large échelle sur l’incidence du choléra parmi les 280'000 habitants d’Uvira. La ville a été divisée en 16 grappes, dans lesquelles de nouvelles bornes fontaines et branchements individuels seront installés suivant une séquence randomisée sur une période allant jusqu’à 8 semaines par grappe. Le principal résultat de l’essai sera l’incidence mensuelle des cas de choléra « confirmés » (patients positifs par tests de détection rapide) et des cas « suspects » (patients admis au centre de traitement du choléra). Des évaluations de processus et économique menées en parallèle fourniront des informations complémentaires sur le contexte, les coûts et l’efficience de l’intervention. DISCUSSION: Dans ce protocole, nous présentons une approche pragmatique pour effectuer une recherche rigoureuse visant à évaluer les impacts d’une intervention complexe d’approvisionnement en eau sur la diarrhée sévère et le choléra dans un contexte instable et à faibles ressources, représentatif des zones affectées par le choléra. En particulier, nous considérons une série de risques pré-identifiés et les stratégies de mitigation associées ainsi que la valeur de combiner différentes méthodes de collecte de données et de préparer de multiples scénarios d’analyse pour tenir compte d’éventuelles déviations du protocole. L’étude présentée ici a le potentiel de fournir des évidences scientifiques robustes pour soutenir des stratégies de contrôle du choléra plus efficientes dans les contextes difficiles qui sont fortement affectés. ENREGISTREMENT DE L’ESSAI: Cet essai est enregistré sur clinicaltrials.gov ( NCT02928341 , 10 octobre 2016) et a reçu les approbations éthiques de la London School of Hygiene and Tropical Medicine (8913, 10603) ainsi que de l’Ecole de Santé Publique de l’Université de Kinshasa, République Démocratique du Congo (ESP/CE/088/2015).

We conducted a controlled before-and-after trial to evaluate the impact of an onsite urban sanitation intervention on the prevalence of enteric infection, soil transmitted helminth re-infection, and diarrhea among children in Maputo, Mozambique. A non-governmental organization replaced existing poor-quality latrines with pour-flush toilets with septic tanks serving household clusters. We enrolled children aged 1-48 months at baseline and measured outcomes before and 12 and 24 months after the intervention, with concurrent measurement among children in a comparable control arm. Despite nearly exclusive use, we found no evidence that intervention affected the prevalence of any measured outcome after 12 or 24 months of exposure. Among children born into study sites after intervention, we observed a reduced prevalence of Trichuris and Shigella infection relative to the same age group at baseline (

MRI-derived features of presumed cerebral small vessel disease are frequently found in Alzheimer’s disease. Influences of such markers on disease-progression measures are poorly understood. We measured markers of presumed small vessel disease (white matter hyperintensity volumes; cerebral microbleeds) on baseline images of newly enrolled individuals in the Alzheimer’s Disease Neuroimaging Initiative cohort (GO and 2) and used linear mixed models to relate these to subsequent atrophy and neuropsychological score change. We also assessed heterogeneity in white matter hyperintensity positioning within biomarker abnormality sequences, driven by the data, using the Subtype and Stage Inference algorithm. This study recruited both sexes and included: controls: [n = 159, mean(SD) age = 74(6) years]; early and late mild cognitive impairment [ns = 265 and 139, respectively, mean(SD) ages =71(7) and 72(8) years, respectively]; Alzheimer’s disease [n = 103, mean(SD) age = 75(8)] and significant memory concern [n = 72, mean(SD) age = 72(6) years]. Baseline demographic and vascular risk-factor data, and longitudinal cognitive scores (Mini-Mental State Examination; logical memory; and Trails A and B) were collected. Whole-brain and hippocampal volume change metrics were calculated. White matter hyperintensity volumes were associated with greater whole-brain and hippocampal volume changes independently of cerebral microbleeds (a doubling of baseline white matter hyperintensity was associated with an increase in atrophy rate of 0.3 ml/year for brain and 0.013 ml/year for hippocampus). Cerebral microbleeds were found in 15% of individuals and the presence of a microbleed, as opposed to none, was associated with increases in atrophy rate of 1.4 ml/year for whole brain and 0.021 ml/year for hippocampus. White matter hyperintensities were predictive of greater decline in all neuropsychological scores, while cerebral microbleeds were predictive of decline in logical memory (immediate recall) and Mini-Mental State Examination scores. We identified distinct groups with specific sequences of biomarker abnormality using continuous baseline measures and brain volume change. Four clusters were found; Group 1 showed early Alzheimer’s pathology; Group 2 showed early neurodegeneration; Group 3 had early mixed Alzheimer’s and cerebrovascular pathology; Group 4 had early neuropsychological score abnormalities. White matter hyperintensity volumes becoming abnormal was a late event for Groups 1 and 4 and an early event for 2 and 3. In summary, white matter hyperintensities and microbleeds were independently associated with progressive neurodegeneration (brain atrophy rates) and cognitive decline (change in neuropsychological scores). Mechanisms involving white matter hyperintensities and progression and microbleeds and progression may be partially separate. Distinct sequences of biomarker progression were found. White matter hyperintensity development was an early event in two sequences., Fiford et al. report that presumed small vessel disease markers (white matter hyperintensities and cerebral microbleeds) independently predict increased brain atrophy and cognitive decline. Data-driven analysis of sequences of biomarker abnormality identified distinct groups, two of which had white matter hyperintensity development as an early event., Graphical Abstract Graphical Abstract

Background : In multiple sclerosis (MS) neurofilament light chain (NfL) is a marker of neuronal damage secondary to inflammation and neurodegeneration. NfL levels drop after commencement of disease-modifying treatment, especially the highly active ones. However, the factors that influence this drop are unknown. Objective : To examine the patient and treatment-related factors that influence CSF NfL before and after starting treatment. Methods : Eligible patients across two centres with two CSF NfL measurements, clinical and MRI data were included as part of an observational cohort study. Results : Data were available in 61 patients, of which 40 were untreated at the first CSF sampling (T1) and treated at the second (T2; mean T1-T2: 19 months). CSF NfL reduction correlated with age (beta=1.24 95%CI(1.07,1.43); R2=0.17; p=0.005), Expanded Disability Status Scale (EDSS) (beta=1.12 95%CI(1.00,1.25); R2=0.21; p=0.05) and the type of MS (beta=0.63 95%CI(0.43, 0.92); R2=0.12; p=0.018; reference=relapsing MS). The treatment effect on a baseline NfL of 702 pg/mL was 451 pg/ml 95%CI(374,509) in a 30-year-old versus 228 pg/ml 95%CI(63,350) in a 60-year-old. There was no association in CSF NfL reduction with BMI, disease duration or sex. In cladribine- and alemtuzumab-treated patients, the CSF NfL T2/T1 ratio did not correlate with lymphocyte depletion rate at 23 weeks. Conclusions : In this observational study, we found that factors reflecting early disease stage, including a younger age, lower disability and relapsing MS were associated with treatment response in CSF NfL. Other factors were not found to be related, including lymphopaenia in highly-active treatments.

Introduction Within CF-EpiNet; Harnessing Data to Improve Lives (a CF Trust funded Strategic Research Centre) we will investigate relationships of lung function in early childhood with growth patterns (here considered as change in weight) before the age of five years. We use flexible longitudinal modelling methods to describe early growth trajectories, and identify factors associated with suboptimal growth. Methods Growth measurements from diagnosis to five years were extracted from two national CF registries: UK (n=2999, years 2007–2015) and Canada (n=2690, years 1990–2013). SITAR (super-imposition by translation and rotation) was used to model weight (kg) over the 5 years. Output parameters were average growth curve, summaries of growth velocity and overall weight. Associations of growth and growth velocity with sex, genotype and new born screening (NBS) were investigated. Results Most children in the UK had been diagnosed early in life (median age of diagnosis 0.06 years; inter quartile range 0.03 to 0.1) by NBS. 52% were homozygous for deltaF508. Despite similar initial average weight in boys and girls, males were heavier than females over the first five years. Children homozygous for deltaF508 were lighter than other children. No tested factor was associated with velocity of weight gain. Only 10% of the Canadian children were diagnosed by NBS, and, overall, the age at diagnosis was later (median 0.17 years; inter quartile range 0.08 to 0.53). Over the first five years, Canadian CF children were lighter than those in the UK (figure 1). Associations of weight with sex and genotype were similar to those seen in the UK. In addition, we observed that those diagnosed by NBS were heavier than those who were not. Conclusions In children with CF there are sex differences in weight during the first 5 years, despite similar initial weight. In Canada, NBS has a positive impact on early growth. SITAR allows exploration of growth patterns in CF patients, but time independent characteristics were not associated with velocity of growth. Statistical modelling incorporating time dependent factors (e.g., infections, treatments) are required to explain variability of growth trajectories.

Background: Case-mix classification is a focus of international attention in considering how best to manage and fund services, by providing a basis for fairer comparison of resource utilization. Yet there is little evidence of the best ways to establish case mix for child and adolescent mental health services (CAMHS).Aim: To develop a case mix classification for CAMHS that is clinically meaningful and predictive of number of appointments attended and to investigate the influence of presenting problems, context and complexity factors and provider variation.Method: We analysed 4573 completed episodes of outpatient care from 11 English CAMHS. Cluster analysis, regression trees and a conceptual classification based on clinical best practice guidelines were compared regarding their ability to predict number of appointments, using mixed effects negative binomial regression.Results: The conceptual classification is clinically meaningful and did as well as data-driven classifications in accounting for number of appointments. There was little evidence for effects of complexity or context factors, with the possible exception of school attendance problems. Substantial variation in resource provision between providers was not explained well by case mix.Conclusion: The conceptually-derived classification merits further testing and development in the context of collaborative decision making.

Gene transfer for hemophilia A offers the potential for a one-time disease altering treatment, eliminating the risk of bleeds while freeing patients from the burden of lifelong chronic therapy. SPK-8011 consists of a bioengineered AAV capsid expressing B domain-deleted factor VIII (FVIII) under the control of a liver-specific promoter. In pre-clinical studies, we showed a dose-dependent increase in circulating FVIII levels in non-human primates infused with SPK-8011. We conducted a Phase I/II study of SPK-8011 in 12 men (ages 18-52 years) with severe (n=11) or moderately severe (n=1) hemophilia A. Prior to gene therapy, 8/12 subjects were on prophylaxis, and 4/12 received on-demand treatment. Subjects were enrolled in 1 of 3 dose cohorts, 5E11 vg/kg (n=2), 1E12(n=3), or 2E12(N=7). Safety analysis showed no inhibitor formation. A single serious adverse event (SAE) was reported, associated with an immune response to AAV capsid characterized by simultaneous decline in FVIII, transaminase elevation peaking at Grade 2, and development of positive IFN-g ELISPOTs to capsid was observed beginning at week 6.5 after vector infusion. The asymptomatic transaminase elevation did not respond promptly to initiation of oral steroids and the subject received two infusions of IV methylprednisolone in hospital, thereby fulfilling SAE criteria. The SAE has resolved. All vector doses led to expression of FVIII levels adequate to prevent bleeding and allow cessation of prophylaxis. Across the 12 subjects at 3 doses, there was a 97% reduction in annualized bleeding rate (ABR), and a 97% reduction in annualized infusion rate (AIR). In the 5E11 dose cohort, mean FVIII levels beginning 12 weeks post vector infusion are 13%, with no bleeding events, no elevated transaminase levels, no use of steroids, and stable FVIII expression out to 66 weeks (ongoing). In the 1E12 dose cohort, mean FVIII levels are 15% beginning at 12 weeks post-infusion and stable out to 46 weeks (ongoing). The first subject in the 1E12 dose infused a single dose of factor concentrate for a spontaneous joint bleed at day 159, and the second received multiple infusions for a traumatic bleed beginning at day 195. Declining FVIII levels triggered initiation of a course of tapering steroids in both subjects, at 12 and 7 weeks post vector infusion respectively, which led to stabilization of FVIII levels. The third subject has had no bleeding and did not receive factor infusions or steroids. In the 2E12 (highest) dose cohort, 5/7 subjects currently have FVIII levels 16-49%; their mean FVIII level beginning 12 weeks post-infusion is 30%. No bleeds have been reported among these subjects beginning 4 weeks post vector infusion. Additionally, 5/7 subjects in the 2E12 dose cohort received a course of steroids, initiated at 6-11 weeks post vector infusion, for one or more of the following: declining FVIII levels, rise in ALT above subject baseline, or elevated IFN-g ELISPOTs to AAV capsid. Steroid initiation normalized ALT levels and extinguished the ELISPOT signal in all cases; 2 subjects showed limited stabilization of FVIII levels, which fell to Our data indicate that the kinetics of SPK-8011 expression are similar to those observed with investigational SPK-9001 for hemophilia B. All subjects demonstrated durable transgene expression for up to 66 weeks post vector administration (data cutoff 7/13/18). On cumulative follow up of 345 weeks, SPK-8011 demonstrated a favorable safety profile with no evidence of FVIII inhibitor formation, a single SAE, and 2/12 subjects who experienced ALT elevation above the upper limit of normal that resolved with steroid initiation. Data from the 5E11 (lowest) dose cohort are consistent with published natural history data indicating FVIII:C 12% is adequate to prevent spontaneous bleeding events. Given that 2 subjects in the 2E12 dose cohort lost some FVIII expression, which then stabilized on steroids, and 5/7 subjects in this cohort required steroids, prophylactic steroids may be warranted. We conclude that infusion of SPK-8011 in 12 subjects with severe or moderately severe hemophilia A resulted in safe, durable, dose-dependent FVIII expression resulting in an excellent preliminary efficacy profile with an overall 97% reduction in ABR and AIR. Disclosures High: Spark Therapeutics: Employment, Equity Ownership, Patents & Royalties. George:University of Pennsylvania: Equity Ownership; Pfizer: Consultancy. Ragni:CSL Behring: Research Funding; Alnylam: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sangamo: Research Funding; Shire: Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Bioverativ: Consultancy, Research Funding; MOGAM: Membership on an entity's Board of Directors or advisory committees; SPARK: Consultancy, Research Funding. Croteau:Novo Nordisk: Consultancy; Octapharma: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding; Spark Therapeutics: Research Funding; Tremeau Pharmaceuticals: Consultancy; Genetech: Consultancy, Research Funding; CSL-Behring: Consultancy; Catalyst Biosciences: Consultancy; Bioveritiv: Consultancy; Biomarin: Consultancy; Bayer: Consultancy; Baxalta/Shire: Consultancy, Research Funding. Joseney-Antoine:Spark Therapeutics: Employment. Macdougall:Spark Therapeutics: Employment. Tompkins:Spark Therapeutics: Employment. Hait:Spark Therapeutics: Employment. Couto:Spark Therapeutics: Employment. Bassiri:Spark Therapeutics: Employment. Valentino:Spark Therapeutics: Employment. Carr:Spark Therapeutics: Employment. Hui:Spark Therapeutics: Employment. Wachtel:Spark Therapeutics: Employment. Takefman:Spark Therapeutics: Employment. Mingozzi:Spark Therapeutics, Inc.: Employment. Anguela:Spark Therapeutics, Inc.: Employment. Reape:Spark Therapeutics: Employment.