Calderón, Enrique

Carrillo-Linares, Juan Luis

Morado, Marta

Morales, Montserrat

Muñoz, Gema

Quintero, Víctor

Torralba, Miguel Angel

Villarrubia, Jesús

Vitoria, Isidro

English

Repositorio Universidad de Zaragoza

subjects with high speed Internet capability in their home. Beforeinitiating virtual visits, the study team determined which activitiescould be completed remotely. An encrypted virtual video platformprovided confidentiality and privacy. Before the virtual researchvisit, a test visit was completed to familiarize subjects with remoteresearch processes. Instructions on using the virtual visit platformwere sent ahead of time, including a study team contact telephonenumber in case problems arose during connecting. Test visitactivities included assessment of audio/video quality and evalua-tion of the home study site. A quiet space, free of distractions andinterruptions in the subject's home was selected with sufficientlighting and appropriate space and positioning for assessment.Seating position was optimized to enhance the examiner's view ofthe subject's face and body, as body language could be missed overvideo. For the research visit, eConsent was obtained utilizingREDCap, a secure website which allowed for synchronous consentreview and sign off. Study team members were scheduled to joinat certain times or kept in a virtual “waiting room” until they wereneeded to reduce visit disruptions. Some subjects opted tocomplete portions of the visit at different times of the day. In the6 months since the beginning of pandemic restriction, we com-pleted 19 virtual study visits across two separate researchprotocols. Virtual visit activities have included neurologic exam,neuropsychological assessment, and administration of a disease-specific rating scale. Future goals include use of wearable devicesand biometric assessments in the home environment. Virtual visitsare a feasible way to continue to engage subjects when travel isimpossible.doi:10.1016/j.ymgme.2020.12.267262Neuro-networks investigating the neurological impairment ofmucopolysaccharidoses using a system biology approachGerda Cristal Villalba Silva, Ursula Matte, Universidade Federal do RioGrande do Sul, Porto Alegre, BrazilMucopolysaccharidoses (MPS) are lysosomal diseases character-ized by defects in the activity of lysosomal hydrolases involved inglycosaminoglycan degradation, with progressive multisystemicinvolvement. Neurological damage is present in MPS I; MPS II; MPSIIIB, and MPS VII. Using biological networks for searching for geneswith functional relevance give us clues about pathophysiologicalmechanisms of neurological diseases. The aims of this work was toidentify potential biomarkers for neurological impairment in differ-ent types of MPS using public available transcriptomic data. The mostrelevant proteins in the networks and ontology terms related toneurological damage in MPS were identified and compared amongdiseases. We performed the clustering analysis for GSE111906(MPSI), GSE95224 (MPSII), GSE23075 (MPSIIIB), GSE15758(MPSIIIB), and GSE76283 (MPSVII). Regarding biomarker discoveryanalysis, the top 10 genes were ranked according to the maximalclique centrality. Different ontologies were present in the differenttypes of MPS. For instance, for MPS I, the related ontologies wereclathrin derived vesicle budding and clathrin-mediated endocytosis.MPS II top genes were related to brain renin-angiotensin system.MPS IIIB top genes comprises the ontologies acetylation andchromatin regulation. The MPS IIIB top 10 genes were related tothe activation of the mRNA cap-binding complex. Finally, MPS VII topgenes were present in the ontologies C-MYB transcription factornetwork. Moreover, we identified several immune system processeslike adaptive and innate immune systems, Class I MHC mediatedantigen processing and presentation; and activated TLR4 signalingacross the different MPS types. Other ontologies were also present inall the MPS types, like axon guidance, Calcium signaling, PI3K-Aktsignaling pathway, and Wnt signaling pathway. We hypothesize thatthese pathways are deranged because glycosaminoglycans play anessential role in the extracellular matrix composition, helping toregulate several processes. System biology approaches may help tounderstand the mechanisms of neuropathology in the different typesof mucopolysaccharidoses.doi:10.1016/j.ymgme.2020.12.268263PREDIGA project: Preliminary results of the Spanish multicenterepidemiological and medical education project in acidsphingomyelinase deficiency disease (ASMD) and Gaucher disease(GD)Jesus Villarrubiaa, Enrique Calderonb, Miguel Angel Torralbac, IsidroVitoriad, Marta Moradoe, Victor Quinteroa, Monserrat Moralesf, JuanLuis Carrillo-Linaresg, Gema Muñozh, aHospital Universitario Ramon yCajal, Madrid, Spain, bHospital Universitario Virgen del Rocio, Sevilla,Spain, cHospital Clinico Universitario Lozano Blesa, Zaragoza, Spain,dHospital Universitari i Politecnic La Fe, Valencia, Spain, eHospitalUniversitario La Paz, Madrid, Spain, fHospital Universitario Doce deOctubre, Madrid, Spain, gHospital Universitario Virgen de la Victoria,Malaga, Spain, hComplejo Hospitalario Universitario A Coruña, ACoruña, SpainIntroductionGD and ASMD are lysosomal disorders caused by deficiency oflysosomal enzymes acid beta-glucosidase and acid Sphingomyelinase.These enzyme deficiencies cause accumulation of glucocerebroside andsphingomyelin, respectively, mainly in macrophages, inducing deterio-ration of the organs in which they accumulate. Theoretical prevalence ofASMD is 0.4 per 100,000 and GD is 1 per 40,000 inhabitants. Theabsence of epidemiological studies in Spain lead us to believe that ASMDis highly underdiagnosed, and that the incidence of GD data is still to bedefined.AimTo put in place a national medical education program to increaseknowledge of the pathophysiology of ASMD and GD, as well asdissemination of diagnostic algorithms for these diseases. An epidemi-ological study of unknown origin splenomegaly was planned as a 3–5years retrospective search and as a 2 years prospect for new patients,implementing the diagnostic algorithms defined for both, ASMD and GD.The epidemiological results obtained will be analysed.MethodsA total of 52 HCPs (22 Hematologists / 18 Internal Medicine / 12Pediatricians) from 34 hospitals in Spain are implementing the medicaleducation program and epidemiological searching in their health area ofinfluence for two consecutive years. It is planned to impart about 100clinical sessions within the medical education program and reach 200Abstracts / Molecular Genetics and Metabolism 132 (2020) S13–S116 S109patients fulfilling diagnostic criteria for ASMD and GD in the recruitmentprocess.ResultsIn the first 6months of the project, 12 educational sessions wereheld with more than 220 assistants (1 GD patient diagnosed) and 39patients with diagnostic criteria were reviewed with the result of 1positive for ASMD and 3 positives for GD.CommentsMedical education plan and epidemiological study have increasedawareness of these conditions allowing the diagnosis of new patientsand can further define the prevalence of these two lysosomal diseases inSpain.doi:10.1016/j.ymgme.2020.12.269264First in-human intracisternal dosing of RGX-111 (adeno-associ-ated virus 9/human α-L-iduronidase) for a 20-month-old childwith mucopolysaccharidosis type I (MPS I): 1 year follow-upRaymond Y. Wanga, Tammam Beydouna, Nina Movsesyanb, Shih-Hsin Kanb, Mery Taylorb, Winnie Stocktonb, Igor Nestrasilc, BryanPukenasd, Paulo Falabellae, Yoonjin Choe, Marie-Laure Névorete,aCHOC Children's Specialists, Orange, CA, United States, bCHOCChildren's Hospital, Orange, CA, United States, cUniversity of Minnesota,Minneapolis, MN, United States, dHospital of the University ofPennsylvania, Philadelphia, PA, United States, eREGENXBIO, Inc., Rock-ville, MD, United StatesMucopolysaccharidosis (MPS) type I is a lysosomal disordercaused by mutations in the IDUA gene and resultant deficiency oflysosomal α-L-iduronidase (IDUA) enzyme. Patients with severe MPS Ihave mutations encoding completely inactive IDUA enzyme, and haveearly-onset developmental delay and cognitive regression in addition tomultisystemic manifestations. Treatment for severe MPS I involvesintravenous recombinant human IDUA (rhIDUA) enzyme infusionsfollowed by stem cell transplant (SCT). However, SCT carries risks ofengraftment syndrome, graft failure, graft-versus-host disease, death,and potentially incomplete correction of neurodevelopmental manifes-tations. We will report one-year follow-up in a child with severe MPS I(IDUA p.R628*/R628*, absent IDUA activity) treated with intracisternalRGX-111 (recombinant adeno-associated virus serotype 9 capsidcontaining the human IDUA expression cassette – AAV9.CB7.hIDUA) atage 21months utilizing a single-patient investigator-initiated investiga-tional new drug application, due to two MPS I-affected older siblingshaving died of SCT-related complications. Following baseline volumetricbrain imaging, the child received a dose of 1 × 1010 genome copies/gbrain mass. Prednisone (12weeks), tacrolimus (32weeks), andsirolimus (48weeks) were administered. As of 8months after dosing,the child has experienced no drug-related serious adverse events.Cerebrospinal fluid (CSF) biomarkers indicated increased IDUA activity(12weeks) over baseline levels below the limit of quantification. Highheparan sulfate (HS) levels in CSF were measured at baseline, and initialdata demonstrated sustained decreases in total HS levels with a 50%reduction from baseline at Week 12 and a 45% reduction from baselineat Week 33. At Week 32 post-administration of RGX-111,neurocognitive evaluations indicated that the patient, who was then29months of age, continued to acquire cognitive developmental skills ata normal rate. Regular biomarker and neurodevelopmental assessmentsare ongoing.doi:10.1016/j.ymgme.2020.12.270265Adults with chronic acid sphingomyelinase deficiency showsignificant visceral, pulmonary, and hematologic improvementsafter enzyme replacement therapy with olipudase-alfa: 1-yearresults of the ASCEND placebo-controlled trialMelissa Wassersteina, Laila Arash-Kapsb, Antonio Barbatoc, Renata C.Gallagherd, Roberto Giuglianie, Norberto B. Guelbertf, Carla Hollakg,Takayuki Ikezoeh, Robin Lachmanni, Oliver Lidovej, Paulina Mabek,Eugen Mengell, Maurizio Scarpam, Ebubekir Senatesn, Michel Tchano,Jesus Villarrubiap, Yixin Chenq, Patricia A. Fraserq, Beth L. Thurbergq,Atef Zaherq, Monica Kumarq, aChildren’s Hospital at Montefiore, AlbertEinstein College of Medicine, Bronx, NY, United States, bUniversityMedical Center Mainz, Mainz, Germany, cFederico II University Hospital,Naples, Italy, dUniversity of California San Francisco, San Francisco, CA,United States, eHospital de Clínicas de Porto Alegre/Federal University ofRio Grande do Sul, Porto Alegre, Brazil, fHospital de Niños de laSantísima Trinidad, Córdoba, Argentina, gAmsterdam University MedicalCenter, University of Amsterdam, Amsterdam, Netherlands, hFukushimaMedical University, Fukushima, Japan, iNational Hospital for Neurologyand Neurosurgery, London, United Kingdom, jLa Croix St Simon Hospital,Paris, France, kClinica Santa Maria, Santiago, Chile, lClinical Science forLysosomal Storage Disorders, SpinCS, Hochheim, Germany, mUniversityHospital of Udine, Udine, Italy, nIstanbul Medeniyet University, Istanbul,Turkey, oWestmead Hospital, Sydney, Australia, pHospital UniversitarioRamón y Cajal, Madrid, Spain, qSanofi Genzyme, Cambridge, MA, UnitedStatesAcid sphingomyelinase (ASM) deficiency (ASMD) is a rare anddebilitating lysosomal disease with no available treatment. ASCEND(NCT02004691/Sanofi Genzyme) is a Phase 2/3, multicenter, ran-domized, double-blind, placebo-controlled trial of olipudase alfa(recombinant human ASM) enzyme replacement therapy in 36adults with chronic visceral ASMD. Inclusion criteria included spleenvolume ≥ 6 multiples of normal (MN), percent-predicted diffusioncapacity for carbon monoxide (DLco) ≤ −70%, and abnormal (≥5)Splenomegaly Related Score (SRS, a patient-reported outcome).Patients were randomized 1:1 to placebo or olipudase alfa (intrave-nous every 2 weeks with a ~ 16-week dose-escalation from 0.1 to3.0 mg/kg or maximum tolerated dose). Independent primaryefficacy endpoints were percent change in percent-predicted DLcoand percent change in spleen volume MN (for the USA, combinedwith change in SRS) at Week 52. Other endpoints included percentchange from baseline in liver volume, platelet count, lipids,chitotriosidase, and lyso-sphingomyelin. Least-square (LS) meandifferences at Week 52 between olipudase alfa and placebo groupsfavored olipudase alfa for percent predicted DLco (+22.0% vs. +3.0%,p= 0.0004), spleen volume (−39.4% vs +0.5%, p b 0.0001), livervolume (−31.7% vs. 1.4%, p b 0.0001) and platelets (+16.8% vs+2.5%, p= 0.019), with clinical differences seen by Week 26. SRSdecreased in both groups (−8.0 for olipudase vs −9.3 for placebo atWeek 52, p= 0.70). LS mean differences from baseline to Week 52favored olipudase alfa for HDL (33.5%, p = 0.0016), LDL (−25.9%,p = 0.0021), and chitotriosidase (41.9%, p= 0.0003). Pre-infusionmean plasma lyso-sphingomyelin decreased by 78.0% and 6.1% atWeek 52 in olipudase-alfa and placebo groups, respectively.Olipudase alfa was generally well-tolerated with an acceptable safetyprofile. Most adverse events (AEs) were mild to moderate. Therewere no treatment-related serious AEs and no AE-related discontin-uations. The study showed significant improvements in clinicallyrelevant disease endpoints at Week 52 in adults with chronic ASMDtreated with olipudase alfa compared to placebo.doi:10.1016/j.ymgme.2020.12.271Abstracts / Molecular Genetics and Metabolism 132 (2020) S13–S116S110

PREDIGA project: Preliminary results of the Spanish multicenter epidemiological and medical education project in acid sphingomyelinase deficiency disease (ASMD) and Gaucher disease (GD)

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PREDIGA project: Preliminary results of the Spanish multicenter epidemiological and medical education project in acid sphingomyelinase deficiency disease (ASMD) and Gaucher disease (GD)

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