An empowered, clinically viable hematopoietic stem cell gene therapy for the treatment of multisystemic mucopolysaccharidosis type II.

Mucopolysaccharidosis type II (MPS II), or Hunter syndrome, is a rare X-linked recessive lysosomal storage disorder due to a mutation in the lysosomal enzyme iduronate-2-sulfatase (IDS) gene. IDS deficiency leads to a progressive, multisystem accumulation of glycosaminoglycans (GAGs) and results in central nervous system (CNS) manifestations in the severe form. We developed up to clinical readiness a new hematopoietic stem cell (HSC) gene therapy approach for MPS II that benefits from a novel highly effective transduction protocol. We first provided proof of concept of efficacy of our approach aimed at enhanced IDS enzyme delivery to the CNS in a murine study of immediate translational value, employing a lentiviral vector (LV) encoding a codon-optimized human IDS cDNA. Then the therapeutic LV was tested for its ability to efficiently and safely transduce bona fide human HSCs in clinically relevant conditions according to a standard vs. a novel protocol that demonstrated superior ability to transduce bona fide long-term repopulating HSCs. Overall, these results provide strong proof of concept for the clinical translation of this approach for the treatment of Hunter syndrome.

A close-up view of the Hunter syndrome.

The Lysosomal Storage disease known as Mucopolysaccharidosis type II, is caused by mutations affecting the iduronate-2-sulfatase required for heparan and dermatan sulfate catabolism. The central nervous system (CNS) is mostly and severely affected by the accumulation of both substrates. The complexity of the CNS damage observed in MPS II patients has been limitedly explored. The use of mass spectrometry (MS)-based proteomics tools to identify protein profiles may yield valuable information about the pathological mechanisms of Hunter syndrome. In this further study, we provide a new comparative proteomic analysis of MPS II models by using a pipeline consisting of the identification of native protein complexes positioned selectively by using a specific antibody, coupled with mass spectrometry analysis, allowing us to identify changes involving in a significant number of new biological functions, including a specific brain antioxidant response, a down-regulated autophagic, the suppression of sulfur catabolic process, a prominent liver immune response and the stimulation of phagocytosis among others.

Effect of genistein and coenzyme Q10 in oxidative damage and mitochondrial membrane potential in an attenuated type II mucopolysaccharidosis cellular model.

Mucopolysaccharidosis type II (MPS II) is an inborn error of the metabolism resulting from several possible mutations in the gene coding for iduronate-2-sulfatase (IDS), which leads to a great clinical heterogeneity presented by these patients. Many studies demonstrate the involvement of oxidative stress in the pathogenesis of inborn errors of metabolism, and mitochondrial dysfunction and oxidative stress can be related since most of reactive oxygen species come from mitochondria. Cellular models have been used to study different diseases and are useful in biochemical research to investigate them in a new promising way. The aim of this study is to develop a heterozygous cellular model for MPS II and analyze parameters of oxidative stress and mitochondrial dysfunction and investigate the in vitro effect of genistein and coenzyme Q10 on these parameters for a better understanding of the pathophysiology of this disease. The HP18 cells (heterozygous c.261_266del6/c.259_261del3) showed almost null results in the activity of the IDS enzyme and presented accumulation of glycosaminoglycans (GAGs), allowing the characterization of this knockout cellular model by MPS II gene editing. An increase in the production of reactive species was demonstrated (p < .05 compared with WT vehicle group) and genistein at concentrations of 25 and 50 µm decreased in vitro its production (p < .05 compared with HP18 vehicle group), but there was no effect of coenzyme Q10 in this parameter. There was a tendency for lysosomal pH change in HP18 cells in comparison to WT group and none of the antioxidants tested demonstrated any effect on this parameter. There was no increase in the activity of the antioxidant enzymes superoxide dismutase and catalase and oxidative damage to DNA in HP18 cells in comparison to WT group and neither genistein nor coenzyme q10 had any effect on these parameters. Regarding mitochondrial membrane potential, genistein induced mitochondrial depolarization in both concentrations tested (p < .05 compared with HP18 vehicle group and compared with WT vehicle group) and incubation with coenzyme Q10 demonstrated no effect on this parameter. In conclusion, it is hypothesized that our cellular model could be compared with a milder MPS II phenotype, given that the accumulation of GAGs in lysosomes is not as expressive as another cellular model for MPS II presented in the literature. Therefore, it is reasonable to expect that there is no mitochondrial depolarization and no DNA damage, since there is less lysosomal impairment, as well as less redox imbalance.

Clinical investigator perspectives on patient outcomes in children with neuronopathic mucopolysaccharidosis II during intrathecal idursulfase-IT treatment.

BACKGROUND: Mucopolysaccharidosis II (MPS II) is a rare lysosomal storage disease characterized by iduronate-2-sulfatase gene (IDS) deficiency and downstream glycosaminoglycan accumulation. Two-thirds of patients present with neuronopathic disease and evaluating cognitive function in these patients is challenging owing to limitations of currently available tests. During the clinical development of intrathecal idursulfase (idursulfase-IT), regulatory authorities requested qualitative data to further understand the neurocognitive changes observed by the investigators through the clinical trials. RESULTS: This qualitative study consisted of semi-structured interviews with all nine of the principal investigators who participated in the idursulfase-IT phase 2/3 (NCT02055118) and extension (NCT02412787) trials. These investigators enrolled the 56 patients with neuronopathic MPS II who qualified for the extension phase of the trial. The investigators were asked to rate the disease status of their patients. Of the 56 patients, 49 (88%) were rated as having disease that was improved/improving, stabilized or slowing progression compared with the expected outcomes with no treatment. Three patients were rated as worsening, while the remaining four patients were considered to have slowing progression or worsening disease. Similar results were demonstrated for patients aged from 3 to under 6 years at baseline, with 33 of 39 patients (85%) rated as having disease that was improved/improving, stabilized or slowing progression. Of the seven patients rated with slowing progression/worsening or worsening disease, five of them had an IDS variant other than missense, while two had a missense class variant. All the assigned improved/improving ratings were in patients receiving idursulfase-IT from the start of the phase 2/3 trial. Moreover, patients under 3 years of age at baseline were all rated as either improved/improving or stabilized disease. In a blinded review of patient profiles, investigators were requested to assign a disease status rating to 18 patients with large IDS deletions; 67% of these patients were rated as improved/improving or stabilized disease. CONCLUSIONS: This qualitative analysis provides a snapshot of clinicians' considerations when evaluating treatment in patients with neuronopathic MPS II, compared with the expected decline in cognitive function in the absence of treatment. The results highlight the importance of robust assessment tools in treatment evaluation.

Caregiver experiences and observations of intrathecal idursulfase-IT treatment in a phase 2/3 trial in pediatric patients with neuronopathic mucopolysaccharidosis II.

BACKGROUND: Approximately two-thirds of patients with mucopolysaccharidosis II (MPS II) have a severe, neuronopathic phenotype, characterized by somatic, cognitive, and behavioral issues. Current standard of care for the treatment of MPS II is enzyme replacement therapy with intravenous recombinant human iduronate-2-sulfatase (idursulfase). To target cognitive manifestations of MPS II, idursulfase has been formulated for intrathecal administration into the cerebrospinal fluid (idursulfase-IT). In accordance with recommendations for patient-focused drug development, semi-structured interviews were conducted to assess caregiver experiences and observations in a 52-week phase 2/3 trial of idursulfase-IT, in addition to intravenous idursulfase in pediatric patients with neuronopathic MPS II, or a substudy which enrolled patients younger than 3 years old, all of whom received idursulfase-IT. RESULTS: Overall, 46 caregivers providing care for 50 children (mean [range] age 7.9 [3-17] years at interview) took part in a single 60-min exit interview; six of these children had participated in the substudy. Qualitative and quantitative data were obtained demonstrating the burden of MPS II experienced by caregivers and their families. Following participation in the trials, 39 (78%) of the children were reported by their caregivers to have experienced improvements in the symptoms and impact of disease. Of those with improvements, 37 (95%) experienced cognitive improvements and 26 (67%) experienced emotional/behavioral improvements. Overall, 43 children (86%) were rated by caregivers as having moderate or severe symptoms before the trials; after the trials, 28 children (56%) were considered to have mild or no symptoms. For the six children who participated in the substudy, these proportions were 83% and 100%, respectively. Caregivers' qualitative descriptions of trial experiences suggested improvements in children's verbal and non-verbal functioning and spatial and motor skills, as well as a positive impact on family life. CONCLUSIONS: This study revealed caregiver-reported improvements in children's MPS II symptoms and the impact of the disease on patients and their families. There was a trend for cognitive improvement and a reduction in severity of MPS II symptoms. After many years of extensive review and regulatory discussions of idursulfase-IT, the clinical trial data were found to be insufficient to meet the evidentiary standard to support regulatory filings.

Analysis of caregiver perspectives on patients with mucopolysaccharidosis II treated with pabinafusp alfa: results of qualitative interviews in Japan.

BACKGROUND: Mucopolysaccharidosis type II (MPS II), or Hunter syndrome, is a rare X-linked metabolic disorder predominantly affecting males. Pabinafusp alfa, an iduronate-2-sulfatase enzyme designed to cross the blood-brain barrier, was approved in Japan in 2021 as the first enzyme replacement therapy targeting both the neuropathic and somatic signs and symptoms of MPS II. This study reports caregivers' experiences of MPS II patients receiving pabinafusp alfa through qualitative interviews. METHODS: Semi-structured, qualitative interviews were conducted with caregivers at seven clinical sites in Japan using a semi-structured moderation guide (Voice of the Caregiver guide). Thematic analysis was applied to the interview transcripts to identify symptoms and health-related quality of life impacts at baseline, changes during treatment, and overall treatment experience. RESULTS: Seven caregivers from 16 trial sites participated, representing seven children aged 8-18 years who had received pabinafusp alfa for 3.3-3.5 years at the time of the interviews. Data suggest a general trend toward improvement in multiple aspects, although not all caregivers observed discernible changes. Reported cognitive improvements included language skills, concentration, self-control, eye contact, mental clarity, concept understanding, following instructions, and expressing personal needs. Further changes were reported that included musculoskeletal improvements and such somatic changes as motor function, mobility, organ involvement, joint mobility, sleep patterns, and fatigue. Four caregivers reported improvements in family quality of life, five expressed treatment satisfaction, and all seven indicated a strong willingness to continue treatment of their children with pabinafusp alfa. CONCLUSION: Caregivers' perspectives in this study demonstrate treatment satisfaction and improvement in various aspects of quality of life following therapy with pabinafusp alfa. These findings enhance understanding of pabinafusp alfa's potential benefits in treating MPS II and contribute to defining MPS II-specific outcome measures for future clinical trials.

Mucopolysaccharidosis type II zebrafish model exhibits early impaired proteasomal-mediated degradation of the axon guidance receptor Dcc.

Most of the patients affected by neuronopathic forms of Mucopolysaccharidosis type II (MPS II), a rare lysosomal storage disorder caused by defects in iduronate-2-sulfatase (IDS) activity, exhibit early neurological defects associated with white matter lesions and progressive behavioural abnormalities. While neuronal degeneration has been largely described in experimental models and human patients, more subtle neuronal pathogenic defects remain still underexplored. In this work, we discovered that the axon guidance receptor Deleted in Colorectal Cancer (Dcc) is significantly dysregulated in the brain of ids mutant zebrafish since embryonic stages. In addition, thanks to the establishment of neuronal-enriched primary cell cultures, we identified defective proteasomal degradation as one of the main pathways underlying Dcc upregulation in ids mutant conditions. Furthermore, ids mutant fish-derived primary neurons displayed higher levels of polyubiquitinated proteins and P62, suggesting a wider defect in protein degradation. Finally, we show that ids mutant larvae display an atypical response to anxiety-inducing stimuli, hence mimicking one of the characteristic features of MPS II patients. Our study provides an additional relevant frame to MPS II pathogenesis, supporting the concept that multiple developmental defects concur with early childhood behavioural abnormalities.

Eficácia e segurança da terapia com idursulfase em pacientes com mucopolissacaridose tipo II, com e sem comparação com placebo: revisão sistemática e metanálise / Efficacy and safety of idursulfase therapy in patients with mucopolysaccharidosis type II with and without comparison to placebo: systematic review and meta-analysis / Eficacia y seguridad del tratamiento con idursulfasa en pacientes con mucopolisacaridosis tipo II con y sin comparación con el placebo: revisión sistemática y metaanálisis

A mucopolissacaridose tipo II (MPS II) é uma doença genética de amplo espectro clínico, caracterizada por deficiência da enzima iduronato-2sulfatase. Revisão sistemática avaliou a eficácia e segurança da terapia de reposição enzimática (TRE) com idursulfase (IDS) na MPS II. As bases de dados PubMed/MEDLINE, Embase, LILACS e Biblioteca Cochrane foram pesquisados até 30 de novembro de 2012. Apenas cinco estudos preencheram os critérios de inclusão (ensaios clínicos randomizados - ECRs, ECRs abertos ou séries de caso prospectivas, incluindo cinco ou mais pacientes e avaliando desfechos relevantes). Metanálise foi realizada para capacidade vital forçada (CVF; valores absolutos e em %) e para a distância percorrida no teste da caminhada dos seis minutos, com mudanças significativas em ambas as variáveis; também foi encontrado risco aumentado de reações leves relacionadas à infusão e de desenvolvimento de anticorpos IgG à IDS. Em face dos dados apresentados neste estudo, conclui-se que a TRE com IDS é segura e tem benefício potencial em MPS II, mas estudos adicionais são necessários.

Mucopolysaccharidosis type II (MPS II) is a genetic disease of broad clinical spectrum, characterized by a deficiency of the enzyme iduronate2-sulfatase. The aim of this study was to assess whether enzyme replacement therapy (ERT) with idursulfase (IDS) for MPS II is effective and safe. PubMed/MEDLINE, Embase, LILACS, and Cochrane Library were searched until November 30, 2012. Only five articles met the inclusion criteria (randomized controlled trials - RCTs, or open-label trials/prospective case series including > 5 patients and evaluating relevant outcomes). A meta-analysis was performed for forced vital capacity (FVC; absolute and %) and for distance walked on the 6-minute walking test (6MWT). There was a statistically significant increase, but not clinically relevant, in both variables; an increased risk for development of mild infusion-related reactions and IgG antibodies to IDS were also found. The data suggest that ERT with IDS is safe and has a potential benefit for MPS II patients, but further studies are required.

La mucopolisacaridosis tipo II (MPS II) es una enfermedad genética de amplio espectro clínico, caracterizada por una deficiencia de la enzima iduronato-2-sulfatasa. El objetivo fue evaluar la seguridad y eficacia de la Terapia de Reemplazo Enzimático (TRE) con idursulfasa (IDS) en la MPS II. En las bases PubMed/MEDLINE, EMBASE, LILACS y Cochrane Library se inició la búsqueda hasta el 30 de noviembre de 2012. Sólo cinco estudios cumplieron los criterios de inclusión (ensayos controlados aleatorios -ECA, o ECA abiertos o series de casos prospectivo incluyendo > 5 pacientes y evaluación de los resultados pertinentes). El metaanálisis se realizó para la capacidad vital forzada (FVC; absoluta y %) y la distancia caminada en 6 minutos, con cambios significativos en ambas variables; el riesgo también se encuentra aumentado por reacciones leves y anticuerpos IgG, relacionados con la infusión con IDS. El TRE con IDS es seguro y tiene un beneficio potencial en la MPS II, pero se necesitan estudios adicionales.

Consequências da judicialização das políticas de saúde: custos de medicamentos para as mucopolissacaridoses / Consequences of the judicialization of health policies: the cost of medicines for mucopolysaccharidosis

O estudo analisa os gastos da judicialização de medicamentos para a mucopolissacaridose (MPS), uma doença rara, de alto custo, fora da política de assistência farmacêutica e com benefício clínico. O levantamento de dados foi realizado nos arquivos de 196 dossiês que determinou que o Ministério da Saúde fornecesse medicamentos no período entre 2006 e 2010, e nos registros administrativos e contábeis do Ministério da Saúde. A análise identifica sujeição do governo brasileiro a monopólios de distribuição de medicamentos e, consequentemente, perda de sua capacidade de administrar compras. Também identifica que a imposição da aquisição imediata e individualizada impede a obtenção de economias de escala com a compra planejada de maiores quantidades de medicamento, e impõe dificuldades logísticas para o controle das quantidades consumidas e estocadas. Conclui-se que a judicialização decorre da ausência de uma política clara do sistema de saúde para doenças raras em geral, e tem como consequência gastos acima do necessário para o tratamento.

This study analyzes expenditures backed by court rulings to ensure the public provision of medicines for treatment of mucopolysaccharidosis (MPS), a rare disease that requires high-cost drugs not covered by the Brazilian government's policy for pharmaceutical care and which have disputed clinical efficacy. The methodology included a review of files from 196 court rulings ordering the Brazilian Ministry of Health to provide the medicines, in addition to Ministry of Health administrative records. According to the analysis, the "judicialization" of the health system subjected the Brazilian government to a monopoly in the distribution of medicines and consequently the loss of its capacity to manage drug purchases. The study also indicates that the imposition of immediate, individualized purchases prevents obtaining economies of scale with planned procurement of larger amounts of the medication, besides causing logistic difficulties in controlling the amounts consumed and stored. In conclusion, litigation results from the lack of a clear policy in the health system for rare diseases in general, thereby leading to excessive expenditures for MPS treatment.

Human sulfatase transiently and functionally active expressed in E. coli K12

The recombinant human iduronate 2-sulfate sulfatase (hrIDS) was transiently and functionally active expressed in E. coli K12. The enzyme activity (crude extract) at 100 ml and 400 ml oscillated between 0.25 and 10.58 nmol h-1 mg-1. The wide Western-blot peptide profile suggest that hrIDS is proteolitically processed randomly which agrees with the ultrafiltration assay in which the hrIDS activity was found in all fractions (<30kDa, 30-100kDa and >100kDa). No glycation sites were found by computer analysis of the hIDS sequence; discarding the possibility of marks for glycation and proteolytic processing.

Producción de anticuerpos policlonales IgG contra la proteína iduronato-2-sulfato sulfatasa y desarrollo de un sistema de detección para IDS humana recombinante / Production of polyclonal antibodies to protein iduronate-2-sulphate sulphatase (IDS) and development of a detection system for human recombinant IDS

Introducción. La enfermedad de Hunter es un trastorno lisosómico caracterizado por la deficiencia de la enzima iduronato-2-sulfato sulfatasa (IDS) (EC 3.1.6.13). Esta enfermedad, al igual que muchos trastornos metabólicos, son patologías intratables mediante la terapéutica convencional; sin embargo, existe la posibilidad de ser tratada alternativamente mediante terapia génica o terapia de reemplazo enzimático. Objetivo. El Instituto de Errores Innatos del Metabolismo (IEIM) ha desarrollado un sistema de expresión de sulfatasas para producir IDS humana recombinante (IDShr) en Escherichia coli y Pichia pastoris,con resultados favorables. El objetivo principal de este trabajo fue desarrollar un sistema de detección de IDS humana recombinante. Materiales y métodos. Para el efecto, se inmunizaron con IDS comercial de TKT (Cambridge, MA) dos conejos de raza Nueva Zelanda blanca y los anticuerpos purificados a partir del suero se utilizaron en el desarrollo de una técnica semicuantitativa por dot-blot. Diferentes muestras de extractos crudos de fermentaciones con P. pastoris y E. coli se procesaron con el fin de poder determinar la presencia de la enzima. Resultados. Se demostró que los anticuerpos eran específicos en el reconocimiento de la IDS sin presentar reactividad cruzada con proteínas contaminantes de los extractos crudos. Conclusión. Por consiguiente, los anticuerpos se podrán usar en el desarrollo de una técnica ELISA tipo sandwich como método de detección y cuantificación de la enzima y en procesos de purificación de la misma mediante cromatografía de afinidad

Influencia del a-Factor sobre la expresión de IDShr en Pichia pastoris: Revisión sistemática de literatura y análisis computacional / Influence of a-Factor over the expression of hrIDS in Pichia pastoris: Literature review and computational analysis

En la búsqueda de alternativas para mejorar la expresión de la enzima Iduronato Sulfatasa (IDSh) en la levaduraPichia pastoris, se realizó una Revisión Sistemática de la Literatura con el fin de recopilar información quepermitiera relacionar los niveles de expresión de proteínas humanas recombinantes con la señal de secreción y las características propias de la molécula a expresar. Se hallaron 349 publicaciones de las cuales sólo 7 (2)porciento reportaron la expresión de proteínas que cumplían con los criterios de inclusión manejados en el estudio. Con la información obtenida en los 7 artículos se realizó una prueba de hipótesis tomando como muestras los datos recopilados y un análisis cualitativo de la información, con los cuales se evidenció que al reemplazar la señal de secreción nativa por el a-Factor como péptido líder se incrementa el nivel de expresión de proteínas humanas recombinantes en P. pastoris (p=0.053). Se encontró que la eliminación de la secuencia que codifica para el péptido nativo heterólogo en el ADNc de la proteína, es imprescindible para que el a-Factor pueda favorecer la secreción de proteínas heterólogas y por consiguiente incrementar el nivel de expresión. En el caso de la IDShr se halló que en la construcción GS115/pPIC9-IDS, aparecen dos secuencias de péptido señal al mismo tiempo, la nativa de la IDSh y la putativa proveniente de Saccharomyces cerevisiae; sin embargo, se han obtenidos expresiones hasta de ~30mmol/h mg de proteína, lo que deja la incógnita de un posible conflicto en el reconocimiento erróneo de una u otra señal de secreción, teniendo en cuenta el grado de hidrofobicidad de ambas.

Mucopolissacaridose tipo Hunter, com anátomo-patológico hepático de glicogenose / Mucopolyssacaridosis type II (MPSII-Hunter) with a hepatic biopsy

Objetivo: Relatar um caso de Mucopolissacaridose tipo II (MPSII Hunter), com quadro clínico e laboratorial desta doença, porém com biópsia hepática apresentando depósito citoplasmático de glicogênio. Métodos: Estudo do quadro clínico e de exames complementares de uma criança de 8 anos de idade, internada em nosso serviço, com importante hepatoesplenomegalia. Resultados: Foram encontradas alterações clínicas, tais como, fascies grosseira, alterações de ausculta cardíaca, hepatoesplenomegalia, deformidades articulares MMSS e certo grau de deterioração mental. Os achados de exames complementares de imagem (ecocardiográficos, radiológicos e ultrassonográficos) também foram compatíveis com MPS. Laboratorialmente, foi detectado na urina, Dermatan Sulfato de Heparan Sulfato (Teste do Azul de Toluidina - positivo) e ensaios enzimáticos que sugerem MPS tipo II. O resultado anátomo-patológico da biópsia hepática, com acúmulo de glicogênio no citoplasma do hepatócito, demonstra característica encontrada na glicogenose, mas não se correlacionando com os achados clínicos. Conclusão: No diagnóstico das Doenças de Depósito (MPS), a biópsia hepática pode ter apresentação semelhante a uma glicogenose e, portanto, para seu diagnóstico definitivo, é importante associarmos o quadro clínico com dados laboratoriais e histopatológicos.

Informe de adopción de ETS: idursulfasa para síndrome de Hunter / ETS adoption report: idursulfase for Hunter syndrome

El uso de Idursulfasa como tratamiento del síndrome de Hunter o Mucopolisacaridosis tipo II, genera beneficios a los pacientes, relacionados a la capacidad de desempeñar algunas funciones como caminar y mejoría en el tamaño del bazo y el hígado que podrían producir molestias al paciente. Se recomienda la cobertura del medicamento Idursulfasa como tratamiento del síndrome de Hunter o Mucopolisacaridosis tipo II, bajo la modalidad de cobertura con generación de evidencia.(AU)

Protocolo de evaluación rápida de seguridad y efectividad del uso de Idursulfasa en el tratamiento de pacientes con síndrome de Hunter / Protocol of rapid evaluation of safety and effectiveness of the use of Idursulfase in the treatment of patients with Hunter syndrome

El Síndrome de Hunter o Mucopolisacaridosis tipo II (MPSII) es una enfermedad de almacenamiento lisosomal ocasionada por la deficiencia de la enzima iduronato 2 sulfatasa, su incidencia se calcula en aproximadamente 1 por cada 132 000 recién nacidos vivos varones de acuerdo al reporte de algunos estudios europeos, esta enfermedad es una entidad progresiva, incapacitante y con daños irreversibles. Las personas que padecen la forma de aparición temprana (severa) generalmente viven durante 10 a 20 años, mientras que las personas con la forma de aparición tardía (leve) viven de 20 a 60 años. El Fondo Intangible Solidario de Salud solicita la evaluación de la tecnología sanitaria idursulfasa como tratamiento síndrome de Hunter, la cual a su vez fue solicitada Instituto Nacional de Salud del Niño, a raíz de la aparición de un caso. Luego de una primera revisión, se determina que la tecnología idursulfasa, comercializada en el Perú como Elaprase 2 mg/mL, supera la tolerancia al riesgo para evaluación de tecnologías sanitarias en el Seguro Integral de Salud, por lo se consideró sea evaluada por el área de Evaluación de Tecnologías Sanitarias en el SIS Central.(AU)