Andressa Federhen

Emerging drugs for the treatment of mucopolysaccharidoses.

ABSTRACT Introduction: Despite being reported for the first time almost one century ago, only in the last few decades effective have treatments become available for the mucopolysaccharidoses (MPSs), a group of 11 inherited metabolic diseases that affect lysosomal function. These diseases are progressive, usually severe, and, in a significant number of cases, involve cognitive impairment. Areas covered: This review will not cover established treatments such as bone marrow/hematopoietic stem cell transplantation and classic intravenous enzyme replacement therapy (ERT), whose long-term outcomes have already been published (MPS I, MPS II, and MPS VI), but it instead focuses on emerging therapies for MPSs. That includes intravenous ERT for MPS IVA and VII, intrathecal ERT, ERT with fusion proteins, substrate reduction therapy, gene therapy, and other novel approaches. Expert opinion: The available treatments have resulted in improvements for several disease manifestations, but they still do not represent a cure for these diseases; thus, it is important to develop alternative methods to approach the unmet needs (i.e. bone disease, heart valve disease, corneal opacity, and central nervous system (CNS) involvement). The work in progress with novel approaches makes us confident that in 2017, when MPS will commemorate 100 years of its first report, we will be much closer to an effective cure for these challenging conditions.

Terapia de reposição enzimática para as mucopolissacaridoses I, II e VI: recomendações de um grupo de especialistas brasileiros

Mucopolysaccharidoses (MPS) are rare genetic diseases caused by deficiency of specific lysosomal enzymes that affect catabolism of glycosaminoglycans (GAG). Accumulation of GAG in various organs and tissues in MPS patients results in a series of signs and symptoms, producing a multisystemic condition affecting bones and joints, the respiratory and cardiovascular systems and many other organs and tissues, including in some cases, cognitive performance. So far, eleven enzyme defects that cause seven different types of MPS have been identified. Before introduction of therapies to restore deficient enzyme activity, treatment of MPS focused primarily on prevention and care of complications, still a very important aspect in the management of these patients. In the 80s treatment of MPS with bone marrow transplantation/hematopoietic stem cells transplantation (BMT/HSCT) was proposed and in the 90s, enzyme replacement therapy (ERT),began to be developed and was approved for clinical use in MPS I, II and VI in the first decade of the 21st century. The authors of this paper are convinced that a better future for patients affected by mucopolysaccharidoses depends upon identifying, understanding and appropriately managing the multisystemic manifestations of these diseases. This includes the provision of support measures (which should be part of regular multidisciplinary care of these patients) and of specific therapies. Although inhibition of synthesis of GAG and the recovery of enzyme activity with small molecules also may play a role in the management of MPS, the breakthrough is the currently available intravenous ERT. ERT radically changed the setting for treatment of mucopolysaccharidosis I, II and VI in the last decade., Benefits can even be extended soon to MPS IV A (ERT for this condition is already in clinical development), with prediction for treatment of MPS III A and the cognitive deficit in MPS II by administration of the enzyme directly into the central nervous system (CNS). A large number of Brazilian services, from all regions of the country, already have experience with ERT for MPS I, II and VI. This experience was gained not only by treating patients but also with the participation of some groups in clinical trials involving ERT for these conditions. Summing up the three types of MPS, more than 250 patients have already been treated with ERT in Brazil. The experience of professionals coupled to the data available in international literature, allowed us to elaborate this document, produced with the goal of bringing together and harmonize the information available for the treatment of these severe and progressive diseases, which, fortunately, are now treatable, a situation which bring new perspectives for Brazilian patients, affected by these conditions.As mucopolissacaridoses (MPS) sao doencas geneticas raras causadas pela deficiencia de enzimas lisossomicas especificas que afetam o catabolismo de glicosaminoglicanos (GAG). O acumulo de GAG em varios orgaos e tecidos nos pacientes afetados pelas MPS resulta em uma serie de sinais e sintomas, integrantes de um quadro clinico multissistemico que compromete ossos e articulacoes, vias respiratorias, sistema cardiovascular e muitos outros orgaos e tecidos, incluindo, em alguns casos, as funcoes cognitivas. Ja foram identificados 11 defeitos enzimaticos que causam sete tipos diferentes de MPS. Antes do advento de terapias dirigidas para a restauracao da atividade da enzima deficiente, o tratamento das MPS tinha como principal foco a prevencao e o cuidado das complicacoes, aspecto ainda bastante importante no manejo desses pacientes. Na decada de 80 foi proposto o tratamento das MPS com transplante de medula ossea/transplante de celulas tronco hematopoieticas (TMO/TCTH) e na decada de 90 comecou o desenvolvimento da Terapia de Reposicao Enzimatica (TRE), que se tornou uma realidade aprovada para uso clinico nas MPS I, II e VI na primeira decada do seculo 21. Os autores deste trabalho tem a conviccao de que um melhor futuro para os pacientes afetados pelas MPS depende da identificacao, compreensao e manejo adequado das manifestacoes multissistemicas dessas doencas, incluindo medidas de suporte (que devem fazer parte da assistencia multidisciplinar regular destes pacientes) e terapias especificas. Embora a inibicao da sintese de GAG e o resgate da atividade enzimatica com moleculas pequenas tambem possam vir a ter um papel no manejo das MPS, o grande avanco disponivel no momento e a TRE intravenosa. A TRE permitiu modificar radicalmente o panorama do tratamento das mucopolissacaridoses I, II e VI na ultima decada, sendo que ainda pode estender seus beneficios em breve para a MPS IV A (cuja TRE ja esta em desenvolvimento clinico), com perspectivas para o tratamento da MPS III A e do deficit cognitivo na MPS II atraves de administracao da enzima diretamente no sistema nervoso central (SNC). Um grande numero de centros brasileiros, incluindo servicos de todas as regioes do pais, ja tem experiencia com TRE para MPS I, II e VI. Essa experiencia foi adquirida nao so com o tratamento de pacientes como tambem com a participacao de alguns grupos em ensaios clinicos envolvendo TRE para essas condicoes. Somados os tres tipos de MPS, mais de 250 pacientes ja foram tratados com TRE em nosso pais. A experiencia dos profissionais brasileiros, somada aos dados disponiveis na literatura internacional, permitiu elaborar este documento, produzido com o objetivo de reunir e harmonizar as informacoes disponiveis sobre o tratamento destas doencas graves e progressivas, mas que, felizmente, sao hoje trataveis, uma realidade que traz novas perspectivas para os pacientes brasileiros afetados por essas condicoes.

Diagnostic and treatment strategies in mucopolysaccharidosis VI

Mucopolysaccharidosis VI (MPS VI) is a very rare autosomal recessive disorder caused by mutations in the ARSB gene, which lead to deficient activity of the lysosomal enzyme ASB. This enzyme is important for the breakdown of the glycosaminoglycans (GAGs) dermatan sulfate and chondroitin sulfate, which accumulate in body tissues and organs of MPS VI patients. The storage of GAGs (especially dermatan sulfate) causes bone dysplasia, joint restriction, organomegaly, heart disease, and corneal clouding, among several other problems, and reduced life span. Despite the fact that most cases are severe, there is a spectrum of severity and some cases are so attenuated that diagnosis is made late in life. Although the analysis of urinary GAGs and/or the measurement of enzyme activity in dried blood spots are useful screening methods, the diagnosis is based in the demonstration of the enzyme deficiency in leucocytes or fibroblasts, and/or in the identification of pathogenic mutations in the ARSB gene. Specific treatment with enzyme replacement has been available since 2005. It is safe and effective, bringing measurable benefits and increased survival to patients. As several evidences indicate that early initiation of therapy may lead to a better outcome, newborn screening is being considered for this condition, and it is already in place in selected areas where the incidence of MPS VI is increased. However, as enzyme replacement therapy is not curative, associated therapies should be considered, and research on innovative therapies continues. The management of affected patients by a multidisciplinary team with experience in MPS diseases is highly recommended.

Emerging treatment options for the mucopolysaccharidoses

Roberto Giugliani1–6 Andressa Federhen1,4 Andre Anjos Silva1,5 Camila Matzenbacher Bittar1,5 Carolina Fischinger Moura de Souza1 Cristina Brinckmann Oliveira Netto1 Fabiana Quoos Mayer2,7 Guilherme Baldo1,2,8 Ursula Matte1–5 1Medical Genetics Service, 2Gene Therapy Center, Hospital de Clinicas (HCPA), Porto Alegre, RS, Brazil; 3Department of Genetics, 4Postgraduate Program in Child and Adolescent Health, 5Postgraduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil; 6National Institute of Population Medical Genetics (INAGEMP), Porto Alegre, RS, Brazil; 7Fundacao Estadual de Pesquisa Agropecuaria (FEPAGRO), Eldorado do Sul, RS, Brazil; 8Department of Biophysics, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil

Relative frequency and estimated minimal frequency of Lysosomal Storage Diseases in Brazil: Report from a Reference Laboratory

Abstract Lysosomal storage diseases (LSDs) comprise a heterogeneous group of more than 50 genetic conditions of inborn errors of metabolism (IEM) caused by a defect in lysosomal function. Although there are screening tests for some of these conditions, diagnosis usually depends on specific enzyme assays, which are only available in a few laboratories around the world. A pioneer facility for the diagnosis of IEM and LSDs was established in the South of Brazil in 1982 and has served as a reference service since then. Over the past 34 years, samples from 72,797 patients were referred for investigation of IEM, and 3,211 were confirmed as having an LSD (4.41%, or 1 in 22), with 3,099 of these patients originating from Brazil. The rate of diagnosis has increased over time, in part due to the creation of diagnostic networks involving a large number of Brazilian services. These cases, referred from Brazilian regions, provide insight about the relative frequency of LSDs in the country. The large amount of data available allows for the estimation of the minimal frequency of specific LSDs in Brazil. The reported data could help to plan health care policies, as there are specific therapies available for most of the cases diagnosed.

Enzyme Replacement Therapy With Elosulfase Alfa Decreases Storage of Glycosaminoglycan in White Blood Cells of Patients With Morquio A Syndrome

Mucopolysaccharidosis IVA (MPS IVA; Morquio A syndrome) is a lysosomal storage disorder caused by a deficient N-acetylgalactosamine-6-sulfate sulfatase activity, leading to cellular storage of undegraded keratan sulfate. Recently enzyme replacement therapy (ERT) was approved for MPS IVA, but some of ERT effects are still unknown. In the present study, we aimed to evaluate the efficacy of elosulfase alfa upon glycosaminoglycan (GAG) storage in peripheral blood white blood cells of patients with MPS IVA treated for 6 months, comparing samples from patients who received weekly infusions of enzyme (ERT-W) versus infusions every other week (ERT-EOW) versus placebo. A significant reduction in GAG storage was observed in both ERT-treated groups, with weekly ERT showing slightly better performance than ERT-EOW.