Gene Therapy for Lysosomal Storage Disorders: Recent Advances and Limitations

Abstract Lysosomal storage disorders (LSDs) are a group of diseases with multisystemic features. Current treatments have limitations and gene therapy arises as a promising treatment option. Here, we discuss some of the most recent studies for gene therapy in LSD, vectors used, and outcomes. In particular, the approaches used in animal models aiming to correct the central nervous system, the eye, and the bones are highlighted. Finally, we discuss the recent reports of clinical trials using this technology for these diseases. We conclude that gene therapy for LSD has gathered a substantial amount of evidence from animal models to know its potential and limitations. First evidences from clinical trials using both adeno-associated and lentiviral vectors show that this approach is safe and efficient and therefore could provide an effective treatment for several LSD in the near future.

Mucopolisacaridosis: características clínicas, diagnóstico y de manejo / Mucopolysaccharidosis: clinical features, diagnosis and management

Las mucopolisacaridosis (MPS) son un grupo de enfermedades raras (huérfanas), de baja prevalencia, caracterizadas por la deficiencia de enzimas que participan en el metabolismo de glucosaminglucanos (GAG) a nivel lisosomal. Se caracteriza por acumulación de GAG intracelular, produciendo alteraciones de múltiples órganos y sistemas. Su diagnóstico se basa en el conocimiento de las manifestaciones clínicas, realizar el análisis bioquímico para identificar el tipo de GAG que se está acumulando y confirmar el tipo de enfermedad con la determinación enzimática correspondiente. Su identificación es fundamental para iniciar un tratamiento oportuno, teniendo en cuenta que actualmente existe manejo transdisciplinario y tratamiento de reemplazo enzimático para MPS I (síndrome de Hurler), MPS II (síndrome de Hunter), MPS IV (síndrome de Morquio) y MPS VI (síndrome de Maroteaux-Lamy). En esta revisión se analizan cada uno de estos síndromes, su diagnóstico y tratamiento.

The mucopolysaccharidoses (MPS) are a group of rare (orphan) diseases, characterised by a deficiency of enzymes involved in the metabolism of glycosaminoglycans (GAGs) at lysosomal level. When there is a deficiency of a particular enzyme there is an accumulation of GAGs in the cells resulting in progressive cellular damage, which can affect multiple organ systems and lead to organ failure. Diagnosis is based on knowledge of the clinical manifestations, performing biochemical analyses to identify the type of GAG that is accumulating, and confirm the type of disorder with the corresponding enzymatic determination. Their identification is essential to initiate early treatment, taking into account that multidisciplinary management and enzyme replacement therapy is available for MPS I (Hurler syndrome), MPS II (Hunter syndrome), MPS IV (Morquio syndrome), and MPS VI (Maroteaux-Lamy syndrome. In this review, an analysis is made of each of these syndromes, as well as their diagnosis and treatment.

Mucopolisacaridosis (síndrome de Hunter) / Mucopolysaccharidosis (Hunter syndrome)

Se realiza una presentación de un caso interesante, no comúnmente visto en la práctica médica, de unos de los tipos de mucopolisacaridosis, específicamente de un síndrome de Hunter. Se hace esta presentación con el objetivo de dar a conocer a estudiantes y profesionales de la salud, mediante fotos, las características físicas del paciente con dicho sídrome, quien llegó desnutrido al hospital; se le operó de la hernia umbilical y se mejoró su estado nutricional al compensarse su hepatopatía. Se le da el alta médica en mejores condiciones(AU)

We present here an interesting case of mucopolysaccharidoses, which is not commonly seen in medical practice, specifically a Hunter syndrome. This presentation is done in order to make known to students and health professionals, through photos, the physical characteristics of the patient with such syndrome. This patient arrived malnourished at the hospital, he was operated on the umbilical hernia and improved his nutritional status by compensating for his liver disease. This patient had medical discharge in better conditions(AU)

Mucopolisacaridosis de tipo I Hurler: Informe de un caso / Mucopolysaccharidosis I, Hurler syndrome: A case report

La mucopolisacaridosis de tipo I (MPS I), es una enfermedad genética autosómica recesiva de origen lisosomal, caracterizada por la deficiencia de la enzima a-L-iduronidasa. La deficiencia en el catabolismo de los glucosaminoglucanos resulta en su acumulación en diferentes tejidos y órganos. La incidencia global de la MPS I es de 0,99-1,99/100 000 nacidos vivos. Existen tres presentaciones clínicas: Hurler (grave), Hurler-Scheie (moderada) y Scheie (leve). Presentamos el caso de un niño de 10 años de edad a quien se le diagnosticó MPS I, de variedad grave en el año 2006, mediante medición de la actividad enzimática de a-L-iduronidasa en leucocitos. Este caso es el único con diagnóstico confirmado y tratamiento enzimático hasta el momento, en el Perú. Presenta infecciones respiratorias recurrentes, hernia umbilical, opacidad corneal, rasgos toscos, macroglosia, hipoacusia, rigidez articular, estenosis de la válvula pulmonar leve-moderada, manos en garra, retardo mental y retraso del crecimiento. Recibe terapia de reemplazo enzimático desde el año 2008, mostrando mejoría de los síntomas viscerales, más no del daño neurológico.

Mucopolysaccharidosis I (MPS I) is a rare, recessively inherited, lysosomal storage disorder caused by deficiency on the enzyme a-L-iduronidase. This defect results in accumulation of heparan and dermatan sulfate in different tissues and organs due to a deficiency in the catabolism of glycosaminoglycans. The overall incidence of MPS I is 0.99-1.99/100.000 live births. There are three clinical presentations: Hurler (severe), Hurler Scheie (mild) and Scheie (mild). We report the case of a 10-years-old male patient diagnosed with Hurler syndrome, the severe presentation, 5 years ago by enzyme a-L-iduronidase activity measurement in leukocytes; with a history of recurrent respiratory infections, umbilical hernia, corneal opacity, coarse facial features, macroglossia, hearing loss, stiffness of joints, cardiac compromise, claw hands, mental retardation and stunted growth. After enzyme replacement therapy the patient has shown improvement of visceral symptoms, but the neurological damage continuous in progress.

Oral findings in patients with mucolipidosis type III

Mucolipidosis type III is a rare, autosomal recessive disorder, which is part of a group of storage diseases as a result of inborn error of lysosomal enzyme metabolism. It is characterized by the gradual onset of signs and symptoms affecting the physical and mental development as well as visual changes, heart, skeletal and joint. Although oral findings associated with mucolipidosis type II have been extensively reported, there is a shortage of information on mucolipidosis type III. This paper presents radiological and histological findings of multiple radiolucent lesions associated with impacted teeth in the jaw of a 16 year-old youngster with mucolipidosis type III.

A mucolipidose tipo III é uma doença rara, autossômica recessiva, que faz parte de um grupo de doenças de depósito, decorrentes do erro inato do metabolismo das enzimas lisossômicas. Caracteriza-se pelo aparecimento progressivo de sinais e sintomas com repercussão no desenvolvimento físico e mental, bem como alterações visuais, cardíacas, esqueléticas e articulares. Apesar de achados bucais estarem bem relatados em associação à mucolipidose tipo II, esse artigo descreve achados radiográficos e histológicos de múltiplas lesões radiolúcidas, associadas a dentes inclusos nos maxilares, em uma jovem de 16 anos de idade com mucolipidose tipo III.

Manejo anestésico en paciente pediátrico con síndrome de Hurler / Anesthetic management of pediatric patient with Hurler syndrome

La mucopolisacaridosis (MPS) es un trastorno hereditario degenerativo progresivo, causado por la acumulación excesiva intralisosomal de glicoaminoglicanos en diversos tejidos. Estos cúmulos producen hipertrofia celular, produciendo alteración de las funciones y de la estructura de los tejidos involucrados. El síndrome de Hurler es un tipo de MPS caracterizado por una vía aérea difícil, considerándose la vía aérea más dificil de la anestesia pediátrica. Además pueden presentar retraso mental progresivo y miocardiopatías. Presentamos un caso de un niño de 4 años de edad diagnosticado de síndrome de Hurler sometido a anestesia general para la colocación de un reservorio en yugular interna derecha. Discutimos manejo anestésico de estos pacientes.

Mucopolysaccharidosis (MPS) is a hereditary progressively degenerative disease caused by excessive intralysosomal accumulation of glycosaminoglycans in various tissues. This accumulation causes cellular hypertrophy, altering functions and the structure of the tissues involved. Hurler syndrome is a type of MPS, characterized by a difficult respiratory tract, considered the most problematic one for pediatric anesthesia; it may also present progressive mental retard and myocardiopathies. We describe a case of a 4-year-old child diagnosed with Hurler syndrome who underwent general anesthesia for placement of a reservoir in his right internal jugular vein. We analyzed the anesthetic handling of these patients.

A mucopolissacaridose (MPS) é uma doença hereditária degenerativa progressiva causada pelo acúmulo intralisossomal excessivo de glicoaminoglicanos em diversos tecidos. Esse acúmulo produz hipertrofia celular, que por sua vez altera as funções e estrutura dos tecidos envolvidos. O síndrome de Hurler é um tipo de MPS caracterizado por uma via aérea difícil, considerada a mais problemática para a anestesia pediátrica, que também pode apresentar retardo mental progressivo e miocardiopatias. Descrevemos o caso de um criança de 4 anos de idade, diagnosticada de síndrome de Hurler e submetida a anestesia geral para a colocação de um dispositivo reservatório na jugular interna direita. Analisamos o manejo anestésico destes pacientes.

Mucopolysaccharidosis I, II, and VI: brief review and guidelines for treatment

Mucopolysaccharidoses (MPS) are rare genetic diseases caused by the deficiency of one of the lysosomal enzymes involved in the glycosaminoglycan (GAG) breakdown pathway. This metabolic block leads to the accumulation of GAG in various organs and tissues of the affected patients, resulting in a multisystemic clinical picture, sometimes including cognitive impairment. Until the beginning of the XXI century, treatment was mainly supportive. Bone marrow transplantation improved the natural course of the disease in some types of MPS, but the morbidity and mortality restricted its use to selected cases. The identification of the genes involved, the new molecular biology tools and the availability of animal models made it possible to develop specific enzyme replacement therapies (ERT) for these diseases. At present, a great number of Brazilian medical centers from all regions of the country have experience with ERT for MPS I, II, and VI, acquired not only through patient treatment but also in clinical trials. Taking the three types of MPS together, over 200 patients have been treated with ERT in our country. This document summarizes the experience of the professionals involved, along with the data available in the international literature, bringing together and harmonizing the information available on the management of these severe and progressive diseases, thus disclosing new prospects for Brazilian patients affected by these conditions.

Biochemical Characteristics of a Korean Patient with Mucolipidosis III (Pseudo-Hurler Polydystrophy)

We performed a biochemical study on the patient with mucolipidosis III (ML-III, pseudo-Hurler polydystrophy) in Korea. Confluent fibroblasts from the patient and from normal controls were cultured for 4, 12, 24, 48, and 72 hr, respectively. Lysosomal enzyme activities in culture media after different incubation times and in plasma, leukocytes, and fibroblasts were determined. Most of the leukocyte lysosomal enzymes were within normal limits or slightly lowered; however, plasma lysosomal enzyme activities such as those of hexosaminidase and arylsulfatase A were markedly increased. Numerous phase-dense inclusions were present in the cytoplasm of cultured fibroblasts. Lysosomal enzyme activities of fibroblasts were markedly decreased except for beta-glucosidase. The rates of increase of the lysosomal enzyme activities with incubation time were greater in the culture medium of the patient than in normal control, whereas no difference in the beta-glucosidase activity of the culture media of the patient and the control was found. This study describes the first case of ML-III in Korea, with its typical biochemical characteristics, i.e., a problem with targeting and transporting of lysosomal enzymes which results in a marked increase in plasma lysosomal enzyme activities and a high ratio of extracellular to intracellular lysosomal enzyme activities in cultured fibroblasts.