Enzyme Replacement Therapy with Idursulfase in Patients with Mucopolysaccharidosis Type II: Literature Review

Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is X-linked hereditary disease from the group of lysosomal storage disease. Its prevalence is 3–7 cases per 1 million live-born boys. MPS II occurs due to the deficiency of iduronate-2-sulfatase enzyme because of pathological changes in the structure of the IDS gene. Enzyme deficiency leads to the accumulation of glycosaminoglycans (GAGs), dermatan sulfate and heparan sulfate, in lysosomes. This leads to the damage of various organs and systems in the body with further development of clinical picture of the disease: coarse face, recurrent infections of upper respiratory tract, hearing loss up to deafness, cardiovascular and respiratory systems pathologies, hepatosplenomegaly, musculoskeletal system abnormalities, low growth, central nervous system damage. Enzyme replacement therapy with idursulfase, that was introduced in clinical practice 15 years ago, has significantly changed the quality of life of these patients. Idursulfase is purified form of natural lysosomal enzyme iduronate-2-sulfatase obtained via human cell line. Exogenous enzyme entry promotes GAGs catabolism in cells. This article provides outcomes analysis of foreign and Russian studies on the efficacy and safety of this medication, and its effect on MPS II patients survivability.

Allergic Reactions at Enzyme Replacement Therapy in Children with Mucopolysaccharidosis Type II

Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is rare hereditary disease caused by changes in the IDS gene and associated deficiency of lysosomal enzyme iduronate-2-sulfatase (I2S). The main treatment scheme for children with MPS II is enzyme replacement therapy (ERT) with recombinant human I2S. The major issue of ERT is development of allergic (sometimes up to severe anaphylaxis) reactions to recombinant enzymes. The article covers features of infusion-related reactions to ERT, it describes pathogenesis, diagnostic criteria management algorithm of anaphylaxis. Whereas, there is the need of further studies on allergic infusion-related reactions to ERT in children.

Analysis of cognitive ability and adaptive behavior assessment tools used in an observational study of patients with mucopolysaccharidosis II

Background Mucopolysaccharidosis II (MPS II) is a rare lysosomal storage disease characterized by cognitive impairment in most patients. This post hoc analysis evaluated changes in cognitive function, adaptive behavior and functional outcomes in patients with neuronopathic MPS II over time. Fifty-five children with MPS II were enrolled in a 24-month observational study (NCT01822184). The Differential Ability Scales, second edition (DAS-II; early years battery for ages 2 years 6 months to 6 years 11 months, school age battery for ages 7 years to 17 years 11 months), Vineland Adaptive Behavior Scales, second edition (VABS-II) and the Hunter Syndrome-Functional Outcomes for Clinical Understanding Scale (HS-FOCUS) were performed at baseline and 3-month intervals over 2 years. A subgroup of 38 children with a DAS-II General Conceptual Ability (GCA) score of 55–85 (below average–very low abilities) at any time during the study were included in this analysis. Results Mean (standard deviation [SD]) early years DAS-II GCA score decreased from 73.4 (15.7, n = 22) at baseline to 62.7 (34.9, n = 6) at month 24. For the six patients with early years GCA assessments at baseline and month 24, mean (SD) GCA scores decreased from 72.3 (21.3) at baseline to 62.7 (34.9) at month 24. School age GCA scores were stable over 2 years: mean (SD) 72.4 (11.8, n = 10) at baseline; 74.3 (12.3, n = 8) at month 24. Mean (SD) VABS-II Adaptive Behavior Composite (ABC) scores were stable throughout the study (baseline, 81.8 [11.8, n = 36]; month 24, 81.0 [10.2, n = 13]). Some associations between items and domains of HS-FOCUS (p < 0.05) and DAS-II GCA and VABS-II ABC scores were shown, but there was no clear pattern of changes in HS-FOCUS over 2 years. Conclusions The DAS-II measured changes in cognitive function over 2 years in younger patients with MPS II, whereas cognitive function in older patients remained stable. Further research is required to confirm the content validity of the DAS-II in different patient populations with MPS II. The VABS-II and HS-FOCUS were not sensitive tools for measuring behavioral and functional changes over 2 years. These findings may inform selection of appropriate cognitive and behavioral assessment tools for future studies.

Golgi requires a new casting in the screenplay of mucopolysaccharidosis II cytopathology

Lysosome (L), a hydrolytic compartment of the endo-lysosomal system (ELS), plays a central role in the metabolic regulation of eukaryotic cells. Furthermore, it has a central role in the cytopathology of several diseases, primarily in lysosomal storage diseases (LSDs). Mucopolysaccharidosis II (MPS II, Hunter disease) is a rare LSD caused by idunorate-2-sulphatase (IDS) enzyme deficiency. To provide a new platform for drug development and clarifying the background of the clinically observed cytopathology, we established a human in vitro model, which recapitulates all cellular hallmarks of the disease. Some of our results query the traditional concept by which the storage vacuoles originate from the endosomal system and suggest a new concept, in which endoplasmic reticulum-Golgi intermediate compartment (ERGIC) and RAB2/LAMP positive Golgi (G) vesicles play an initiative role in the vesicle formation. In this hypothesis, Golgi is not only an indirectly affected organelle but enforced to be the main support of vacuole formation. The purposes of this minireview are to give a simple guide for understanding the main relationships in ELS, to present the storage vacuoles and their relation to ELS compartments, to recommend an alternative model for vacuole formation, and to place the Golgi in spotlight of MPS II cytopathology.

Loss of Function of Mutant IDS Due to Endoplasmic Reticulum-Associated Degradation: New Therapeutic Opportunities for Mucopolysaccharidosis Type II

Mucopolysaccharidosis type II (MPS II) results from the dysfunction of a lysosomal enzyme, iduronate-2-sulfatase (IDS). Dysfunction of IDS triggers the lysosomal accumulation of its substrates, glycosaminoglycans, leading to mental retardation and systemic symptoms including skeletal deformities and valvular heart disease. Most patients with severe types of MPS II die before the age of 20. The administration of recombinant IDS and transplantation of hematopoietic stem cells are performed as therapies for MPS II. However, these therapies either cannot improve functions of the central nervous system or cause severe side effects, respectively. To date, 729 pathogenetic variants in the IDS gene have been reported. Most of these potentially cause misfolding of the encoded IDS protein. The misfolded IDS mutants accumulate in the endoplasmic reticulum (ER), followed by degradation via ER-associated degradation (ERAD). Inhibition of the ERAD pathway or refolding of IDS mutants by a molecular chaperone enables recovery of the lysosomal localization and enzyme activity of IDS mutants. In this review, we explain the IDS structure and mechanism of activation, and current findings about the mechanism of degradation-dependent loss of function caused by pathogenetic IDS mutation. We also provide a potential therapeutic approach for MPS II based on this loss-of-function mechanism.

Evaluation of the long-term treatment effects of intravenous idursulfase in patients with mucopolysaccharidosis II (MPS II) using statistical modeling: data from the Hunter Outcome Survey (HOS)

Background Mucopolysaccharidosis II (MPS II; Hunter syndrome) is a rare, life-limiting lysosomal storage disease caused by deficient iduronate-2-sulfatase activity. Enzyme replacement therapy (ERT) with intravenous (IV) idursulfase can stabilize or improve many somatic manifestations, but there remains a need for further analysis of long-term treatment outcomes. Using data from patients with MPS II enrolled in the Hunter Outcome Survey (HOS), mixed modeling was performed to evaluate and predict the effects of IV idursulfase treatment on selected clinical parameters for up to 8 years following treatment start. The modeling population comprised male patients followed prospectively in HOS who had received IV idursulfase for at least 5 years and who had data available for two or more time points (at least one post-ERT). Age at ERT start and time since ERT start were included as covariates. Results In total, 481 patients were eligible for inclusion in at least one model. At 8 years post-ERT start, improvement from baseline was predicted for each age group (< 18 months, 18 months to < 5 years and ≥ 5 years at treatment start) in the following parameters: mean urinary glycosaminoglycan levels (percentage changes of > –75% in each group), mean left ventricular mass index (decreases of ~ 1 g/m2) and mean palpable liver size (decreases of > 2 cm). Improvements in mean 6-min walk test distance (increase of > 50 m) and stabilization in percent predicted forced vital capacity and forced expiratory volume in 1 s (decreases of ~ 4 and ~ 9 percentage points, respectively) at 8 years post-ERT start were predicted for patients aged ≥ 5 years at ERT start (these assessments are unsuitable for patients aged < 5 years). Predicted changes over time were similar across the three age groups; however, overall outcomes were most favorable in children aged < 18 months at ERT start. Conclusions These findings suggest that the previously reported positive effects of IV idursulfase on the somatic manifestations of MPS II are predicted to be maintained for at least 8 years following ERT initiation and highlight the value of statistical modeling to predict long-term treatment outcomes in patients with rare diseases.

In vitro pharmacological profiling of selected small molecules compound using recombinant human iduronate-2-sulphatase

Background: Mucopolysaccharidoses type II (MPS II) is an X-linked lysosomal storage disease (LSD). It is due to mutation in IDS gene encoding iduronate-2-sulphatase (IDS) involved in the catabolism of dermatan sulphate and heparan sulphate. Currently, the treatments for MPS II patients are enzyme replacement therapy (ERT) and bone marrow transplantation (BMT). However, ERT is not effectively reducing the central nervous system manifestation and finding the suitable donor maybe quite challenging in BMT. Over the past decades, pharmacological chaperone has been an alternative approach for management of MPS II patient. Here, we described the in vitro profiling of small molecules in group of chondroitin/dermatan (CD) sulphate disaccharide, heparin oligosaccharides, unsaturated heparin disaccharides and 6-O-desulphated heparin oligosaccharide, using recombinant human iduronate-2-sulphatase (rhIDS). Twenty-one small molecule compounds with several concentrations were each screened by inhibition and thermal stability assays. Results: Our study revealed that condroitin dermatan trisulphate (CD3S), heparin tetrasaccharide (H4Sac), heparin octasaccharide (H8Sac) and heparin octadecasaccharide (H18Sac) showed high inhibition constant, Ki and low inhibition concentration, IC50 in comparison to others. In the thermal stability study, only rhIDS incubated with CD3S was found to preserve enzyme activity (20%) after incubated at 67oC. Conclusion: Overall, our experiments discovered that CD3S was able to bind, inhibit and chaperone rhIDS. These features suggest a potential pharmacological chaperone for MPS II.

Enzyme Replacement Therapy with Pabinafusp Alfa for Neuronopathic Mucopolysaccharidosis II: An Integrated Analysis of Preclinical and Clinical Data

Enzyme replacement therapy (ERT) improves somatic manifestations in mucopolysaccharidoses (MPS). However, because intravenously administered enzymes cannot cross the blood–brain barrier (BBB), ERT is ineffective against the progressive neurodegeneration and resultant severe central nervous system (CNS) symptoms observed in patients with neuronopathic MPS. Attempts to surmount this problem have been made with intrathecal and intracerebroventricular ERT in order to achieve CNS effects, but the burdens on patients are inimical to long-term administrations. However, since pabinafusp alfa, a human iduronate-2-sulfatase fused with a BBB-crossing anti-transferrin receptor antibody, showed both central and peripheral efficacy in a mouse model, subsequent clinical trials in a total of 62 patients with MPS-II (Hunter syndrome) in Japan and Brazil substantiated this dual efficacy and provided an acceptable safety profile. To date, pabinafusp alfa is the only approved intravenous ERT that is effective against both the somatic and CNS symptoms of patients with MPS-II. This article summarizes the previously obtained preclinical and clinical evidence related to the use of this drug, presents latest data, and discusses the preclinical, translational, and clinical challenges of evaluating, ameliorating, and preventing neurodegeneration in patients with MPS-II.

Preimplantation genetic testing for mucopolysaccharidosis type II: a case report

Цель: представление клинического случая успешного преимплантационного генетического тестирования моногенного заболевания (ПГТ-М) - мукополисахаридоза второго типа (МПС II, синдром Хантера). Методы. Супружеская пара (32 и 31 год), имеющая ребенка с МПС II, обратилась за проведением ПГТ-М (патогенный вариант гена IDS - c.613delG). У женщины также имелась инверсия хромосомы 10. Для семьи была разработана система таргетного преимплантационного тестирования МПС II, валидирована на единичных лимфоцитах и продуктах полногеномной амплификации. Использовали метод двухраундной ПЦР с детекцией фрагментным анализом. В двух программах экстракорпорального оплодотворения (ЭКО) применяли стандартные протоколы стимуляции суперовуляции, оплодотворение проводили методом ИКСИ (инъекция сперматозоида в цитоплазму ооцита). Биопсию эмбрионов выполняли на пятые сутки развития (один эмбрион на шестые), эмбрионы витрифицировали. ПГТ-М проводили в транспортном варианте по схеме, разработанной на подготовительном этапе. Пренатальную диагностику выполняли методом хорионбиопсии, анализировали кариотип, ген IDS и пол плода. Результаты. При разработке системы были подобраны и протестированы 14 STR-маркеров (коротких тандемных повторов), сцепленных с геном IDS, из которых половина была информативна и давала амплификацию для единичных клеток. Разработанная для семьи система ПГТ-М МПС II включала анализ патогенного варианта гена IDS, семи информативных STR-маркеров, генов AMEL и SRY. Преимплантационное тестирование анеуплоидии не проводилось (пациентка отказалась). В первой программе ЭКО протестировано и рекомендовано к переносу три эмбриона, однако перенос был отложен по желанию супружеской пары. Во второй программе ЭКО пять эмбрионов были протестированы, три рекомендованы к переносу. Проведен криоперенос одного эмбриона мужского пола с нормальной хромосомой X в отношении патогенного варианта гена IDS. Наступила одноплодная беременность. Пренатальная диагностика полностью подтвердила результаты ПГТ-М. Беременность успешно завершилась срочными родами здорового мальчика в июле 2021 года. Заключение Разработанная нами система, успешное проведение всех этапов ЭКО и ПГТ-М и хороший репродуктивный потенциал супружеской пары позволили достичь беременности и рождения здорового ребенка в семье с высоким генетическим риском в отношении МПС II. Aim: we report of our data of successful preimplantation genetic testing (PGT-M) for mucopolysaccharidosis type II (MPS II, Hunter syndrome). Methods. A couple (32 and 31 years old) with Hunter syndrome affected child asked for PGT-M for MPS II (pathogenic variant c.613delG of the IDS gene). In addition, the woman has an inversion of chromosome 10. A system of targeted preimplantation testing was developed for the family, validated on single lymphocytes and whole genome amplification products.. Nested PCR method and fragmentary analysis were used for molecular genetic studies. Two IVF (in vitro fertilization) programs was carried out. Standard protocols for controlled ovarian hyperstimulation with fertilization by ICSI (intracytoplasmic sperm injection) were used. Embryo biopsy was performed on the 5th day of embryo development (day 6th for one embryo), embryos were vitrified. Transport PGT-M (PGT for monogenic/single gene defects) was carried using system created at pre-examination setup. Prenatal diagnosis was performed using the chorion villus biopsy method; karyotype, IDS gene and fetal sex were analyzed. Results. During setup, 14 STR (short tandem repeat) markers linked to the IDS gene were selected and tested, half of them were informative and acceptable for single cells. Developed for the family the PGT-M MPS II system included analysis of a pathogenic variant of the IDS gene, seven informative STR markers, AMEL and SRY genes. No PGT-A (PGT for aneuploidy) was carried out. In the first IVF program, three embryos were tested and recommended for transfer, but the transfer was postponed at the patient request. In the second IVF program, five embryos were tested, three recommended for transfer. Frozen single embryo transfer of normal male embryo at the second of IVF-PGT-M program was carried out. A singleton pregnancy was achieved. Prenatal diagnosis fully confirmed PGT-M results. A healthy boy was delivered in July 2021. Conclusions. The successful implementation IVF-PGT-M with developed system and good reproductive potential of the couple made it possible to achieve pregnancy and the birth of a healthy child in a family with a high genetic risk for MPS II.