Clinical manifestations and treatment of mucopolysaccharidosis type I patients in Latin America as compared with the rest of the world

Background Mucopolysaccharidosis I (MPS I) comprises a spectrum of clinical manifestations and is divided into three phenotypes reflecting clinical severity: Hurler, Hurler-Scheie, and Scheie syndromes. There may be important variations in clinical manifestations of this genetic disease in patients residing in different regions of the world.Methods Using data from the MPS I Registry (as of September 2009), we evaluated patients from Latin America (n=118) compared with patients from the rest of the world [ROW (n=727)].Results Phenotype distribution differed among patients in Latin America compared to ROW(Hurler 31 vs. 62%, Hurler-Scheie 36 vs. 21%, Scheie 10 vs. 11%, and unknown 22 vs. 6%). the frequency of certain symptoms, such as cardiac valve abnormalities, sleep impairment, and joint contractures, also differed between Latin America and ROW for some phenotypes. Median age at MPS I diagnosis was earlier in the ROW than Latin America for all phenotypes, and age at first treatment for Hurler and Hurler-Scheie patients was also earlier in the ROW. Hurler patients in Latin America showed a gap of 3.1 years between median ages of diagnosis and first treatment compared to only 0.5 years in the ROW. Treatment allocation in Latin America compared to ROW was as follows: enzyme replacement therapy (ERT) only, 80 vs. 45%; hematopoietic stem cell transplantation (HSCT) only, 0.9 vs. 27%; both ERT and HSCT, 0 vs. 16%; and neither treatment, 19 vs. 13%.Conclusion These data highlight important differences in MPS I patients between Latin America and ROW in terms of phenotypic distribution, clinical manifestations, and treatment practices.MPS I Registry team at Genzyme CorporationHosp Nacl Pediat JP Garrahan, Unidad Errores Congenitos Metab, Buenos Aires, DF, ArgentinaHosp Especialidades UMAE 25, Monterrey, MexicoGenzyme Corp, Latin Amer Grp, Registry Program, Rio de Janeiro, BrazilUniv Rosario, Fdn Univ Ciencias Salud, Bogota, ColombiaUniv Valparaiso, Fac Med, Neurol Infantil Programa Formac Neuropediat, Valparaiso, ChileUniv Chile, INTA, Lab Genet & Enfermedades Metab, Santiago, ChileUniversidade Federal de São Paulo, Ctr Referencia Erros Inatos Metab, São Paulo, BrazilGenzyme Corp, Latin Amer Grp, Compassionate Use Program, Rio de Janeiro, BrazilUniversidade Federal de São Paulo, Ctr Referencia Erros Inatos Metab, São Paulo, BrazilWeb of Scienc

A Plant-Derived Recombinant Human Glucocerebrosidase Enzyme—A Preclinical and Phase I Investigation

Gaucher disease is a progressive lysosomal storage disorder caused by the deficiency of glucocerebrosidase leading to the dysfunction in multiple organ systems. Intravenous enzyme replacement is the accepted standard of treatment. In the current report, we evaluate the safety and pharmacokinetics of a novel human recombinant glucocerebrosidase enzyme expressed in transformed plant cells (prGCD), administered to primates and human subjects. Short term (28 days) and long term (9 months) repeated injections with a standard dose of 60 Units/kg and a high dose of 300 Units/kg were administered to monkeys (n = 4/sex/dose). Neither clinical drug-related adverse effects nor neutralizing antibodies were detected in the animals. In a phase I clinical trial, six healthy volunteers were treated by intravenous infusions with escalating single doses of prGCD. Doses of up to 60 Units/kg were administered at weekly intervals. prGCD infusions were very well tolerated. Anti-prGCD antibodies were not detected. The pharmacokinetic profile of the prGCD revealed a prolonged half-life compared to imiglucerase, the commercial enzyme that is manufactured in a costly mammalian cell system. These studies demonstrate the safety and lack of immunogenicity of prGCD. Following these encouraging results, a pivotal phase III clinical trial for prGCD was FDA approved and is currently ongoing.ClinicalTrials.gov NCT00258778

Clinical trial of laronidase in Hurler syndrome after hematopoietic cell transplantation.

BackgroundMucopolysaccharidosis I (MPS IH) is a lysosomal storage disease treated with hematopoietic cell transplantation (HCT) because it stabilizes cognitive deterioration, but is insufficient to alleviate all somatic manifestations. Intravenous laronidase improves somatic burden in attenuated MPS I. It is unknown whether laronidase can improve somatic disease following HCT in MPS IH. The objective of this study was to evaluate the effects of laronidase on somatic outcomes of patients with MPS IH previously treated with HCT.MethodsThis 2-year open-label pilot study of laronidase included ten patients (age 5-13 years) who were at least 2 years post-HCT and donor engrafted. Outcomes were assessed semi-annually and compared to historic controls.ResultsThe two youngest participants had a statistically significant improvement in growth compared to controls. Development of persistent high-titer anti-drug antibodies (ADA) was associated with poorer 6-min walk test (6MWT) performance; when patients with high ADA titers were excluded, there was a significant improvement in the 6MWT in the remaining seven patients.ConclusionsLaronidase seemed to improve growth in participants <8 years old, and 6MWT performance in participants without ADA. Given the small number of patients treated in this pilot study, additional study is needed before definitive conclusions can be made

The role of enzyme replacement therapy in severe Hunter syndrome—an expert panel consensus

Intravenous enzyme replacement therapy (ERT) with idursulfase for Hunter syndrome has not been demonstrated to and is not predicted to cross the blood–brain barrier. Nearly all published experience with ERT with idursulfase has therefore been in patients without cognitive impairment (attenuated phenotype). Little formal guidance is available on the issues surrounding ERT in cognitively impaired patients with the severe phenotype. An expert panel was therefore convened to provide guidance on these issues. The clinical experience of the panel with 66 patients suggests that somatic improvements (e.g., reduction in liver volume, increased mobility, and reduction in frequency of respiratory infections) may occur in most severe patients. Cognitive benefits have not been seen. It was agreed that, in general, severe patients are candidates for at least a 6–12-month trial of ERT, excluding patients who are severely neurologically impaired, those in a vegetative state, or those who have a condition that may lead to near-term death. It is imperative that the treating physician discuss the goals of treatment, methods of assessment of response, and criteria for discontinuation of treatment with the family before ERT is initiated. Conclusion: The decision to initiate ERT in severe Hunter syndrome should be made by the physician and parents and must be based on realistic expectations of benefits and risks, with the understanding that ERT may be withdrawn in the absence of demonstrable benefits

A Comparative Approach Linking Molecular Dynamics of Altered Peptide Ligands and MHC with In Vivo Immune Responses

The recognition of peptide in the context of MHC by T lymphocytes is a critical step in the initiation of an adaptive immune response. However, the molecular nature of the interaction between peptide and MHC and how it influences T cell responsiveness is not fully understood.We analyzed the immunological consequences of the interaction of MHC class II (I-Au) restricted 11-mer peptides of myelin basic protein with amino acid substitutions at position 4. These mutant peptides differ in MHC binding affinity, CD4+ T cell priming, and alter the severity of peptide-induced experimental allergic encephalomyelitis. Using molecular dynamics, a computational method of quantifying intrinsic movements of proteins at high resolution, we investigated conformational changes in MHC upon peptide binding. We found that irrespective of peptide binding affinity, MHC deformation appears to influence costimulation, which then leads to effective T cell priming and disease induction. Although this study compares in vivo and molecular dynamics results for three altered peptide ligands, further investigation with similar complexes is essential to determine whether spatial rearrangement of peptide-MHC and costimulatory complexes is an additional level of T cell regulation

Autoimmune and autoinflammatory mechanisms in uveitis

The eye, as currently viewed, is neither immunologically ignorant nor sequestered from the systemic environment. The eye utilises distinct immunoregulatory mechanisms to preserve tissue and cellular function in the face of immune-mediated insult; clinically, inflammation following such an insult is termed uveitis. The intra-ocular inflammation in uveitis may be clinically obvious as a result of infection (e.g. toxoplasma, herpes), but in the main infection, if any, remains covert. We now recognise that healthy tissues including the retina have regulatory mechanisms imparted by control of myeloid cells through receptors (e.g. CD200R) and soluble inhibitory factors (e.g. alpha-MSH), regulation of the blood retinal barrier, and active immune surveillance. Once homoeostasis has been disrupted and inflammation ensues, the mechanisms to regulate inflammation, including T cell apoptosis, generation of Treg cells, and myeloid cell suppression in situ, are less successful. Why inflammation becomes persistent remains unknown, but extrapolating from animal models, possibilities include differential trafficking of T cells from the retina, residency of CD8(+) T cells, and alterations of myeloid cell phenotype and function. Translating lessons learned from animal models to humans has been helped by system biology approaches and informatics, which suggest that diseased animals and people share similar changes in T cell phenotypes and monocyte function to date. Together the data infer a possible cryptic infectious drive in uveitis that unlocks and drives persistent autoimmune responses, or promotes further innate immune responses. Thus there may be many mechanisms in common with those observed in autoinflammatory disorders

Diagnosing Hunter syndrome in pediatric practice: practical considerations and common pitfalls

Mucopolysaccharidosis II (MPS II), or Hunter syndrome, is an X-linked lysosomal storage disorder caused by a deficiency in the enzyme iduronate-2-sulfatase. Affected patients suffer progressive damage to multiple organ systems and early mortality. Two thirds of patients also manifest cognitive impairment and developmental delays. MPS II can be extremely difficult to diagnose before irreversible organ and tissue damage has occurred because of an insidious onset and the overlap in signs and symptoms with common childhood complaints. This is particularly true of patients without cognitive impairment (attenuated phenotype). Although not curative, early treatment with enzyme replacement therapy before irreversible organ damage has occurred may result in the greatest clinical benefit. Here, the signs, symptoms, and surgical history that should trigger suspicion of MPS II are described, and the diagnostic process is reviewed with a focus on practical considerations and the avoidance of common diagnostic pitfalls. Once a diagnosis is made, multidisciplinary management with an extended team of pediatric specialists is essential and should involve the pediatrician or family practice physician as facilitator and medical home for the patient and family. Conclusion: Because routine newborn screening is not yet available for MPS II, the involvement and awareness of pediatricians, family practice physicians, and pediatric specialists is critical for early identification, diagnosis, and referral in order to help optimize patient outcomes

Galanin Transgenic Mice with Elevated Circulating Galanin Levels Alleviate Demyelination in a Cuprizone-Induced MS Mouse Model

Multiple Sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system (CNS) with a presumed autoimmune etiology. Approved treatments for MS are immunoregulatory and are able to reduce the inflammatory components of the disease. However, these treatments do not suppress progressive clinical disability. Approaches that directly protect myelin-producing oligodendrocytes and enhance remyelination are likely to improve long-term outcomes and reduce the rate of axonal damage. Galanin (GAL) is a bioactive neuropeptide that is widely distributed throughout the nervous system and has diverse neuromodulatory effects. In this study, using the cuprizone (CPZ) demyelination model of MS, we demonstrate that GAL has pronounced neuroprotective effects with respect to demyelination and remyelination. Using our GAL transgenic mouse (GAL-Tg), we identified a novel attenuation of OLs against CPZ induced demyelination, which was exerted independently of progenitor cells. Alleviation of myelin breakdown in the GAL-Tg mice was observed to be significant. Furthermore, we observed changes in the expression of the GAL receptor GalR1 during the demyelination and remyelination processes. Our data strongly indicate that GAL has the capacity to influence the outcome of primary insults that directly target OLs, as opposed to cases where immune activation is the primary pathogenic event. Taken together, these results suggest that GAL is a promising next-generation target for the treatment of MS