Predicting intelligence in MPS IH with biomarkers

Hematopoietic cell transplantation for Mucopolysaccharidosis I in the presence of decreased cardiac function

In mucopolysaccharidosis I, deficiency of alpha-L-iduronidase can cause spinal cord compression (SCC) due to storage of glycosaminoglycans (GAGs) within the cervical meninges. As intravenous enzyme replacement therapy (ERT) is not likely to provide enzyme across the blood-brain barrier, standard treatment for this complication is usually surgical, which has a high morbidity and mortality risk. We report on the use of intrathecal (IT) laronidase in a MPS I patient with SCC who refused the surgical treatment. Assessments were performed at baseline, with clinical and biochemical evaluations, 4-extremity somatosensory evoked potentials, 12 min walk test and MRI studies of the CNS. Changes on these parameters were evaluated after 4 IT infusions of laronidase administered monthly via lumbar puncture. To our knowledge, this was the first MPS patient who received IT ERT. No major adverse events were observed. There were no clinically significant changes in serum chemistries. CSF GAG results revealed pretreatment values slightly above normal standards: 13.3 mg/L (NV < 12 mg/L) which after IT laronidase infusions were within normal levels (10.3 mg/L). 12MWT presented a 14% improvement, with better performance on stability and gait control. Maximum voluntary ventilation showed 55.6% improvement considering the percentage of predicted (26.7% at baseline compared to 41.9%); Maximum Inspiration Pressure improved 36.6% of predicted (26.8% at baseline to 36.7%); Pulmonary diffusion improved 17.6% of predicted %. In conclusion, although the improvement observed in this case with IT laronidase should be confirmed in further patients, this procedure seems to be a safe treatment for SCC in MPS I.

ABSTRACTIntroduction: Mucopolysaccharidosis Type II (MPS II; Hunter syndrome) is an X- linked lysosomal storage disorder caused by a deficiency of iduronate-2-sulfatase (IDS). IDS deficiency leads to primary accumulation of dermatan sulfate (DS) and heparan sulfate (HS). MPS II is both multi-systemic and progressive. Phenotypes are classified as either attenuated or severe (based on absence or presence of central nervous system impairment, respectively).Areas covered: Current treatments available are intravenous enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT), anti-inflammatory treatment, and palliative care with symptomatic surgeries. Clinical trials are being conducted for intrathecal ERT and gene therapy is under pre-clinical investigation. Treatment approaches differ based on age, clinical severity, prognosis, availability and feasibility of therapy, and health insurance. This review provides a historical account of MPS II treatment as well as treatment development with insights into benefits and/or limitations of each specific treatment.Expert opinion: Conventional ERT and HSCT coupled with surgical intervention and palliative therapy are currently the treatment options available to MPS II patients. Intrathecal ERT and gene therapy are currently under investigation as future therapies. These investigative treatments are critical to address the limitations in treatment of the central nervous system (CNS).

Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is an X-linked hereditary disorder associated with a deficiency of iduronate2-sulfatase (IDS). IDS deficiency provokes the accumulation of dermatan sulfate and heparan sulfate in different tissues. Clinical manifestations of MPS II are heterogeneous and involve different organs. Two phenotypes are distinguished: attenuated or severe; classification is based on central nervous system impairment signs. The review provides data on the current treatments opportunities for Hunter syndrome and perspectives for development of new therapeutic approaches. Current treatment includes intravenous enzyme replacement therapy (ERT), hematopoietic stem cell transplantation, and symptomatic treatment. Intravenous enzyme replacement therapy does not promote the enzyme to penetrate the blood-brain barrier which leads to the treatment failure for neurological signs and symptoms; hematopoietic stem cell transplantation has high risk of post-transplantation complications but can improve some neurological problems. Intrathecal ERT, substrate reduction, pharmacological chaperones, and gene therapy are currently under investigation as therapies for severe form of MPS II. Development of new approaches to treatment of Hunter syndrome and other hereditary diseases is extremely vital.

ABSTRACTIntroduction: 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.

Mucopolysaccharidosis type II (MPS II) is a rare, pediatric, neurometabolic disorder due to the lack of activity of the lysosomal hydrolase iduronate 2-sulfatase (IDS), normally degrading heparansulfate and dermatansulfate within cell lysosomes. The deficit of activity is caused by mutations affecting the IDS gene, leading to the pathological accumulation of both glycosaminoglycans in the lysosomal compartment and in the extracellular matrix of most body districts. Although a continuum of clinical phenotypes is described, two main forms are commonly recognized-attenuated and severe-the latter being characterized by an earlier and faster clinical progression and by a progressive impairment of central nervous system (CNS) functions. However, attenuated forms havealso been recently described as presenting some neurological involvement, although less deep, such as deficits of attention and hearing loss. The main treatment for the disease is represented by enzyme replacement therapy (ERT), applied in several countries since 2006, which, albeit showing partial efficacy on some peripheral organs, exhibited a very poor efficacy on bones and heart, and a total inefficacy on CNS impairment, due to the inability of the recombinant enzyme to cross the blood-brain barrier (BBB). Together with ERT, whose design enhancements, performed in the last few years, allowed a possible brain penetration of the drug through the BBB, other therapeutic approaches aimed at targeting CNS involvement in MPS II were proposed and evaluated in the last decades, such as intrathecal ERT, intracerebroventricular ERT, ex vivo gene therapy, or adeno-associated viral vector (AAV) gene therapy. The aim of this review is to summarize the main clinical aspects of MPS II in addition to current therapeutic options, with particular emphasis on the neurological ones and on the main CNS-targeted therapeutic approaches explored through the years.

Intraventricular Enzyme Replacement Improves Disease Phenotypes in a Mouse Model of Late Infantile Neuronal Ceroid Lipofuscinosis

This review aims to provide clinicians in Latin America with the most current information on the clinical aspects, diagnosis, and management of Hunter syndrome, a serious and progressive disease for which specific treatment is available. Hunter syndrome is a genetic disorder where iduronate-2-sulfatase (I2S), an enzyme that degrades glycosaminoglycans, is absent or deficient. Clinical manifestations vary widely in severity and involve multiple organs and tissues. An attenuated and a severe phenotype are recognized depending on the degree of cognitive impairment. Early diagnosis is vital for disease management. Clinical signs common to children with Hunter syndrome include inguinal hernia, frequent ear and respiratory infections, facial dysmorphisms, macrocephaly, bone dysplasia, short stature, sleep apnea, and behavior problems. Diagnosis is based on screening urinary glycosaminoglycans and confirmation by measuring I2S activity and analyzing I2S gene mutations. Idursulfase (recombinant I2S) (Elaprase(®), Shire) enzyme replacement therapy (ERT), designed to address the underlying enzyme deficiency, is approved treatment and improves walking capacity and respiratory function, and reduces spleen and liver size and urinary glycosaminoglycan levels. Additional measures, responding to the multi-organ manifestations, such as abdominal/inguinal hernia repair, carpal tunnel surgery, and cardiac valve replacement, should also be considered. Investigational treatment options such as intrathecal ERT are active areas of research, and bone marrow transplantation is in clinical practice. Communication among care providers, social workers, patients and families is essential to inform and guide their decisions, establish realistic expectations, and assess patients' responses.

Outcomes following treatment for ADA-deficient severe combined immunodeficiency: a report from the PIDTC

Unexpected coronary artery findings in mucopolysaccharidosis. Report of four cases and literature review

Hurler syndrome (MPS IH) is the most severe form of mucopolysaccharidosis type I. It is caused by deficiency or absence of the enzyme alpha-L-iduronidase. Cardiac involvement includes cardiomyopathy and valve and coronary pathology. Cardiomyopathy causing symptoms in an infant with MPS IH carries a very poor prognosis. We describe a previously healthy 10-week-old boy who was admitted to hospital critically ill with severe heart failure. Echocardiography on admission showed severe dilatation of the left ventricle and moderate insufficiency of the left-sided cardiac valves. Accumulation of heparan sulfate and dermatan sulfate substrates in the urine and leukocyte analysis confirmed the diagnosis of MPS IH. Enzyme replacement therapy (ERT) with intravenous laronidase at a standard dosage of 100 U/kg weekly was started soon after. This improved the child's general clinical wellbeing dramatically. His cardiac function improved steadily over a period of months. Stem cell transplantation from cord blood is not available in Norway and he underwent successful transplantation from an unrelated bone marrow donor at the age of 11 months. ERT was stopped four months later. At the age of 26 months his heart function is close to normal and he is currently on no medication. This report highlights three important clinical issues: (1) MPS IH must be considered in infants with cardiomyopathy; (2) early ERT may have a significant impact on short-term outcome in children less than 18 months old with severe cardiomyopathy; (3) our report confirms that patients in poor condition benefit from ERT before stem cell transplantation.

BackgroundSanfilippo type B is a mucopolysaccharidosis (MPS) with a major neuronopathic component characterized by heparan sulfate (HS) accumulation due to mutations in the NAGLU gene encoding alfa-N-acetyl-glucosaminidase. Enzyme replacement therapy for neuronopathic MPS requires efficient enzyme delivery throughout the brain in order to normalize HS levels, prevent brain atrophy, and potentially delay cognitive decline.MethodsIn this phase I/II open-label study, patients with MPS type IIIB (n = 22) were treated with tralesinidase alfa administered i.c.v. The patients were monitored for drug exposure; total HS and HS nonreducing end (HS-NRE) levels in both cerebrospinal fluid (CSF) and plasma; anti-drug antibody response; brain, spleen, and liver volumes as measured by MRI; and cognitive development as measured by age-equivalent (AEq) scores.ResultsIn the Part 1 dose escalation (30, 100, and 300 mg) phase, a 300 mg dose of tralesinidase alfa was necessary to achieve normalization of HS and HS-NRE levels in the CSF and plasma. In Part 2, 300 mg tralesinidase alfa sustained HS and HS-NRE normalization in the CSF and stabilized cortical gray matter volume (CGMV) over 48 weeks of treatment. Resolution of hepatomegaly and a reduction in spleen volume were observed in most patients. Significant correlations were also established between the change in cognitive AEq score and plasma drug exposure, plasma HS-NRE levels, and CGMV.ConclusionAdministration of tralesinidase alfa i.c.v. effectively normalized HS and HS-NRE levels as a prerequisite for clinical efficacy. Peripheral drug exposure data suggest a role for the glymphatic system in altering tralesinidase alfa efficacy.Trial registrationClinicaltrials.gov NCT02754076.FUNDINGBioMarin Pharmaceutical Inc. and Allievex Corporation.

e19503 Background: HCT is commonly used for consolidation for MM patients (pts). These pts have a significant risk of VTE and may potentially be candidates for prophylactic anticoagulation. However, incidence and outcomes of VTE in peri-transplant period remain unclear for MM pts. Methods: Between 2006 and 2016, 160 MM pts underwent autologous HCT at our institution. Peri-transplant period was defined as between initiation of stem cell collection (SCC) and 30 days after discharge from HCT hospitalization. No pts received routine VTE prophylaxis. Clinically significant bleeding was defined as a bleeding event that led to a specific clinical intervention, such as transfusion. We used Cox regression to assess risk factors for peri-transplant VTE. We compared overall survival (OS) using log-rank test. Results: In peri-transplant period, 18 symptomatic VTE occurred in 17 pts (10.6%; 95% CI 7 - 17). Twelve (7.5%) were catheter-related, 4 (2.5%) were non-catheter-related deep venous thrombosis, and 2 (1.3%) were pulmonary emboli. Seven VTE occurred between SCC and HCT. Importantly, among 11 VTE after HCT, only 1 VTE occurred before neutrophil engraftment and only 2 VTE occurred at a platelet count less than 50 x 109/L (median: 138, range: 30 - 464). Clinically significant bleeding occurred in 9 (5.6%) pts during peri-transplant period, without any fatal bleeding. Multivariate analysis was performed including; treatment with immunomodulatory drugs (p = 0.008), HCT comorbidity index ≥ 2 (p = 0.036), age &gt; 60 (p = 0.07), smoking at any time (p = 0.07), BMI &gt; 30 at HCT (p = 0.19), partial remission at HCT (p = 0.20), ISS stage 3 at diagnosis (p = 0.37). At median follow-up of 31 months since HCT, 3-year OS for pts with and without peri-transplant VTE was 58.8% (CI 38% - 91%) and 77.6% (CI 70% - 86%), respectively (p = 0.11). Conclusions: Peri-transplant symptomatic VTE was highly prevalent in our cohort of pts with MM and vast majority of VTE events occurred either between SCC and HCT or after neutrophil engraftment. Our findings indicate that routine VTE prophylaxis in peri-transplant period should be considered for MM pts and timing of VTE prophylaxis can be tailored to optimize balance between safety and efficacy.

Although not curative, enzyme replacement therapy (ERT) with recombinant human acid alpha-glucosidase enzyme has shown to be effective in the treatment of late-onset Pompe disease (LOPD). For this potentially life-long treatment, little is known on the clinical effect of cessation and resuming ERT. Due to a Swiss supreme court decision on ERT reimbursement, a temporary stop of ERT occurred in our study population. The aim of this study was to report the 36-months follow-up assessments after resuming ERT. After resuming ERT, seven patients suffering from genetically and enzymatically confirmed LOPD had periodic, mandatory, prospective assessments of pulmonary function tests, muscle strength summary scores, distances walked in timed walking tests, and patient-reported questionnaires. Data were statistically analyzed for significant differences between time points at ERT cessation, at ERT resuming, and 36 months thereafter. After resuming ERT forced vital capacity (p = 0.007) and distance walked in the 6min walk test (6-MWT, p = 0.011) significantly increased at 36 months. Compared to before ERT cessation, distance walked in 6-MWT at 36 months still remained significantly lower (p = 0.005). Self-reported scores in the fatigue severity scale significantly declined at 36 months after resuming ERT (p = 0.019). No other functional or reported parameter significantly changed at 36 months after resuming ERT. Our data suggests that long-term interruption of ERT in LOPD may lead to deterioration of clinical meaningful parameters and quality of life. In addition, a clinical restoration after ERT cessation is possible for most of the LOPD patients within a 36 months follow-up.

Enzyme replacement therapy (ERT) with cerliponase alfa (Brineura) has been shown to slow the progression of milestone deterioration in neuronal ceroid lipofuscinosis type 2 (CLN2), an inherited neurodegenerative lysosomal storage disorder. Cerliponase alfa must be administered intraventricularly every 2 weeks, necessitating the placement of ventricular reservoirs and requiring frequent access. Traditionally, positive cerebrospinal fluid (CSF) cultures obtained from implanted ventricular reservoirs are managed with device replacement and antibiotic treatment. The authors sought to establish which circumstances might allow for careful observation without device removal. In this study, the authors report their single-institution experience with the clinical outcomes of positive CSF cultures in 16 CLN2 patients with ventricular reservoirs over 6 years. The authors retrospectively reviewed a cohort of 16 patients with CLN2 disease who had ventricular reservoirs placed for ERT administration. At each ERT infusion, CSF was collected by sterile technique and cultured with both thioglycolate broth and agar plate. This CSF collection was standard practice as per the initial trial protocol for use of ERT in CLN2. Epidemiological and microbiological data, symptomatology, total antibiotic days, removal and replacement of the ventricular reservoir, hospital length of stay, and mortality were analyzed for each patient. In the authors' cohort, 11 of 16 patients (69%) had at least 1 positive CSF culture. Of the 11 patients with positive cultures, only 3 had their device removed and replaced due to a positive culture with concurrent antibiotic treatment at the authors' center, and 2 patients subsequently were treated with prophylactic antibiotic infusion. Of 1401 total CSF cultures, 64 (4.56%) were positive. The most common organism grown was Cutibacterium acnes, which typically only grew in broth culture (82%), suggesting low bacterial burden. The other 8 patients with positive cultures remained asymptomatic with no intervention required. At the authors' institution, we have found that in asymptomatic patients with frequently accessed ventricular reservoirs, positive CSF culture with low virulence skin flora was common. Rarely did positive cultures with common skin flora necessitate intervention. The authors' experience has shown that nonvirulent infection of ventricular reservoirs with low virulence skin flora can be monitored without intervention. This strategy reduces the risks of invasive surgery, prolonged antibiotic courses, and missed infusions.