Clinical Utility of Elosulfase Alfa in the Treatment of Morquio A Syndrome.

Mucopolysaccharidosis type IVA (MPS IVA or Morquio A) is an autosomal recessive disorder and is one of the lysosomal storage diseases. Patients with MPS IVA have a striking skeletal phenotype but normal intellect. The phenotypic continuum of MPS IVA ranges from severe and rapid progress to mild and slow progress. The diagnosis of MPS IVA is usually suspected based on abnormal bone findings and dysplasia on physical examination and radiographic investigation in the preschool years. In the past, only supportive care was available. Due to the early and severe skeletal abnormalities, the orthopedic specialist was usually the main care provider. However, patients need aggressive monitoring and management of their systemic disease. Therefore, they need an interdisciplinary team for their care, comprising medical geneticists, cardiologists, pulmonary specialists, gastroenterologists, otolaryngologists, audiologists, and ophthalmologists. After the US Food and Drug Administration approved elosulfase alfa in 2014, patients older than 5 years could benefit from this treatment. Clinical trials showed clinically meaningful improvements with once-a-week intravenous dosing (2.0 mg/kg per week), significantly improving the 6min walk test, the 3min stair climb test, and respiratory function when compared with placebo. Elosulfase alfa is well-tolerated, and there is a good response indicated by decreasing urine glycosaminoglycans.

Oral immunotherapy tolerizes mice to enzyme replacement therapy for Morquio A syndrome.

Immune response to therapeutic enzymes poses a detriment to patient safety and treatment outcome. Enzyme replacement therapy (ERT) is a standard therapeutic option for some types of mucopolysaccharidoses, including Morquio A syndrome caused by N-acetylgalactosamine-6-sulfate sulfatase (GALNS) deficiency. Current protocols tolerize patients using cytotoxic immunosuppressives, which can cause adverse effects. Here we show development of tolerance in Morquio A mice via oral delivery of peptide or GALNS for 10 days prior to ERT. Our results show that using an immunodominant peptide (I10) or the complete GALNS enzyme to orally induce tolerance to GALNS prior to ERT resulted in several improvements to ERT in mice: (a) decreased splenocyte proliferation after in vitro GALNS stimulation, (b) modulation of the cytokine secretion profile, (c) decrease in GALNS-specific IgG or IgE in plasma, (d) decreased GAG storage in liver, and (e) fewer circulating immune complexes in plasma. This model could be extrapolated to other lysosomal storage disorders in which immune response hinders ERT.

Effect of enzyme replacement therapy on the growth of patients with Morquio A.

Mucopolysaccharidosis IVA (MPS IVA) is a degenerative systemic skeletal dysplasia, in which children exhibit marked short stature and become physically handicapped. This study evaluated the growth patterns of patients treated with enzyme replacement therapy (ERT), compared with those of untreated patients. Cross-sectional and longitudinal data of heights and weights were collected from 128 MPS IVA patients and compared with the growth charts of MPS IVA. Twelve patients (six males, six females) starting ERT before 5 years old were treated for at least 2 years. Six out of 12 patients (50%) with ERT over 2 years stopped growing between 94 and 98 cm (mean height of 95.1 ± 2.2 cm) from 5.0 years to 9.0 years of age (mean age of 6.2 ± 1.6 years). The other patients, except one attenuated case, exhibited a marked slow growth velocity from 3.6 years to 7.7 years. Treated and untreated patients with severe phenotype reached their final heights by ~10 years of age. Patients treated with ERT exhibited a reduced pubertal growth spurt analogous to their untreated counterparts, which contributes to the marked short stature associated with MPS IVA. Compared with the growth charts for untreated patients, patients treated with ERT did not show any significant increase in growth in any age group. Overall, ERT-treated patients do not experience growth improvement and continue to exhibit poor growth despite early ERT intervention before 5 years of age. These findings indicate that current intravenous ERT is ineffective at correcting abnormal growth in MPS IVA.

Long-term endurance and safety of elosulfase alfa enzyme replacement therapy in patients with Morquio A syndrome.

Long-term efficacy and safety of elosulfase alfa enzyme replacement therapy were evaluated in Morquio A patients over 96weeks (reaching 120weeks in total from pre-treatment baseline) in an open-label, multi-center, phase III extension study. During this extension of a 24-week placebo-controlled phase III study, all patients initially received 2.0mg/kg elosulfase alfa either weekly or every other week, prior to establishment of 2.0mg/kg/week as the recommended dose, at which point all patients received weekly treatment. Efficacy measures were compared to baseline of the initial 24-week study, enabling analyses of changes over 120weeks. In addition to performing analyses for the entire intent-to-treat (ITT) population (N=173), analyses were also performed for a modified per-protocol (MPP) population (N=124), which excluded patients who had orthopedic surgery during the extension study or were non-compliant with the study protocol (as determined by ≥20% missed infusions). Six-minute walk test (6MWT) was the primary efficacy measure; three-minute stair climb test (3MSCT) and normalized urine keratan sulfate (uKS) were secondary efficacy measures. Mean (SE) change from baseline to Week 120 in 6MWT distance was 32.0 (11.3)m and 39.9 (10.1)m for patients receiving elosulfase alfa at 2.0mg/kg/week throughout the study (N=56) and 15.1 (7.1)m and 31.7 (6.8)m in all patients combined, regardless of dosing regimen, for the ITT and MPP populations, respectively. Further analyses revealed that durability of 6MWT improvements was not impacted by baseline 6MWT distance, use of a walking aid, or age. Mean (SE) change at Week 120 in the 3MSCT was 5.5 (1.9) and 6.7 (2.0)stairs/min for patients receiving elosulfase alfa at 2.0mg/kg/week throughout the study and 4.3 (1.2) and 6.8 (1.3)stairs/min in all patients combined, regardless of dosing regimen, for the ITT and MPP populations, respectively Across all patients, mean (SE) change at Week 120 in normalized uKS was -59.4 (1.8)% and -62.3 (1.8)% in the ITT and MPP populations, respectively. In the absence of a placebo group, significance of the sustained improvements could not be evaluated directly. However, to provide context for interpretation of results, comparisons were performed with untreated patients from a Morquio A natural history study. In contrast to the results of the extension study, the untreated patients experienced constant uKS levels and a gradual decline in endurance test results over a similar period of time. Differences from the untreated natural history study patients were significant for 6MWT, 3MSCT, and uKS outcomes for the cohort of patients receiving optimal dosing throughout the study and for all cohorts pooled together, for both ITT and MPP populations (P<0.05). Safety findings were consistent with those of the initial 24-week study, with no new safety signals identified.

[Morquio disease (Mucopolysaccharidosis type IV-A): clinical aspects, diagnosis and new treatment with enzyme replacement therapy]. / Enfermedad de Morquio (mucopolisacaridosis IV-A): aspectos clínicos, diagnósticos y nuevo tratamiento con terapia de reemplazo enzimático.

Mucopolysaccharidosis type IV-A (Morquio A disease) is an autosomal recessive lysosomal storage disease caused by mutations in the gene encoding the N-acetylgalactosamine-6-sulfate sulfatase, that results in impaired catabolism of two glycosaminoglycans, chondroitin-6-sulfate and keratan sulfate. Clinical presentations reflect a spectrum of progression from a severe phenotype to an attenuated expression. Accumulation of substrate manifests predominantly as short stature and skeletal dysplasia, including atlantoaxial instability and cervical cord compression. Other abnormalities in the visual, auditory, cardiovascular and respiratory systems can also affect individuals with Morquio disease. Elosulfase alfa showed in clinical trials in children and adults a significant and sustained improvement in endurance and urinary levels of keratan sulfate. Data from the ongoing observational, multinational Morquio A Registry Study will provide valuable information on the long-term efficacy and safety of elosulfase alfa in patients, as well as on the natural history of this very rare disease.

Oxidative stress and inflammation in mucopolysaccharidosis type IVA patients treated with enzyme replacement therapy.

Mucopolysaccharidosis type IVA (MPS IVA) is an inborn error of glycosaminoglycan (GAG) catabolism due to the deficient activity of N-acetylgalactosamine-6-sulfate sulfatase that leads to accumulation of the keratan sulfate and chondroitin 6-sulfate in body fluids and in lysosomes. The pathophysiology of this lysosomal storage disorder is not completely understood. The aim of this study was to investigate oxidative stress parameters, pro-inflammatory cytokine and GAG levels in MPS IVA patients. We analyzed urine and blood samples from patients under ERT (n=17) and healthy age-matched controls (n=10-15). Patients presented a reduction of antioxidant defense levels, assessed by a decrease in glutathione content and by an increase in superoxide dismutase activity in erythrocytes. Concerning lipid and protein damage, it was verified increased urine isoprostanes and di-tyrosine levels and decreased plasma sulfhydryl groups in MPS IVA patients compared to controls. MPS IVA patients showed higher DNA damage than control group and this damage had an oxidative origin in both pyrimidine and purine bases. Interleukin 6 was increased in patients and presented an inverse correlation with GSH levels, showing a possible link between inflammation and oxidative stress in MPS IVA disease. The data presented suggest that pro-inflammatory and pro-oxidant states occur in MPS IVA patients even under ERT. Taking these results into account, supplementation of antioxidants in combination with ERT can be a tentative therapeutic approach with the purpose of improving the patient's quality of life. To the best of our knowledge, this is the first study relating MPS IVA patients with oxidative stress.

Enzyme replacement in a human model of mucopolysaccharidosis IVA in vitro and its biodistribution in the cartilage of wild type mice.

Mucopolysaccharidosis IVA (MPS IVA; Morquio A syndrome) is a lysosomal storage disorder caused by deficiency of N-acetylgalactosamine-6-sulfatase (GALNS), an enzyme that degrades keratan sulfate (KS). Currently no therapy for MPS IVA is available. We produced recombinant human (rh)GALNS as a potential enzyme replacement therapy for MPS IVA. Chinese hamster ovary cells stably overexpressing GALNS and sulfatase modifying factor-1 were used to produce active ( approximately 2 U/mg) and pure (>or=97%) rhGALNS. The recombinant enzyme was phosphorylated and was dose-dependently taken up by mannose-6-phosphate receptor (K(uptake) = 2.5 nM), thereby restoring enzyme activity in MPS IVA fibroblasts. In the absence of an animal model with a skeletal phenotype, we established chondrocytes isolated from two MPS IVA patients as a disease model in vitro. MPS IVA chondrocyte GALNS activity was not detectable and the cells exhibited KS storage up to 11-fold higher than unaffected chondrocytes. MPS IVA chondrocytes internalized rhGALNS into lysosomes, resulting in normalization of enzyme activity and decrease in KS storage. rhGALNS treatment also modulated gene expression, increasing expression of chondrogenic genes Collagen II, Collagen X, Aggrecan and Sox9 and decreasing abnormal expression of Collagen I. Intravenous administration of rhGALNS resulted in biodistribution throughout all layers of the heart valve and the entire thickness of the growth plate in wild-type mice. We show that enzyme replacement therapy with recombinant human GALNS results in clearance of keratan sulfate accumulation, and that such treatment ameliorates aberrant gene expression in human chondrocytes in vitro. Penetration of the therapeutic enzyme throughout poorly vascularized, but clinically relevant tissues, including growth plate cartilage and heart valve, as well as macrophages and hepatocytes in wild-type mouse, further supports development of rhGALNS as enzyme replacement therapy for MPS IVA.

Enzymatic-assisted vitrectomy.

PURPOSE: This paper discusses the approach of enzymatic vitrectomy and potential applications. METHODS: A description of available agents for enzymatic vitreous surgery will be given and the techniques that have been suggested. RESULTS: Both animal and human results will be presented in this article regarding trials of enzymatic vitreous surgery. CONCLUSION: Enzymatic vitreous surgery may be a useful adjunct or additional agent to treat several vitreoretinal diseases.

Treatment of extravasation from parenteral nutrition solution.

OBJECTIVE: To report two cases of parenteral nutrition extravasation and their treatment in adult patients. CASE SUMMARIES: Case 1: A 23-year old white woman was admitted to our hospital diagnosed with a gastrointestinal infection by Salmonella paratyphi sv. B. The treatment included peripheral parenteral nutrition (osmolarity 652 mOsm/L). After 4 days an extravasation of parenteral nutrition was detected in the left antecubital fossa. The affected area soon became inflamed. Chondroitinsulfatase 150 turbidity-reducing units (TRUs), diluted in 3 mL of NaCl 0.9% and administered in six subcutaneous applications around the area, was prescribed. The treatment was successful. The patient was discharged several days later with no sequelae of the extravasation. Case 2: A 33-year-old white woman was admitted to the intensive care unit after surgery for a necrohemorrhagic pancreatitis. The treatment included parenteral nutrition via a central catheter (osmolarity 2130 mOsm/L). Two days later the patient presented a parenteral nutrition subcutaneous extravasation in her left hemithorax around the catheter access site. Chondroitinsulfatase 200 TRUs, diluted in 2 mL of NaCl 0.9% and administered in eight subcutaneous applications around the area, was prescribed. No sequelae of the incident remained. The patient was discharged home 2 months later. DISCUSSION: Parenteral nutrition solution can cause tissue harm after extravasation. Both patients presented an intense inflammatory reaction after the accident. Three treatments have been used in extravasation of parenteral nutrition, but in our patients hyaluronidase was the only applicable treatment. As this enzyme is not commercially available in Spain, chondroitinsulfatase, an enzyme very similar to hyaluronidase, was used. CONCLUSIONS: Chondroitinsulfatase was useful in treating extravasation of parenteral nutrition in two adult patients.

Treatment of extravasation of both doxorubicin and vincristine administration in a Y-site infusion.

OBJECTIVE: To describe a patient treated with vincristine, doxorubicin, and dexamethasone who experienced extravasation of both doxorubicin and vincristine during a Y-site infusion. CASE SUMMARY: A 74-year-old white woman was diagnosed with multiple myeloma IgA kappa in stage IIA. One year after a complete remission she relapsed. Her treatment included daily doxorubicin 16 mg in 500 mL of dextrose 5% and vincristine 0.4 mg in 500 mL of dextrose 5% administered in a Y-site continuous infusion into a peripheral vein of her left forearm. Extravasation occurred during administration of these drugs. Immediately, chondroitinsulfatase, a mucopolysaccharidase similar to hyaluronidase, was administered subcutaneously around the extravasation area and repeated 24 hours later. Furthermore, dimethyl sulfoxide 90% v/v was applied topically on the area four times daily for 2 weeks. All inflammatory signs resolved and no necrosis developed. DISCUSSION: Ths is the first report of an extravasation of two cytotoxic drugs. Doxorubicin and vincristine have different antidotes and opposite physical treatments for their extravasation. The antidotes dimethyl sulfoxide and chondroitinsulfatase have different mechanisms of action, but both cause uptake of the cytotoxic agent from the tissue and are likely to be administered together. No warming or cooling was performed. CONCLUSIONS: Topical dimethyl sulfoxide four times daily for 14 days plus subcutaneous chondroitinsulfatase in one or two applications effectively treated an extravasation of both doxorubicin and vincristine in our patient.

Ifosfamide extravasation.

OBJECTIVE: To report a case in which a local reaction is attributed to an ifosfamide extravasation. Previously, extravasated ifosfamide has been considered a nonirritant. CASE SUMMARY: A 54-year-old woman with a non-Hodgkin's lymphoma in stage IV B developed a local reaction in her right arm after an ifosfamide extravasation. No pressure was prescribed, no bandaging was applied on the affected area, and the limb was elevated to the heart level. In addition, chondroitinsulfatase 150 turbidity-reducing units was administered subcutaneously around the area. This procedure was repeated 12 hours later, resulting in a satisfactory decrease in the inflammatory signs and pain. DISCUSSION: The local reaction in the patient's arm cannot be attributed to the hypertonicity of the infusing solution or to the vehicle of the infusate. The antidote used was chondroitinsulfatase, an enzyme similar to hyaluronidase. It enhances the systemic uptake of the drug from the tissue. CONCLUSIONS: Extravasated ifosfamide is a potential irritant. General measures applied after its extravasation can be potentiated strongly by local subcutaneous administration of chondroitinsulfatase or hyaluronidase, repeated if necessary.