Enzyme Replacement Therapy with Elosulfase alfa for Mucopolysaccharidosis IVA (Morquio A Syndrome): Milestones and Challenges

  title={Enzyme Replacement Therapy with Elosulfase alfa for Mucopolysaccharidosis IVA (Morquio A Syndrome): Milestones and Challenges},
  author={Y. Puckett and H. Mulinder and A. Monta{\~n}o},
  journal={Expert Opinion on Orphan Drugs},
  pages={741 - 752}
ABSTRACT Introduction: Mucopolysaccharidosis IVA (Morquio A syndrome) is an inherited, autosomal recessive disease caused by a deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS), which results in excessive lysosomal storage of keratan sulfate and chondroitin-6-sulfate in many tissues and organs. This accumulation causes a systemic skeletal dysplasia and leads to multiple clinical manifestations, including impaired endurance and respiratory function. Elosulfase alfa (trade name… Expand
Enzyme Replacement Therapy in Mucopolysaccharidoses Vartanyan , Montaño e 157
Mucopolysaccharidoses (MPS) are a group of genetic diseases that are caused by deficient lysosomal enzymes involved in the breakdown of glycosaminoglycans (GAGs), resulting in the accumulation ofExpand
Causal Therapies in Mucopolysaccharidoses: Enzyme Replacement Therapy
Intravenous weekly infusions of recombinant enzymes for MPS I, II, IVA, VI, and VII have proven to be safe and efficacious for somatic symptoms, and ERT has been shown to decrease urinary glycosaminoglycan levels and organomegaly, while improving stamina of patients, respiratory function, and quality of life. Expand
Oral immunotherapy tolerizes mice to enzyme replacement therapy for Morquio A syndrome.
Using an immunodominant peptide or the complete enzyme to orally induce tolerance to GALNS prior to ERT, resulted in several improvements to ERTs in mice, which could be extrapolated to other lysosomal storage disorders where immune response hinders ERT. Expand
Characterization of Human Recombinant N-Acetylgalactosamine-6-Sulfate Sulfatase Produced in Pichia pastoris as Potential Enzyme for Mucopolysaccharidosis IVA Treatment.
The production of an active GALNS enzyme produced in the yeast Pichia pastoris (prGALNS), which showed internalization by cultured cells through a potential receptor-mediated process and similar post-translational processing as human enzyme, represents an important step in the development of a P. pastoris-based platform for production of a therapeutic GAL NS for MPS IVA enzyme replacement therapy. Expand
Effect of enzyme replacement therapy on the growth of patients with Morquio A
Overall, ERT-treated patients do not experience growth improvement and continue to exhibit poor growth despite early ERT intervention before 5 years of age, indicating that current intravenous ERT is ineffective at correcting abnormal growth in MPS IVA. Expand
Umbilical mesenchymal stem cell-derived extracellular vesicles as enzyme delivery vehicle to treat Morquio A fibroblasts
This enzyme delivery method, which was unaffected by M6P inhibition, can function as a novel technique for reducing GAG accumulation in cells in avascular tissues, thereby providing a potential treatment option for Morquio A syndrome. Expand
Biodegradable polyethylene glycol hydrogels for sustained release and enhanced stability of rhGALNS enzyme
The developed hydrogel delivery device could overcome current limits of rhGALNS replacement and improve quality of life for Morquio A patients by preserving its activity, and provides sustained release for a period of at least 7 days. Expand
Tailoring the AAV2 capsid vector for bone-targeting
Inserting a bone-targeting peptide into the vector capsid increases gene delivery and expression in the bone without decreasing enzyme expression and could be a novel strategy to treat systemic bone diseases. Expand


Elosulfase Alfa: A Review of Its Use in Patients with Mucopolysaccharidosis Type IVA (Morquio A Syndrome)
In clinical trials in children and adults with MPS IVA, intravenous elosulfase alfa 2 mg/kg/week provided significant and sustained improvements in urinary levels of KS and chondroitin-6-sulfate, a pharmacodynamic biomarker for the disease. Expand
Elosulfase alfa (BMN 110) for the treatment of mucopolysaccharidosis IVA (Morquio A Syndrome)
  • C. Hendriksz
  • Medicine
  • Expert review of clinical pharmacology
  • 2016
This work has shown that accurate biomarkers for evaluating disease state and drug responsiveness would greatly aid in the treatment of patients with Morquio A, and improved and innovative daily lifestyle measures are greatly needed to adequately measure clinical response and true impact on quality of life. Expand
Immunogenicity of Elosulfase Alfa, an Enzyme Replacement Therapy in Patients With Morquio A Syndrome: Results From MOR-004, a Phase III Trial.
Despite the universal development of antidrug antibodies, elosulfase alfa treatment was both safe and well tolerated and immunogenicity was not associated with reduced treatment effect. Expand
Role of elosulfase alfa in mucopolysaccharidosis IVA
The treatment was generally well tolerated, and the uncommon infusion reactions responded well to traditional enzyme replacement therapy infusion reaction management algorithms. Expand
Enzyme replacement therapy in a murine model of Morquio A syndrome.
These preclinical studies demonstrate the clearance of tissue and blood KS by administered GALNS, providing the in vivo rationale for the design of ERT trials in MPS IVA. Expand
Pharmacokinetic and Pharmacodynamic Evaluation of Elosulfase Alfa, an Enzyme Replacement Therapy in Patients with Morquio A Syndrome
Despite the association between NAb and decreased drug clearance, neither dosing cohort showed associations between drug exposure and change in urinary keratan sulfate, 6-min walk test distances, or the occurrence of adverse events. Expand
Mucopolysaccharidosis type IVA (Morquio A disease): clinical review and current treatment.
An overview of the clinical manifestations, diagnosis and symptomatic management of patients with MPS IVA is provided and potential perspectives of ERT and HSCT are described. Expand
Enzyme Replacement in a Human Model of Mucopolysaccharidosis IVA In Vitro and Its Biodistribution in the Cartilage of Wild Type Mice
It is shown 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. Expand
Mucopolysaccharidosis IVA: identification of mutations and methylation study in GALNS gene
Investigations of the molecular nature of MPS IVA have been facilitated by purifying the enzyme, and by isolating and characterising both the GALNS gene and the full-length cDNA encoding the human GAL NS protein. Expand
Safety and clinical activity of elosulfase alfa in pediatric patients with Morquio A syndrome (mucopolysaccharidosis IVA) less than 5 y
Early intervention with elosulfase alfa is well-tolerated and produces a decrease in uKS and a trend toward improvement in growth, which is similar to that seen in untreated patients. Expand