Enzyme replacement therapy with galsulfase for mucopolysaccharidosis type VI

Brunelli, M.J.; Atallah, Álvaro Nagib; Silva, Edina MK da

doi:10.1002/14651858.cd009806.pub3

Cited by 6 publications

(10 citation statements)

References 26 publications

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“…[5][6][7][8][9] Galsulfase has limited effects on cardiovascular, ophthalmological, or skeletal manifestations of MPS VI. 5,[10][11][12][13] Odiparcil is an orally available small molecule previously studied at doses up to 1000 mg/day for prevention of venous thrombosis with no safety findings observed in >1900 subjects/patients. 14,15 By acting as a substrate for galactosyltransferase I, odiparcil diverts the synthesis of endogenous and soluble dermatan sulfate (DS) and chondroitin sulfate (CS) GAG bound to odiparcil, excreted from the cells, bypassing lysosomal degradation, reducing GAG load, and eliminated via the urine as shown in in vitro and in vivo models.…”

Section: Synopsismentioning

confidence: 99%

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Oral treatment for mucopolysaccharidosis VI: Outcomes of the first phase IIa study with odiparcil

Guffon

Chowdary

Teles

et al. 2021

J of Inher Metab Disea

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Mucopolysaccharidosis (MPS) disorders are a group of rare, progressive lysosomal storage diseases characterized by the accumulation of glycosaminoglycans (GAGs) and classified according to the deficient enzyme. Enzyme replacement therapy (ERT) of MPS VI has limited effects on ophthalmic, cardiovascular, and skeletal systems. Odiparcil is an orally available small molecule that results in the synthesis of odiparcil‐linked GAGs facilitating their excretion and reducing cellular and tissue GAG accumulation. Improve MPS treatment was a Phase 2a study of the safety, pharmacokinetics/pharmacodynamics, and efficacy of two doses of odiparcil in patients with MPS VI. The core study was a 26‐week, randomized, double‐blind, placebo‐controlled trial in patients receiving ERT and an open‐label, noncomparative, single‐dose cohort not receiving ERT. Patients aged ≥ 16 years receiving ERT were randomized to odiparcil 250 or 500 mg twice daily or placebo. Patients without ERT received odiparcil 500 mg twice daily. Of 20 patients enrolled, 13 (65.0%) completed the study. Odiparcil increased total urine GAGs (uGAGs), chondroitin sulfate, and dermatan sulfate concentrations. A linear increase in uGAG levels and odiparcil exposure occurred with increased odiparcil dose. Odiparcil demonstrated a good safety and tolerability profile. Individual analyses found more improvements in pain, corneal clouding, cardiac, vascular, and respiratory functions in the odiparcil groups vs placebo. This study confirmed the mechanism of action and established the safety of odiparcil with clinical beneficial effects after only a short treatment duration in an advanced stage of disease. Further assessment of odiparcil in younger patients is needed.

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Section: Synopsismentioning

confidence: 99%

“…Current treatment guidelines recommend the enzyme replacement therapy (ERT), galsulfase, to improve walking ability, endurance, and pulmonary function and to reduce urinary GAGs (uGAGs) 5‐9 . Galsulfase has limited effects on cardiovascular, ophthalmological, or skeletal manifestations of MPS VI 5,10‐13 …”

Section: Introductionmentioning

confidence: 99%

Oral treatment for mucopolysaccharidosis VI: Outcomes of the first phase IIa study with odiparcil

Guffon

Chowdary

Teles

et al. 2021

J of Inher Metab Disea

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“…The diagnosis of MPS VI is based primarily on a detection of the reduced activity of ASB in blood samples and Sanger sequencing of eight exons of the ARSB gene. The importance of early and effective diagnosis is emphasized by a presence of enzyme replacement therapy with galsulfase (Brunelli et al, 2016). A recent study analyzing 478 individuals diagnosed with MPS VI demonstrated that the ARSB mutational spectrum mainly comprise missense (59.5%), nonsense (12.0%) variants and small deletions (13.5%) (Tomanin et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Non-allelic homologous recombination leading to premature transcription termination in the ARSB gene as a novel cause of Mucopolysaccharidosis type VI

Bychkov

Filatova

Baydakova

et al. 2022

Preprint

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Mucopolysaccharidosis type VI (MPS VI) is a lysosomal storage disorder associated with pathogenic variants in the ARSB gene. Herein, we present a novel type of ARSB mutations, which is an insertion of the LHFPL2 gene fragment derived from unequal non-allelic homologous recombination between these two genes. The 52 kb insertion, containing the LHPL2 exon 3, was identified in reverse complement orientation deep in the intron 4 of ARSB using whole genome sequencing. Subsequent RNA analysis determined its deleterious effect, which is premature transcription termination. Two mobile genetic elements of the L1 class with high sequence similarity were identified in both genes at the site of recombination and their close spatial proximity is suggested to favor structural rearrangements in this locus. The recombination was identified in compound heterozygous state with the nonsense variant c.966G>A (p.Trp322*) in patient with an early-onset form of MPS VI. Almost complete absence of the full-length ARSB mRNA isoform expression from both alleles correlates well with a severe phenotype of the patient. The results of our study expand mutational spectrum of the ARSB gene towards complex structural variants and novel molecular-genetic mechanisms.

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“…The development of protein replacement therapy completely revolutionized the practice of medicine. This approach has allowed bioengineering strategies to leverage existing protein functions to replace defective proteins or supplement compromised physiologic pathways by use of novel protein-based approaches to treat a variety of disease states [ 1 , 2 , 3 , 4 , 5 , 6 , 7 ]. While most protein-based therapeutics are antibody-based and, thus, may not be considered to be as highly immunogenic, some therapeutics represent replacement of inadequately synthesized, dysfunctional, or completely absent protein products [ 7 , 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

Engineering a Therapeutic Protein to Enhance the Study of Anti-Drug Immunity

et al. 2022

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The development of anti-drug antibodies represents a significant barrier to the utilization of protein-based therapies for a wide variety of diseases. While the rate of antibody formation can vary depending on the therapeutic employed and the target patient population receiving the drug, the antigen-specific immune response underlying the development of anti-drug antibodies often remains difficult to define. This is especially true for patients with hemophilia A who, following exposure, develop antibodies against the coagulation factor, factor VIII (FVIII). Models capable of studying this response in an antigen-specific manner have been lacking. To overcome this challenge, we engineered FVIII to contain a peptide (323–339) from the model antigen ovalbumin (OVA), a very common tool used to study antigen-specific immunity. FVIII with an OVA peptide (FVIII-OVA) retained clotting activity and possessed the ability to activate CD4 T cells specific to OVA323–339 in vitro. When compared to FVIII alone, FVIII-OVA also exhibited a similar level of immunogenicity, suggesting that the presence of OVA323–339 does not substantially alter the anti-FVIII immune response. Intriguingly, while little CD4 T cell response could be observed following exposure to FVIII-OVA alone, inclusion of anti-FVIII antibodies, recently shown to favorably modulate anti-FVIII immune responses, significantly enhanced CD4 T cell activation following FVIII-OVA exposure. These results demonstrate that model antigens can be incorporated into a therapeutic protein to study antigen-specific responses and more specifically that the CD4 T cell response to FVIII-OVA can be augmented by pre-existing anti-FVIII antibodies.

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Enzyme replacement therapy with galsulfase for mucopolysaccharidosis type VI

Cited by 6 publications

References 26 publications

Oral treatment for mucopolysaccharidosis VI: Outcomes of the first phase IIa study with odiparcil

Oral treatment for mucopolysaccharidosis VI: Outcomes of the first phase IIa study with odiparcil

Non-allelic homologous recombination leading to premature transcription termination in the ARSB gene as a novel cause of Mucopolysaccharidosis type VI

Engineering a Therapeutic Protein to Enhance the Study of Anti-Drug Immunity

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