Efficacy and safety of intravenous laronidase for mucopolysaccharidosis type I: A systematic review and meta-analysis

Dornelles, Alícia Dorneles; Artigalás, Osvaldo Alfonso Pinto; Silva, André Anjos da; Ardila, Dora Lucía Vallejo; Alegra, Taciane; Pereira, Tiago; Vairo, Filippo Pinto e; Schwartz, Ida Vanessa Döederlein

doi:10.1371/journal.pone.0184065

Cited by 28 publications

(32 citation statements)

References 34 publications

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“…Plant-recombinant IDUA derived from Arabidopsis cgl seeds is biologically active, but does not possess the M6P motif because the plant host cells do not have the required enzymatic machinery-i.e., the PT and UCE. In order to develop the plant-produced IDUA further for ERT, one strategy is to elaborate the M6P tag in vitro, i.e., when IDUA purified from the plant host is sequentially processed by soluble forms of the PT and UCE [2,3,15]. Because of the drawbacks of in vitro processing, our main strategy is to engineer Arabidopsis lines so that they simultaneously express the human M6P enzymatic machinery (i.e., PT and UCE) together with IDUA for in vivo M6P elaboration.…”

Section: Discussionmentioning

confidence: 99%

“…The deficiency of α-L-iduronidase (IDUA) that underlies MPS I disease results in the accumulation of non-degraded glycosaminoglycans (GAGs) and causes multisystem pathology in a progressive manner [1]. Enzyme replacement therapy (ERT) is the conventional treatment for this genetic disease [2], but is costly, partly due to the traditional modes of production of recombinant IDUA. enzymes, the production platform would be particularly attractive since no downstream processing beyond M6P-IDUA purification would be required.…”

Section: Introductionmentioning

confidence: 99%

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Toward Engineering the Mannose 6-Phosphate Elaboration Pathway in Plants for Enzyme Replacement Therapy of Lysosomal Storage Disorders

Zeng

Danyukova

et al. 2019

JCM

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Mucopolysaccharidosis (MPS) I is a severe lysosomal storage disease caused by α-L-iduronidase (IDUA) deficiency, which results in accumulation of non-degraded glycosaminoglycans in lysosomes. Costly enzyme replacement therapy (ERT) is the conventional treatment for MPS I. Toward producing a more cost-effective and safe alternative to the commercial mammalian cell-based production systems, we have produced recombinant human IDUA in seeds of an Arabidopsis mutant to generate the enzyme in a biologically active and non-immunogenic form containing predominantly high mannose N-linked glycans. Recombinant enzyme in ERT is generally thought to require a mannose 6-phosphate (M6P) targeting signal for endocytosis into patient cells and for intracellular delivery to the lysosome. Toward effecting in planta phosphorylation, the human M6P elaboration machinery was successfully co-expressed along with the recombinant human IDUA using a single multi-gene construct. Uptake studies using purified putative M6P-IDUA generated in planta on cultured MPS I primary fibroblasts indicated that the endocytosed recombinant lysosomal enzyme led to substantial reduction of glycosaminoglycans. However, the efficiency of the putative M6P-IDUA in reducing glycosaminoglycan storage was comparable with the efficiency of the purified plant mannose-terminated IDUA, suggesting a poor in planta M6P-elaboration by the expressed machinery. Although the in planta M6P-tagging process efficiency would need to be improved, an exciting outcome of our work was that the plant-derived mannose-terminated IDUA yielded results comparable to those obtained with the commercial IDUA (Aldurazyme ® (Sanofi, Paris, France)), and a significant amount of the plant-IDUA is trafficked by a M6P receptor-independent pathway. Thus, a plant-based platform for generating lysosomal hydrolases may represent an alternative and cost-effective strategy to the conventional ERT, without the requirement for additional processing to create the M6P motif.Toward producing a more cost-effective and safe alternative to the commercial mammalian cell-based production systems, we have established an efficient plant-based recombinant protein production platform resulting in high-level synthesis of active human IDUA in seeds of the complex-glycan-deficient (cgl) mutant of Arabidopsis thaliana. The seed-based platform accumulates human IDUA at~5.7% total soluble protein and the enzyme is generated in a non-immunogenic form containing predominantly high mannose N-linked glycans (~94%) [3][4][5][6]. Purified cgl-recombinant IDUA was used to determine the 3-D structure of the human protein along with the essential details of its catalytic mechanism [7].The seed-derived IDUA possesses biological activities and kinetic properties that are very similar to the commercial IDUA (Aldurazyme ® (Sanofi, Paris, France)) used for ERT and derived from cultured Chinese hamster ovary (CHO) cells [6]. Our high-yielding Arabidopsis cgl seed line is thus a viable system for generating IDUA that is potentially suita...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Toward Engineering the Mannose 6-Phosphate Elaboration Pathway in Plants for Enzyme Replacement Therapy of Lysosomal Storage Disorders

Zeng

Danyukova

et al. 2019

JCM

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“…Another review only included adult patients, while the majority of the attenuated MPS I patients start ERT during childhood . The final systematic review, accompanied by a meta‐analysis mainly of uncontrolled pre‐post differences, included both clinical and surrogate outcomes …”

Section: Introductionmentioning

confidence: 99%

“…This contributes to an "efficacy-effectiveness gap": the difference between pivotal study outcomes and real-world effectiveness. 5,18 Five systematic reviews on the effectiveness of laronidase have been published, all including the pivotal study of Wraith et al 15,[19][20][21][22][23] Two of these reviews only included the pivotal study 20,21 and one review included the pivotal study and the open-label extension study. 22 Another review only included adult patients, while the majority of the attenuated MPS I patients start ERT during childhood.…”

mentioning

confidence: 99%

“…23 The final systematic review, accompanied by a metaanalysis mainly of uncontrolled pre-post differences, included both clinical and surrogate outcomes. 19 The aim of our study was to evaluate the real-world effectiveness of laronidase in pediatric and adult MPS I patients. Therefore, we performed a systematic review including studies with clinically relevant outcome measures as predefined by the reviewers while excluding the pivotal study, and evaluated effectiveness according to different scenarios established by the reviewers.…”

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confidence: 99%

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Limited data to evaluate real‐world effectiveness of enzyme replacement therapy for mucopolysaccharidosis type I

Kuiper

Nijmeijer

Roelofs

et al. 2019

J of Inher Metab Disea

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Orphan medicinal products (OMPs) are often authorized based on pivotal phase II and III trials that do not always meet high quality criteria. Laronidase is an example of an OMP used for treatment of mucopolysaccharidosis I (MPS I). One randomized controlled trial demonstrated efficacy on several somatic symptoms. However, effectiveness in the real‐world setting remains to be determined. We performed a systematic review to evaluate the effectiveness of enzyme replacement therapy (ERT) on clinically relevant outcomes in MPS I. A search in OVID MEDLINE and OVID EMBASE was performed. Postmarketing studies including MPS I patients treated with ERT and reporting data on any of 19 predefined clinical outcome measures obtained before the start of ERT and at follow‐up were eligible. Three scenarios were used to define effectiveness of ERT. The first scenario (A) assumes that improvement is essential, while the second scenario (B) also includes stabilization of signs and symptoms. The third scenario (C) defines failure of therapy. Twenty case series were included. The criteria indicating effectiveness (A), were met for four of 19 outcome measures while the criteria, indicating unclear effectiveness (B) were met for five of 19. For one of 19 nonverifiable data were reported and for nine of 19 no overall conclusions could be drawn (ambiguous results). Real‐world effectiveness of laronidase is extremely difficult to assess, 15 years after marketing authorization. This is partially due to insufficient natural history data. We recommend the conduct of rigorous and independent postmarketing studies including core outcome sets for OMPs, enforced by marketing and/or reimbursing authorities aiming to demonstrate real‐world effectiveness within a reasonable time frame.

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Advances in therapies for neurological lysosomal storage disorders

Ellison

Parker

Bigger

2023

J of Inher Metab Disea

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Lysosomal Storage Disorders (LSDs) are a diverse group of inherited, monogenic diseases caused by functional defects in specific lysosomal proteins. The lysosome is a cellular organelle that plays a critical role in catabolism of waste products and recycling of macromolecules in the body. Disruption to the normal function of the lysosome can result in the toxic accumulation of storage products, often leading to irreparable cellular damage and organ dysfunction followed by premature death. The majority of LSDs have no curative treatment, with many clinical subtypes presenting in early infancy and childhood. Over two‐thirds of LSDs present with progressive neurodegeneration, often in combination with other debilitating peripheral symptoms. Consequently, there is a pressing unmet clinical need to develop new therapeutic interventions to treat these conditions. The blood–brain barrier is a crucial hurdle that needs to be overcome in order to effectively treat the central nervous system (CNS), adding considerable complexity to therapeutic design and delivery. Enzyme replacement therapy (ERT) treatments aimed at either direct injection into the brain, or using blood–brain barrier constructs are discussed, alongside more conventional substrate reduction and other drug‐related therapies. Other promising strategies developed in recent years, include gene therapy technologies specifically tailored for more effectively targeting treatment to the CNS. Here, we discuss the most recent advances in CNS‐targeted treatments for neurological LSDs with a particular emphasis on gene therapy‐based modalities, such as Adeno‐Associated Virus and haematopoietic stem cell gene therapy approaches that encouragingly, at the time of writing are being evaluated in LSD clinical trials in increasing numbers. If safety, efficacy and improved quality of life can be demonstrated, these therapies have the potential to be the new standard of care treatments for LSD patients.

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Efficacy and safety of intravenous laronidase for mucopolysaccharidosis type I: A systematic review and meta-analysis

Cited by 28 publications

References 34 publications

Toward Engineering the Mannose 6-Phosphate Elaboration Pathway in Plants for Enzyme Replacement Therapy of Lysosomal Storage Disorders

Toward Engineering the Mannose 6-Phosphate Elaboration Pathway in Plants for Enzyme Replacement Therapy of Lysosomal Storage Disorders

Limited data to evaluate real‐world effectiveness of enzyme replacement therapy for mucopolysaccharidosis type I

Advances in therapies for neurological lysosomal storage disorders

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