Long-term safety and clinical outcomes of intrathecal heparan-N-sulfatase in patients with Sanfilippo syndrome type A

Wijburg, Frits A.; Heap, Fiona; Rust, Stewart; Ruijter, Jessica de; Tump, Evelien; Marchal, Jan Pieter; Nestrašil, Igor; Shapiro, Elsa; Jones, Simon A.; Alexanderian, David

doi:10.1016/j.ymgme.2021.09.003

Cited by 5 publications

(3 citation statements)

References 10 publications

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“…This concerns various types of therapies, including enzyme replacement therapy (provided intrathecally), gene therapy, and substrate reduction therapy. [18][19][20][21] The physical storage of HS inhibits lysosomal functions; however, it is hardly possible to explain all cellular and organismal defects observed in Sanfilippo disease solely by accumulation of this GAG. 2 Nevertheless, if huge amounts of HS cannot be accommodated inside lysosomes, the undegraded molecules can remain in either the cytoplasm, due to a block in further transport to the target organelle, or outside the cell, where GAGs play their major physiological roles.…”

Section: Complexity Of Sanfilippo Disease Pathomechanismsmentioning

confidence: 99%

Sanfilippo Syndrome: Optimizing Care with a Multidisciplinary Approach

Cyske¹,

Anikiej-Wiczenbach²,

Wiśniewska³

et al. 2022

JMDH

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Sanfilippo syndrome, or mucopolysaccharidosis type III (MPS III), is a disease grouping five genetic disorders, four of them occurring in humans and one known to date only in a mouse model. In every subtype of MPS III (designed A, B, C, D or E), a lack or drastically decreased activity of an enzyme involved in the degradation of heparan sulfate (HS) (a compound from the group of glycosaminoglycans (GAGs)) arises from a genetic defect. This leads to primary accumulation of HS, and secondary storage of other compounds, combined with changes in expressions of hundreds of genes and many defects in organelles and various biochemical processes in the cell. As a result, dysfunctions of tissues and organs occur, leading to severe symptoms in patients. Although changes in somatic organs are considerable, the central nervous system is especially severely affected, and neurological, cognitive and behavioral disorders are the most significant changes, making the disease enormously burdensome for patients and their families. In the light of the current lack of any registered therapy for Sanfilippo syndrome (despite various attempts of many research groups to develop effective treatment, still no specific drug or procedure is available for MPS III), optimizing care with a multidisciplinary approach is crucial for managing this disease and making quality of patients' life passable. This includes efforts to make/organize (i) accurate diagnosis as early as possible (which is not easy due to various possible misdiagnosis events caused by similarity of MPS III symptoms to those of other diseases and variability of patients), (ii) optimized symptomatic treatment (which is challenging because of complexity of symptoms and often untypical responses of MPS III patients to various drugs), and (iii) psychological care (for both patients and family members and/or caregivers). In this review article, we focus on these approaches, summarizing and discussing them.

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Section: Complexity Of Sanfilippo Disease Pathomechanismsmentioning

confidence: 99%

Sanfilippo Syndrome: Optimizing Care with a Multidisciplinary Approach

Cyske¹,

Anikiej-Wiczenbach²,

Wiśniewska³

et al. 2022

JMDH

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“…Thus, treating the CNS is an area of research currently receiving much attention. Although unsuccessful, the first clinical trials to approach CNS were via intrathecal (IT) ERT for MPS II and IIIA [31]. Successively, intracerebroventricular (ICV) ERT has been conducted and approved for MPS II, and phase 2 clinical trials are underway for MPS IIIB (ClinicalTrials.gov identifier: NCT03784287).…”

Section: Introductionmentioning

confidence: 99%

Molecular Mechanisms in Pathophysiology of Mucopolysaccharidosis and Prospects for Innovative Therapy

Ago,

Rintz,

Musini

et al. 2024

IJMS

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Mucopolysaccharidoses (MPSs) are a group of inborn errors of the metabolism caused by a deficiency in the lysosomal enzymes required to break down molecules called glycosaminoglycans (GAGs). These GAGs accumulate over time in various tissues and disrupt multiple biological systems, including catabolism of other substances, autophagy, and mitochondrial function. These pathological changes ultimately increase oxidative stress and activate innate immunity and inflammation. We have described the pathophysiology of MPS and activated inflammation in this paper, starting with accumulating the primary storage materials, GAGs. At the initial stage of GAG accumulation, affected tissues/cells are reversibly affected but progress irreversibly to: (1) disruption of substrate degradation with pathogenic changes in lysosomal function, (2) cellular dysfunction, secondary/tertiary accumulation (toxins such as GM2 or GM3 ganglioside, etc.), and inflammatory process, and (3) progressive tissue/organ damage and cell death (e.g., skeletal dysplasia, CNS impairment, etc.). For current and future treatment, several potential treatments for MPS that can penetrate the blood–brain barrier and bone have been proposed and/or are in clinical trials, including targeting peptides and molecular Trojan horses such as monoclonal antibodies attached to enzymes via receptor-mediated transport. Gene therapy trials with AAV, ex vivo LV, and Sleeping Beauty transposon system for MPS are proposed and/or underway as innovative therapeutic options. In addition, possible immunomodulatory reagents that can suppress MPS symptoms have been summarized in this review.

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“…Several therapeutic options have been studied for MPS III in clinical trials (e.g. ERT and SRT), but none of them resulted in an approved therapeutic option [10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Patients’ view on gene therapy development for lysosomal storage disorders: a qualitative study

Eskes

Beishuizen

Corazolla

et al. 2022

Orphanet J Rare Dis

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Introduction Several new treatment modalities are being developed for lysosomal storage disorders (LSDs), including gene therapy. As the currently available treatment options and their influence on disease progression differ greatly within the spectrum of LSDs, willingness to undergo gene therapy might vary among patients with LSDs and/or their representatives. The width of the LSD spectrum is illustrated by the differences between type 1 Gaucher disease, Fabry disease and Mucopolysaccharidosis type III (MPS III). For type 1 Gaucher and Fabry disease several therapies are available, resulting in a near normal or improved, but individually varying, prognosis. No treatment options are available for MPS III. Aim To identify factors influencing patients’ and/or their representatives’ decisions regarding undergoing gene therapy. Methods Focus group discussions and semi-structured interviews were conducted with patients with type 1 Gaucher disease, Fabry disease and MPS III. Parents of MPS III patients were included as patients’ representatives. Results Nine Gaucher patients, 23 Fabry patients, two adult MPS III patients and five parents of MPS III patients participated in the study. The five main themes that arose were: outcome of gene therapy, risks and side effects, burden of gene therapy treatment, current situation and ethical aspects. Participants’ views ranged from hesitance to eagerness to undergo gene therapy, which seemed to be mostly related to disease severity and currently available treatment options. Severe disease, limited treatment options and limited effectiveness of current treatment augmented the willingness to choose gene therapy. Gaucher and Fabry patients deemed the burden of treatment important. Fabry and MPS III patients and parents considered outcome important, suggesting hope for improvement. When asked to rank the factors discussed in the focus group discussions, Gaucher patients ranked outcome low, which could indicate a more cautious attitude towards gene therapy. Conclusion This study underlines the importance of exploring patients’ needs and expectations before using limited resources in the development of therapies for patient groups of which a significant subset may not be willing to undergo that specific therapy.

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Long-term safety and clinical outcomes of intrathecal heparan-N-sulfatase in patients with Sanfilippo syndrome type A

Cited by 5 publications

References 10 publications

Sanfilippo Syndrome: Optimizing Care with a Multidisciplinary Approach

Sanfilippo Syndrome: Optimizing Care with a Multidisciplinary Approach

Molecular Mechanisms in Pathophysiology of Mucopolysaccharidosis and Prospects for Innovative Therapy

Patients’ view on gene therapy development for lysosomal storage disorders: a qualitative study

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