Intracerebral gene therapy in children with mucopolysaccharidosis type IIIB syndrome: an uncontrolled phase 1/2 clinical trial

Tardieu, Marc; Zérah, Michel; Gougeon, Marie‐Lise; Ausseil, Jérôme; Bournonville, Stéphanie de; Husson, B.; Zafeiriou, Dimitrios I.; Parenti, Giancarlo; Bourget, Philippe; Poirier, Béatrice; Furlan, Valérie; Artaud, Cécile; Baugnon, Thomas; Roujeau, Thomas; Crystal, Ronald G.; Meyer, Christian; Deiva, Kumaran; Heard, Jean‐Michel

doi:10.1016/s1474-4422(17)30169-2

Cited by 158 publications

(139 citation statements)

References 30 publications

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“…It would also help to avoid misdiagnosis and unnecessary treatments resulting from it, as well as help to enroll more presymptomatic patients into clinical trials. This is of great relevance, since starting a therapeutic intervention before the onset of neurological symptoms and potentially irreversible neuropathological damage is essential for the majority of neurological lysosomal diseases, as has been demonstrated in multiple preclinical studies [183][184][185] and clinical gene therapy trials for MPS IIIA and MPS IIIB patients [186,187].…”

Section: Biomarkers Of Mps III Suitable For Diagnosis Clinical Evalumentioning

confidence: 99%

Molecular Bases of Neurodegeneration and Cognitive Decline, the Major Burden of Sanfilippo Disease

Héon-Roberts

Nguyen

Pshezhetsky

2020

JCM

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The mucopolysaccharidoses (MPS) are a group of diseases caused by the lysosomal accumulation of glycosaminoglycans, due to genetic deficiencies of enzymes involved in their degradation. MPS III or Sanfilippo disease, in particular, is characterized by early-onset severe, progressive neurodegeneration but mild somatic involvement, with patients losing milestones and previously acquired skills as the disease progresses. Despite being the focus of extensive research over the past years, the links between accumulation of the primary molecule, the glycosaminoglycan heparan sulfate, and the neurodegeneration seen in patients have yet to be fully elucidated. This review summarizes the current knowledge on the molecular bases of neurological decline in Sanfilippo disease. It emerges that this deterioration results from the dysregulation of multiple cellular pathways, leading to neuroinflammation, oxidative stress, impaired autophagy and defects in cellular signaling. However, many important questions about the neuropathological mechanisms of the disease remain unanswered, highlighting the need for further research in this area.

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Section: Biomarkers Of Mps III Suitable For Diagnosis Clinical Evalumentioning

confidence: 99%

Molecular Bases of Neurodegeneration and Cognitive Decline, the Major Burden of Sanfilippo Disease

Héon-Roberts

Nguyen

Pshezhetsky

2020

JCM

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“…There is currently no effective treatment for MPS III, and patient care is limited to symptom management and palliative support. Disease‐specific treatments for MPS III, including intrathecally delivered enzyme replacement therapy, substrate reduction therapy, hematopoietic stem cell transplantation, and gene therapy, are being studied (Fedele, ; Jones et al, ; Tardieu et al, ; Valstar et al, ).…”

Section: Introductionmentioning

confidence: 99%

Mucopolysaccharidosis III in Taiwan: Natural history, clinical and molecular characteristics of 28 patients diagnosed during a 21‐year period

Lin

Chuang

Lee

et al. 2018

American J of Med Genetics Pt A

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Mucopolysaccharidosis type III (MPS III, Sanfilippo syndrome) has a variable age of onset and variable rate of progression. However, information regarding the natural history of this disorder in Asian populations is limited. A retrospective analysis was carried out for 28 patients with MPS III (types IIIA [n = 3], IIIB [n = 23], and IIIC [n = 2]; 15 males and 13 females; median age, 8.2 years; age range, 2.7-26.5 years) seen in six medical centers in Taiwan from January 1996 through October 2017. The median age at confirmed diagnosis was 4.6 years. The most common initial symptom was speech delay (75%), followed by hirsutism (64%) and hyperactivity (54%). Both z scores for height and weight were negatively correlated with age (r = -.693 and -0.718, respectively; p < .01). The most prevalent clinical manifestations were speech delay (100%) and intellectual disability (100%), followed by hirsutism (93%), hyperactivity (79%), coarse facial features (68%), sleep disorders (61%), and hepatosplenomegaly (61%). Ten patients (36%) had epilepsy, and the median age at the first seizure was 11 years. Thirteen patients (46%) experienced at least one surgical procedure. At the time of the present study, 7 of the 28 patients had passed away at the median age of 13.0 years. Molecular studies showed an allelic heterogeneity without clear genotype and phenotype correlations. MPS IIIB is the most frequent subtype among MPS III in the Taiwanese population. An understanding of the natural history of MPS III may allow early diagnosis and timely management of the disease facilitating better treatment outcomes.

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“…So far, no specific approved treatment is available. Gene therapy [21], bone marrow transplant [22], chaperon molecules [23], substrate deprivation therapy [24] and intrathecal enzyme therapy [25] are among the most active therapeutic research areas. The goal of this work is to apply both targeted and untargeted metabolomics on MPS IIIA, MPS IIIB, MPS IIIC and MPS IIID patients, compared to controls, to investigate metabolic changes in these conditions.…”

Section: Introductionmentioning

confidence: 99%

Unveiling metabolic remodeling in mucopolysaccharidosis type III through integrative metabolomics and pathway analysis

et al. 2018

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BackgroundMetabolomics represent a valuable tool to recover biological information using body fluids and may help to characterize pathophysiological mechanisms of the studied disease. This approach has not been widely used to explore inherited metabolic diseases. This study investigates mucopolysaccharidosis type III (MPS III). A thorough and holistic understanding of metabolic remodeling in MPS III may allow the development, improvement and personalization of patient care.MethodsWe applied both targeted and untargeted metabolomics to urine samples obtained from a French cohort of 49 patients, consisting of 13 MPS IIIA, 16 MPS IIIB, 13 MPS IIIC, and 7 MPS IIID, along with 66 controls. The analytical strategy is based on ultra-high-performance liquid chromatography combined with ion mobility and high-resolution mass spectrometry. Twenty-four amino acids have been assessed using tandem mass spectrometry combined with liquid chromatography. Multivariate data modeling has been used for discriminant metabolite selection. Pathway analysis has been performed to retrieve metabolic pathways impairments.ResultsData analysis revealed distinct biochemical profiles. These metabolic patterns, particularly those related to the amino acid metabolisms, allowed the different studied groups to be distinguished. Pathway analysis unveiled major amino acid pathways impairments in MPS III mainly arginine–proline metabolism and urea cycle metabolism.ConclusionThis represents one of the first metabolomics-based investigations of MPS III. These results may shed light on MPS III pathophysiology and could help to set more targeted studies to infer the biomarkers of the affected pathways, which is crucial for rare conditions such as MPS III.Electronic supplementary materialThe online version of this article (10.1186/s12967-018-1625-1) contains supplementary material, which is available to authorized users.

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Intracerebral gene therapy in children with mucopolysaccharidosis type IIIB syndrome: an uncontrolled phase 1/2 clinical trial

Cited by 158 publications

References 30 publications

Molecular Bases of Neurodegeneration and Cognitive Decline, the Major Burden of Sanfilippo Disease

Molecular Bases of Neurodegeneration and Cognitive Decline, the Major Burden of Sanfilippo Disease

Mucopolysaccharidosis III in Taiwan: Natural history, clinical and molecular characteristics of 28 patients diagnosed during a 21‐year period

Unveiling metabolic remodeling in mucopolysaccharidosis type III through integrative metabolomics and pathway analysis

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