Toward newborn screening of metachromatic leukodystrophy: results from analysis of over 27,000 newborn dried blood spots

Hong, Xinying; Daiker, Jessica; Sadı́lek, Martin; Ruiz-Schultz, Nicole; Kumar, Arun; Norcross, Stevie; Dansithong, Warunee; Suhr, Teryn; Escolar, Maria L.; Scott, C. Ronald; Rohrwasser, Andreas; Gelb, Michael H.

doi:10.1038/s41436-020-01017-5

Cited by 42 publications

(50 citation statements)

References 29 publications

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“…An exploratory sub-analysis of 12 treated patients with their untreated siblings confirmed the main treatment effects described above (appendix pp [27][28][29][30][33][34], supporting the validity of the NHx cohort as a comparator.…”

Section: Resultsmentioning

confidence: 61%

“…The difference was larger at 3 years for patients with both late-infantile and early-juvenile MLD overall (figure 2A), and patients with early-juvenile MLD stratified by symptomatic status at time of treatment (appendix p 26). Furthermore, 25 of 29 treated patients displayed gross motor development similar to or slightly below normally developing children, or stabilisation of motor performance or delay in the rate of motor decline compared with NHx patients (appendix pp [27][28][29][30].…”

Section: Resultsmentioning

confidence: 99%

“…Of note, substantial advances in analytical testing in dried blood spots have been made, with several pilot screening studies underway. 29 , 30 …”

Section: Discussionmentioning

confidence: 99%

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Lentiviral haematopoietic stem-cell gene therapy for early-onset metachromatic leukodystrophy: long-term results from a non-randomised, open-label, phase 1/2 trial and expanded access

et al. 2022

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Summary Background Effective treatment for metachromatic leukodystrophy (MLD) remains a substantial unmet medical need. In this study we investigated the safety and efficacy of atidarsagene autotemcel (arsa-cel) in patients with MLD. Methods This study is an integrated analysis of results from a prospective, non-randomised, phase 1/2 clinical study and expanded-access frameworks. 29 paediatric patients with pre-symptomatic or early-symptomatic early-onset MLD with biochemical and molecular confirmation of diagnosis were treated with arsa-cel, a gene therapy containing an autologous haematopoietic stem and progenitor cell (HSPC) population transduced ex vivo with a lentiviral vector encoding human arylsulfatase A (ARSA) cDNA, and compared with an untreated natural history (NHx) cohort of 31 patients with early-onset MLD, matched by age and disease subtype. Patients were treated and followed up at Ospedale San Raffaele, Milan, Italy. The coprimary efficacy endpoints were an improvement of more than 10% in total gross motor function measure score at 2 years after treatment in treated patients compared with controls, and change from baseline of total peripheral blood mononuclear cell (PBMC) ARSA activity at 2 years after treatment compared with values before treatment. This phase 1/2 study is registered with ClinicalTrials.gov , NCT01560182 . Findings At the time of analyses, 26 patients treated with arsa-cel were alive with median follow-up of 3·16 years (range 0·64–7·51). Two patients died due to disease progression and one due to a sudden event deemed unlikely to be related to treatment. After busulfan conditioning, all arsa-cel treated patients showed sustained multilineage engraftment of genetically modified HSPCs. ARSA activity in PBMCs was significantly increased above baseline 2 years after treatment by a mean 18·7-fold (95% CI 8·3–42·2; p<0·0001) in patients with the late-infantile variant and 5·7-fold (2·6–12·4; p<0·0001) in patients with the early-juvenile variant. Mean differences in total scores for gross motor function measure between treated patients and age-matched and disease subtype-matched NHx patients 2 years after treatment were significant for both patients with late-infantile MLD (66% [95% CI 48·9–82·3]) and early-juvenile MLD (42% [12·3–71·8]). Most treated patients progressively acquired motor skills within the predicted range of healthy children or had stabilised motor performance (maintaining the ability to walk). Further, most displayed normal cognitive development and prevention or delay of central and peripheral demyelination and brain atrophy throughout follow-up; treatment benefits were particularly apparent in patients treated before symptom onset. The infusion was well tolerated and there was no evidence of abnormal clonal proliferation or replication-competent lentivirus. All patients had at least one grade 3 or higher adverse event; most were...

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Section: Resultsmentioning

confidence: 61%

Section: Resultsmentioning

confidence: 99%

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Lentiviral haematopoietic stem-cell gene therapy for early-onset metachromatic leukodystrophy: long-term results from a non-randomised, open-label, phase 1/2 trial and expanded access

et al. 2022

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“…In this approach, we use WES with custom bioinformatics pipelines that restrict the analysis to a single gene initially, but any analysis is expandable to the entire exome if sequencing coverage suffices [9]. This pipeline was used in a pilot study as a second-tier screening method to confirm the results of biochemical screening for metachromatic leukodystrophy (MLD) [10]. Our NGS method was able to identify clinically significant variants for two screen-positive samples, thus improving the specificity for the biochemical MLD screening method.…”

Section: Ngs Methods As a Way To Augment Secondary Variant Analysis In Nbsmentioning

confidence: 99%

Scalable Newborn Screening Solutions: Bioinformatics and Next-Generation Sequencing

Ruiz-Schultz¹,

Asay²,

Rohrwasser³

2021

IJNS

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Expansion of the newborn disorder panel requires the incorporation of new testing modalities. This is especially true for disorders lacking robust biomarkers for detection in primary screening methods and for disorders requiring genotyping or sequencing as a second-tier and/or diagnostic test. In this commentary, we discuss how next-generation sequencing (NGS) methods can be used as a secondary testing method in NBS. Additionally, we elaborate on the importance of genomic variant repositories for the annotation and interpretation of variants. Barriers to the incorporation of NGS and bioinformatics within NBS are discussed, and ideas for a regional bioinformatics model and shared variant repository are presented as potential solutions.

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“…To our knowledge, only one pilot project aimed at demonstrating the feasibility of MLD NBS took place in the USA in 2020, screening 27,335 de-identified DBS [76] .…”

Section: Metachromatic Leukodystrophymentioning

confidence: 99%

Newborn screening of neuromuscular diseases

Dangouloff

Boemer

Servais

2021

Neuromuscular Disorders

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Toward newborn screening of metachromatic leukodystrophy: results from analysis of over 27,000 newborn dried blood spots

Cited by 42 publications

References 29 publications

Lentiviral haematopoietic stem-cell gene therapy for early-onset metachromatic leukodystrophy: long-term results from a non-randomised, open-label, phase 1/2 trial and expanded access

Lentiviral haematopoietic stem-cell gene therapy for early-onset metachromatic leukodystrophy: long-term results from a non-randomised, open-label, phase 1/2 trial and expanded access

Scalable Newborn Screening Solutions: Bioinformatics and Next-Generation Sequencing

Newborn screening of neuromuscular diseases

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