Efficacy of hematopoietic cell transplantation in metachromatic leukodystrophy: the Dutch experience

Rappard, Diane F. van; Boelens, Jaap Jan; Egmond, Martje E van; Kuball, Jürgen; Hasselt, Peter M. van; Oostrom, Kim J.; Pouwels, Petra J. W.; Knaap, Marjo S. van der; Hollak, Carla E. M.; Wolf, Nicole I.

doi:10.1182/blood-2016-03-708479

Cited by 59 publications

(125 citation statements)

References 18 publications

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“…Although most patients ultimately experienced neurologic decline following transplant, the authors showed how HSCT has a more favourable impact on cognitive capabilities compared to motor dysfunction. Furthermore, Van Rappard and colleagues recently showed similar clinical findings on a cohort of 13 MLD patients (2 LI, 5 juvenile and 6 adult) treated in a pre- or early symptomatic phase (IQ > 70 and absence of gross motor impairment) (van Rappard et al 2016). These data indicate that HSCT does not have a clear benefit in LI MLD patients (regardless of symptom status at the time of transplant) or in symptomatic MLD patients, in whom transplantation cannot prevent CNS involvement and damage.…”

Section: Introductionmentioning

confidence: 65%

Gene therapy for lysosomal storage disorders: recent advances for metachromatic leukodystrophy and mucopolysaccaridosis I

Penati

Fumagalli

Calbi

et al. 2017

J of Inher Metab Disea

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Lysosomal storage diseases (LSDs) are rare inherited metabolic disorders characterized by a dysfunction in lysosomes, leading to waste material accumulation and severe organ damage. Enzyme replacement therapy (ERT) and haematopoietic stem cell transplant (HSCT) have been exploited as potential treatments for LSDs but pre-clinical and clinical studies have shown in some cases limited efficacy. Intravenous ERT is able to control the damage of visceral organs but cannot prevent nervous impairment. Depending on the disease type, HSCT has important limitations when performed for early variants, unless treatment occurs before disease onset. In the attempt to overcome these issues, gene therapy has been proposed as a valuable therapeutic option, either ex vivo, with target cells genetically modified in vitro, or in vivo, by inserting the genetic material with systemic or intra-parenchymal, in situ administration. In particular, the use of autologous haematopoietic stem cells (HSC) transduced with a viral vector containing a healthy copy of the mutated gene would allow supra-normal production of the defective enzyme and cross correction of target cells in multiple tissues, including the central nervous system. This review will provide an overview of the most recent scientific advances in HSC-based gene therapy approaches for the treatment of LSDs with particular focus on metachromatic leukodystrophy (MLD) and mucopolysaccharidosis type I (MPS-I).

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Section: Introductionmentioning

confidence: 65%

Gene therapy for lysosomal storage disorders: recent advances for metachromatic leukodystrophy and mucopolysaccaridosis I

Penati

Fumagalli

Calbi

et al. 2017

J of Inher Metab Disea

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“…New therapeutic approaches are currently under investigation 1, 15. There is an increasing body of evidence suggesting that successful therapy is related to early treatment, that is, presymptomatic and early symptomatic,16, 17, 18, 19 and to a slower disease progression, that is, treatments such as HSCT being more effective in the more slowly progressive juvenile form than in the rapidly progressive late‐infantile form 17, 18. Thus, one of the clinical challenges when to recommend HSCT in juvenile MLD is to judge on the dynamics of the disease course.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, it seems important to investigate whether the demyelination load is a clinically relevant parameter, not only to describe, but also to predict disease progression in juvenile MLD. Especially, as HSCT was proven to be a beneficial treatment when done at an early stage of the disease before the phase of rapid progression 16, 17, 18, 19. It seems essential to find predictors of disease progression already early during disease course in order to be able to judge on the “window of opportunity,” for example, whether a treatment has enough time to become effective.…”

Section: Introductionmentioning

confidence: 99%

Demyelination load as predictor for disease progression in juvenile metachromatic leukodystrophy

Strölin

Krägeloh‐Mann

Kehrer

et al. 2017

Ann Clin Transl Neurol

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ObjectiveThe aim of this study was to investigate whether the extent and topography of cerebral demyelination correlates with and predicts disease progression in patients with juvenile metachromatic leukodystrophy (MLD).MethodsA total of 137 MRIs of 46 patients with juvenile MLD were analyzed. Demyelination load and brain volume were quantified using the previously developed Software “clusterize.” Clinical data were collected within the German Leukodystrophy Network and included full scale intelligence quotient (FSIQ) and gross motor function data. Voxel‐based lesion‐symptom mapping (VLSM) across the whole brain was performed to investigate the spatial relationship of cerebral demyelination with motor or cognitive function. The prognostic value of the demyelination load at disease onset was assessed to determine the severity of disease progression.ResultsThe demyelination load (corrected by the individual brain volume) correlated significantly with gross motor function (r = +0.55) and FSIQ (r = −0.55). Demyelination load at disease onset was associated with the severity of disease progression later on (P < 0.01). VLSM results associated frontal lobe demyelination with loss in FSIQ and more central region demyelination with decline of motor function. Especially progression of demyelination within the motor area was associated with severe disease progression.InterpretationWe were able to show for the first time in a large cohort of patients with juvenile MLD that the demyelination load correlates with motor and cognitive symptoms. Moreover, demyelination load at disease onset, especially the involvement of the central region, predicts severity of disease progression. Thus, demyelination load seems a functionally relevant MRI parameter.

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“…Cognitive function was determined through developmental or IQ testing and clinically estimated in evidently non-eligible patients. Depending on age and proficiencies, cognitive function was assessed using the Wechsler Intelligence Scale for Children-III (6–18 years), the Wechsler Nonverbal Scale of Ability (4–22 years) or the Wechsler Adult Intelligence Scale-III (≥18 years) 7. The median follow-up of surviving transplanted patients was 7.7 years (range 4–16.9 years), and of surviving non-transplanted patients 4.1 years (range 2.7–7.8 years).…”

Section: Methodsmentioning

confidence: 99%

Quantitative MR spectroscopic imaging in metachromatic leukodystrophy: value for prognosis and treatment

Rappard¹,

Klauser

Steenweg³

et al. 2017

J Neurol Neurosurg Psychiatry

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Efficacy of hematopoietic cell transplantation in metachromatic leukodystrophy: the Dutch experience

Cited by 59 publications

References 18 publications

Gene therapy for lysosomal storage disorders: recent advances for metachromatic leukodystrophy and mucopolysaccaridosis I

Gene therapy for lysosomal storage disorders: recent advances for metachromatic leukodystrophy and mucopolysaccaridosis I

Demyelination load as predictor for disease progression in juvenile metachromatic leukodystrophy

Quantitative MR spectroscopic imaging in metachromatic leukodystrophy: value for prognosis and treatment

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