Early skeletal outcomes after hematopoietic stem and progenitor cell gene therapy for Hurler syndrome.

Mucopolysaccharidosis type I Hurler (MPSIH) is characterized by severe and progressive skeletal dysplasia that is not fully addressed by allogeneic hematopoietic stem cell transplantation (HSCT). Autologous hematopoietic stem progenitor cell-gene therapy (HSPC-GT) provides superior metabolic correction in patients with MPSIH compared with HSCT; however, its ability to affect skeletal manifestations is unknown. Eight patients with MPSIH (mean age at treatment: 1.9 years) received lentiviral-based HSPC-GT in a phase 1/2 clinical trial (NCT03488394). Clinical (growth, measures of kyphosis and genu velgum), functional (motor function, joint range of motion), and radiological [acetabular index (AI), migration percentage (MP) in hip x-rays and MRIs and spine MRI score] parameters of skeletal dysplasia were evaluated at baseline and multiple time points up to 4 years after treatment. Specific skeletal measures were retrospectively compared with an external cohort of HSCT-treated patients. At a median follow-up of 3.78 years after HSPC-GT, all patients treated with HSPC-GT exhibited longitudinal growth within WHO reference ranges and a median height gain greater than that observed in patients treated with HSCT after 3-year follow-up. Patients receiving HSPC-GT experienced complete and earlier normalization of joint mobility compared with patients treated with HSCT. Mean AI and MP showed progressive decreases after HSPC-GT, suggesting a reduction in acetabular dysplasia. Typical spine alterations measured through a spine MRI score stabilized after HSPC-GT. Clinical, functional, and radiological measures suggested an early beneficial effect of HSPC-GT on MPSIH-typical skeletal features. Longer follow-up is needed to draw definitive conclusions on HSPC-GT's impact on MPSIH skeletal dysplasia.

Evidence of Treatment Benefits in Patients with Mucopolysaccharidosis Type I-Hurler in Long-term Follow-up Using a New Magnetic Resonance Imaging Scoring System.

We developed a brain and spine magnetic resonance scoring system based on a magnetic resonance assessment of 9 patients with mucopolysaccharidosis type I-Hurler who underwent hematopoietic stem-cell transplantation. The score is reliable and correlates with long-term clinical and cognitive outcome in patients with mucopolysaccharidosis type I-Hurler.

Hematopoietic Stem- and Progenitor-Cell Gene Therapy for Hurler Syndrome.

BACKGROUND: Allogeneic hematopoietic stem-cell transplantation is the standard of care for Hurler syndrome (mucopolysaccharidosis type I, Hurler variant [MPSIH]). However, this treatment is only partially curative and is associated with complications. METHODS: We are conducting an ongoing study involving eight children with MPSIH. At enrollment, the children lacked a suitable allogeneic donor and had a Developmental Quotient or Intelligence Quotient score above 70 (i.e., none had moderate or severe cognitive impairment). The children received autologous hematopoietic stem and progenitor cells (HSPCs) transduced ex vivo with an α-L-iduronidase (IDUA)-encoding lentiviral vector after myeloablative conditioning. Safety and correction of blood IDUA activity up to supraphysiologic levels were the primary end points. Clearance of lysosomal storage material as well as skeletal and neurophysiological development were assessed as secondary and exploratory end points. The planned duration of the study is 5 years. RESULTS: We now report interim results. The children's mean (±SD) age at the time of HSPC gene therapy was 1.9±0.5 years. At a median follow-up of 2.10 years, the procedure had a safety profile similar to that known for autologous hematopoietic stem-cell transplantation. All the patients showed prompt and sustained engraftment of gene-corrected cells and had supraphysiologic blood IDUA activity within a month, which was maintained up to the latest follow-up. Urinary glycosaminoglycan (GAG) excretion decreased steeply, reaching normal levels at 12 months in four of five patients who could be evaluated. Previously undetectable levels of IDUA activity in the cerebrospinal fluid became detectable after gene therapy and were associated with local clearance of GAGs. Patients showed stable cognitive performance, stable motor skills corresponding to continued motor development, improved or stable findings on magnetic resonance imaging of the brain and spine, reduced joint stiffness, and normal growth in line with World Health Organization growth charts. CONCLUSIONS: The delivery of HSPC gene therapy in patients with MPSIH resulted in extensive metabolic correction in peripheral tissues and the central nervous system. (Funded by Fondazione Telethon and others; ClinicalTrials.gov number, NCT03488394; EudraCT number, 2017-002430-23.).

The effects of the functional interplay between the Default Mode and Executive Control Resting State Networks on cognitive outcome in preterm born infants at 6 months of age.

Preterm birth can affect cognitive functions, such as attention or more generally executive control mechanisms, with severity in impairments proportional to prematurity. The functional cross-talk between the Default Mode (DMN) and Executive Control (ECN) networks mirrors the integrity of cognitive processing and is directly related to brain development. In this study, a cohort of 20 preterm-born infants was investigated using rs-fMRI. First, we addressed biological maturity of the DMN per se and its interplay with the ECN in terms of patterns of increased functional connectivity. Second, we assessed the impact of the degree of prematurity on the DMN-ECN functional interplay development in relation to cognitive outcome at six months. Our results highlighted the emergence of DMN in preterm neonates, with connectivity strength and synchronization between the anterior DMN hub and frontal areas increasing as a function of biological maturity. Further, cognitive scores at 6 months were predicted by mPFC-ECN connectivity strength with degree of prematurity impacting on mPFC-ECN connectivity and triggering differential patterns of functional maturation of the ECN for very early/early and moderate/late preterm neonates. Our findings suggest that the prematurity window allows to observe precursors of functional plasticity that may underlie different developmental trajectories in preterm children.

Subcortico-Cortical Functional Connectivity in the Fetal Brain: A Cognitive Development Blueprint.

Recent evidence has shown that patterns of cortico-cortical functional synchronization are consistently traceable by the end of the third trimester of pregnancy. The involvement of subcortical structures in early functional and cognitive development has never been explicitly investigated, notwithstanding their pivotal role in different cognitive processes. We address this issue by exploring subcortico-cortical functional connectivity at rest in a group of normally developing fetuses between the 25th and 32nd weeks of gestation. Results show significant functional coupling between subcortical nuclei and cortical networks related to: (i) sensorimotor processing, (ii) decision making, and (iii) learning capabilities. This functional maturation framework unearths a Cognitive Development Blueprint, according to which grounding cognitive skills are planned to develop with higher ontogenetic priority. Specifically, our evidence suggests that a newborn already possesses the ability to: (i) perceive the world and interact with it, (ii) create salient representations for the selection of adaptive behaviors, and (iii) store, retrieve, and evaluate the outcomes of interactions, in order to gradually improve adaptation to the extrauterine environment.

Auditory functional magnetic resonance in awake (nonsedated) and propofol-sedated children.

BACKGROUND: Functional Magnetic Resonance Imaging (fMRI) is often used in preoperative assessment before epilepsy surgery, tumor or cavernous malformation resection, or cochlear implantation. As it requires complete immobility, sedation is needed for uncooperative patients. OBJECTIVE: The aim of this study was to compare the fMRI cortical activation pattern after auditory stimuli in propofol-sedated 5- to 8-year-old children with that of similarly aged nonsedated children. METHODS: When possible, children underwent MRI without sedation, otherwise it was induced with i.v. propofol 2 mg·kg(-1) and maintained with i.v. propofol 4-5 mg·kg(-1) ·h(-1) . Following diagnostic MRI, fMRi was carried out, randomly alternating two passive listening tasks (a fairy-tale and nonsense syllables). RESULTS: We studied 14 awake and 15 sedated children. During the fairy-tale task, the nonsedated children's blood-oxygen-level-dependent (BOLD) signal was bilaterally present in the posterior superior temporal gyrus (STG), Wernicke's area, and Broca's area. Sedated children showed similar activation, with lesser extension to Wernicke's area, and no activation in Broca's area. During the syllable task, the nonsedated children's BOLD signal was bilaterally observed in the STG and Wernicke's area, in Broca's area with leftward asymmetry, and in the premotor area. In sedated children, cortical activation was present in the STG, but not in the frontal lobes. BOLD signal change areas in sedated children were less extended than in nonsedated children during both the fairy-tale and syllable tasks. Modeling the temporal derivative during both the fairy-tale and syllable tasks, nonsedated children showed no response while sedated children did. CONCLUSIONS: After auditory stimuli, propofol-sedated 5- to 8-year-old children exhibit an fMRI cortical activation pattern which is different from that in similarly aged nonsedated children.

Maturation of preterm newborn brains: a fMRI-DTI study of auditory processing of linguistic stimuli and white matter development.

To evaluate brain development longitudinally in premature infants without abnormalities as compared to healthy full-term newborns, we assessed fMRI brain activity patterns in response to linguistic stimuli and white matter structural development focusing on language-related fibres. A total sample of 29 preterm newborns and 26 at term control newborns underwent both fMRI and DTI. Griffiths test was performed at 6 months of corrected age to assess development. Auditory fMRI data were analysed in 17 preterm newborns at three time points [34, 41 and 44 weeks of post menstrual age (wPMA)] and in 15 controls, at term. Analysis showed a distinctive pattern of cortical activation in preterm newborns up to 29 wPMA moving from early prevalent left temporal and supramarginal area activation in the preterm period, to a bilateral temporal and frontoopercular activation in the at term equivalent period and to a more fine-grained left pattern of activity at 44 wPMA. At term controls showed instead greater bilateral posterior thalamic activation. The different pattern of brain activity associated to preterm newborns mirrors their white matter maturation delay in peripheral regions of the fibres and thalamo-cortical radiations in subcortical areas of both hemispheres, pointing to different transient thalamo-cortical development due to prematurity. Evidence for functional thalamic activation and more mature subcortical tracts, including thalamic radiations, may represent the substantial gap between preterm and at term infants. The transition between bilateral temporal activations at term age and leftward activations at 44 weeks of PMA is correlated to better neuropsychological results in Griffiths test.

Prenatal diagnosis by 3D ultrasound and MRI of an unusual malformation of cortical development with brain-in-brain appearance.

A 31-year-old pregnant woman was referred for isolated mild ventriculomegaly and failure to visualize the left lateral ventricle's anterior horn on second trimester sonography (US). Three-dimensional US suspected a frontal lesion deviating the midline. MRI revealed a mass compressing the ventricle. Follow-up MRI described a "brain-in-brain" malformation: infolded microgyric cortex and white matter in frontal lobe extending to frontal horn and midline, irrorated by hypertophic Heubner artery. Conservative approach was chosen. Neurodevelopment at 1 year is normal.

Decreased parietal cortex activity during mental rotation in children with congenital hypothyroidism.

BACKGROUND: The ability to detect the spatial characteristics of objects and to rotate them mentally is frequently impaired in early treated congenital hypothyroidism (CH) children. AIMS: To explore the neural substrate of the visuospatial difficulty in children with CH, we studied 15 children with CH (8-10 years) and 13 age-matched control children with functional magnetic resonance imaging (fMRI) using a mental rotation task (VST). RESULTS: Performance at VST was significantly different between the two groups. Moreover, fMRI data showed greater activation in the superior parietal cortex in control children while children with CH had greater activation in the bilateral SMA and the opercular region of the precentral gyrus, the adjacent insula and the left somatosensory parietal cortex. Furthermore, children with CH deactivated the inferior parietal cortex (Brodmann area 40) more than controls. CONCLUSION: We suggest that the poorer performance of children with CH on VST task is related to the decreased activation in brain areas important for the mental representation of the objects' spatial characteristics, with increased recruitment of regions involved in the representation of somatosensory whole-body information. More studies will be necessary to understand if this different effectiveness in VST reflects immaturity of the neural system or its actual impairment.