Stem Cell-Derived Human Striatal Progenitors Innervate Striatal Targets and Alleviate Sensorimotor Deficit in a Rat Model of Huntington Disease

Huntington disease (HD) is an inherited late-onset neurological disorder characterized by progressive neuronal loss and disruption of cortical and basal ganglia circuits. Cell replacement using human embryonic stem cells may offer the opportunity to repair the damaged circuits and significantly ameliorate disease conditions. Here, we showed that in-vitro-differentiated human striatal progenitors undergo maturation and integrate into host circuits upon intra-striatal transplantation in a rat model of HD. By combining graft-specific immunohistochemistry, rabies virus-mediated synaptic tracing, and ex vivo electrophysiology, we showed that grafts can extend projections to the appropriate target structures, including the globus pallidus, the subthalamic nucleus, and the substantia nigra, and receive synaptic contact from both host and graft cells with 6.6 ± 1.6 inputs cell per transplanted neuron. We have also shown that transplants elicited a significant improvement in sensory-motor tasks up to 2 months post-transplant further supporting the therapeutic potential of this approach

Allele-specific silencing as treatment for gene duplication disorders: Proof-of-principle in autosomal dominant leukodystrophy

Allele-specific silencing by RNA interference (ASP-siRNA) holds promise as a therapeutic strategy for downregulating a single mutant allele with minimal suppression of the corresponding wild-type allele. This approach has been effectively used to target autosomal dominant mutations and single nucleotide polymorphisms linked with aberrantly expanded trinucleotide repeats. Here, we propose ASP-siRNA as a preferable choice to target duplicated disease genes, avoiding potentially harmful excessive downregulation. As a proof-of-concept, we studied autosomal dominant adult-onset demyelinating leukodystrophy (ADLD) due to lamin B1 (LMNB1) duplication, a hereditary, progressive and fatal disorder affecting myelin in the CNS. Using a reporter system, we screened the most efficient ASP-siRNAs preferentially targeting one of the alleles at rs1051644 (average minor allele frequency: 0.45) located in the 3' untranslated region of the gene. We identified four siRNAs with a high efficacy and allele-specificity, which were tested in ADLD patient-derived fibroblasts. Three of the small interfering RNAs were highly selective for the target allele and restored both LMNB1 mRNA and protein levels close to control levels. Furthermore, small interfering RNA treatment abrogates the ADLD-specific phenotypes in fibroblasts and in two disease-relevant cellular models: murine oligodendrocytes overexpressing human LMNB1, and neurons directly reprogrammed from patients' fibroblasts. In conclusion, we demonstrated that ASP-silencing by RNA interference is a suitable and promising therapeutic option for ADLD. Moreover, our results have a broad translational value extending to several pathological conditions linked to gene-gain in copy number variations

NSCR_Dataset_2020

<p>The University of Turin (UniTO) released the open-access dataset NSCR_Dataset collected for the  NEUROSTEMCELLREPAIR (602278) and NSC-Reconstruct (874758) European stem cell consortia for neural cell replacement, reprogramming and functional brain repair (602278)  (https://www.nsc-reconstruct.com/en/index.do).</p> <p>NSCR-Dataset is a dataset of analysis of histological ex-vivo brain samples and behavioral parameters from Huntington's Disease (HD) rat models, after cell replacement approach of striatal progenitor cells at the site of grafting - the striatum, at different time point (see for details at short time-points: https://www.sciencedirect.com/science/article/pii/S2213671120301089?via%3Dihub). The UniTO team released this dataset publicly.</p> <p>The dataset contains images of brain tissue stained for different cellular and molecular markers, acquired with transmission and confocal microscopes, from which analysis were performed, and the behavioral data obtained every month by testing the HD animals in different motor tasks.</p> <p>High-resolution images have been acquired; the images will be made available.</p&gt