A5088232338- Genetic Neurodegenerative Diseases
- Pluripotent Stem Cells Research
- CRISPR and Genetic Engineering
- Extracellular vesicles in disease
- RNA Research and Splicing
- RNA Interference and Gene Delivery
- Neurogenesis and neuroplasticity mechanisms
- Mitochondrial Function and Pathology
- Fuel Cells and Related Materials
- Amyotrophic Lateral Sclerosis Research
- Virus-based gene therapy research
- DNA Repair Mechanisms
- Neurological disorders and treatments
- Cardiomyopathy and Myosin Studies
- RNA regulation and disease
UniQure (Netherlands)
2018-2024
Leiden University Medical Center
2019-2024
Huntington disease (HD) is a fatal neurodegenerative genetic disorder, thought to reflect toxic gain of function in huntingtin (Htt) protein. Adeno-associated viral vector serotype 5 (AAV5)- microRNA targeting (miHTT) HD gene-therapy candidate that efficiently lowers HTT using RNAi. This study analyzed the efficacy and potential for off-target effects with AAV5-miHTT neuronal astrocyte cell cultures differentiated from induced pluripotent stem cells (iPSCs) two individuals (HD71 HD180)....
Spinocerebellar ataxia type 3 (SCA3), or Machado-Joseph disease (MJD), is a progressive neurodegenerative disorder caused by CAG expansion in the ATXN3 gene. The expanded repeat translated into prolonged polyglutamine ataxin-3 protein and accumulates within inclusions, acquiring toxic properties, which results degeneration of cerebellum brain stem. In current study, non-allele-specific silencing approach was investigated using artificial microRNAs engineered to target various regions gene...
Striatal delivery of microRNA-gene therapy results in widespread brain huntingtin protein lowering Huntington’s disease minipigs up to 1 year.
Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of motor neurons and premature death. The limited understanding mechanisms underlying selective neuron death has significantly hindered development disease-modifying treatments. Ferroptosis, a form cell dependent on iron accumulation, been implicated in degeneration ALS. Oxidized phosphatidylcholines (PC-OxPL) have identified as key effectors pathophysiological processes associated with this pathway. Preclinical...
The development of gene therapies for central nervous system disorders is challenging because it difficult to translate preclinical data from current in vitro and vivo models the clinic. Therefore, we developed induced pluripotent stem cell (iPSC)-derived cerebral organoids as a model recombinant adeno-associated virus (rAAV) capsid selection testing efficacy AAV-based therapy human context. Cerebral are physiological 3D structures that better recapitulate brain compared with 2D lines. To...
Abstract Huntington’s disease (HD) is a fatal neurodegenerative caused by trinucleotide repeat expansion in exon 1 of the huntingtin gene (HTT) that results toxic gain function and cell death. Despite its monogenic cause, pathogenesis HD highly complex, increasing evidence indicates that, addition to full-length (FL) mutant HTT protein, expanded (HTTexon1) protein translated from HTT1a transcript generated aberrant splicing prone aggregate might contribute pathology. This finding suggests...
Huntington's disease (HD) is a fatal neurodegenerative disorder caused by GAG expansion in exon 1 of the huntingtin (HTT) gene. AAV5-miHTT an adeno-associated virus serotype 5-based vector expressing engineered HTT-targeting microRNA (miHTT). Preclinical studies demonstrate brain-wide spread following single intrastriatal injection, which partly mediated neuronal transport. miHTT has been previously associated with extracellular vesicles (EVs), but whether EVs mediate intercellular...
The preclinical development of microRNA-based gene therapies for inherited neurodegenerative diseases is accompanied by translational challenges. Due to the inaccessibility brain periodically evaluate therapy effects, accessible and reliable biomarkers indicative dosing, durability therapeutic efficacy in central nervous system are very much needed. This particularly important viral vector-based therapies, which a one-time administration results long-term expression active molecules brain....
<h3>Background</h3> HTT-lowering therapies hold great promise to slow-down or halt neurodegeneration in Huntington disease (HD). We have developed an engineered microRNA targeting human huntingtin (HTT), delivered via adeno-associated viral vector serotype 5 (AAV5-miHTT), leading efficient vitro and vivo rodent models. <h3>Aim</h3> To assess the translatability of our approach a large animal model: transgenic HD (tgHD) minipigs. <h3>Methods</h3> Animals were injected with AAV5-miHTT (1.2 ×...
<h3>Background</h3> We are developing an HTT lowering approach based on adeno-associated serotype 5 virus carrying expression cassette of engineered therapeutic microRNA (AAV5-miHTT). Main efficacy and safety concerns with gene therapy approaches would be long-term possible off-target activity the microRNA. As could both species cell type-specific, analyses were done in a system that as closely resembles human patient situation: neuronal cultures derived from HD induced pluripotent stem...