A5089477827- RNA Interference and Gene Delivery
- Genetic Neurodegenerative Diseases
- CRISPR and Genetic Engineering
- RNA Research and Splicing
- Virus-based gene therapy research
- Plant Pathogens and Fungal Diseases
- Mitochondrial Function and Pathology
- Muscle Physiology and Disorders
- MicroRNA in disease regulation
- HIV Research and Treatment
- Mycotoxins in Agriculture and Food
- RNA regulation and disease
- Viral Infectious Diseases and Gene Expression in Insects
- Advanced biosensing and bioanalysis techniques
- Pluripotent Stem Cells Research
- Nerve injury and regeneration
- Neurogenetic and Muscular Disorders Research
- Amyotrophic Lateral Sclerosis Research
- Viral Infections and Immunology Research
- Plant and fungal interactions
- Mycorrhizal Fungi and Plant Interactions
- Neurological disorders and treatments
- Powdery Mildew Fungal Diseases
- Extracellular vesicles in disease
- RNA modifications and cancer
UniQure (Netherlands)
2012-2021
AIMM Therapeutics (Netherlands)
2011-2012
University of Amsterdam
2006-2010
Amsterdam UMC Location University of Amsterdam
2006-2010
Wageningen University & Research
2004
University of Turku
2004
Plant Protection Institute
2002-2003
Double-stranded RNA can induce gene silencing via a process known as interference (RNAi). Previously, we have shown that stable expression of single shRNA targeting the HIV-1 Nef strongly inhibits replication. However, this was not sufficient to maintain inhibition. One hallmarks RNAi, its sequence specificity, presented way out for virus, nucleotide substitutions in target region abolished For development durable therapy prevents viral escape, proposed combine multiple shRNAs against...
RNA interference (RNAi) is a powerful approach to inhibit human immunodeficiency virus type 1 (HIV-1) replication. However, HIV-1 can escape from RNAi-mediated antiviral therapy by selection of mutations in the targeted sequence. To prevent viral escape, multiple small interfering RNAs (siRNAs) against conserved sequences should be combined. Ideally, these inhibitors expressed simultaneously single transgene transcript. In this study, we tested multiplex microRNA (miRNA) expression strategy...
Adenosine triphosphate (ATP)-binding cassette (ABC) transporters are drug efflux pumps responsible for the multidrug resistance phenotype causing hepatocellular carcinoma (HCC) treatment failure. Here we studied expression of 15 ABC relevant in 19 paired HCC patient samples (16 untreated, 3 treated by chemotherapeutics). Twelve showed up-regulation compared with adjacent healthy liver. These include ABCA2, ABCB1, ABCB6, ABCC1, ABCC2, ABCC3, ABCC4, ABCC5, ABCC10, ABCC11, ABCC12, and ABCE1....
Huntington's disease (HD) is a fatal neurodegenerative disorder caused by CAG trinucleotide repeat expansion in the huntingtin gene. Previously, we showed strong reduction and prevention of neuronal dysfunction HD rodents using an engineered microRNA targeting human huntingtin, delivered via adeno-associated virus (AAV) serotype 5 vector with transgene encoding miRNA against HTT mRNA (AAV5-miHTT). One challenges as model diseases their relatively small brain, making successful translation to...
Huntington's disease (HD) is a neurodegenerative disorder caused by accumulation of CAG expansions in the huntingtin (HTT) gene. Hence, decreasing expression mutated HTT (mtHTT) most upstream approach for treatment HD. We have developed gene-silencing approaches based on cassette-optimized artificial miRNAs (miHTTs). In first approach, total silencing wild-type and mtHTT was achieved targeting exon 1. second allele-specific induced heterozygous single-nucleotide polymorphism (SNP) rs362331...
Huntington's disease (HD) is a fatal progressive neurodegenerative disorder caused by mutation in the huntingtin (HTT) gene. To date, there no treatment to halt or reverse course of HD. Lowering either total only mutant HTT expression expected have therapeutic benefit. This can be achieved engineered micro (mi)RNAs targeting transcripts and delivered an adeno-associated viral (AAV) vector. We previously showed miHTT construct induce knock-down Hu128/21 HD mice, while miSNP50T miSNP67T...
A hexanucleotide GGGGCC expansion in intron 1 of chromosome 9 open reading frame 72 (C9orf72) gene is the most frequent cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The corresponding repeat-containing sense antisense transcripts a gain toxicity through accumulation RNA foci nucleus deposition dipeptide-repeat (DPR) proteins cytoplasm affected cells. We have previously reported on potential engineered artificial anti-C9orf72-targeting miRNAs (miC) targeting...
Huntington disease (HD) is a fatal neurodegenerative disorder caused by an autosomal dominant CAG repeat expansion in the huntingtin (HTT) gene. The translated expanded polyglutamine HTT protein known to cause toxic gain of function. We showed previously that strong lowering prevented neuronal dysfunction HD rodents and minipigs after single intracranial injection adeno-associated viral vector serotype 5 expressing microRNA targeting human (AAV5-miHTT). To evaluate long-term efficacy,...
Abstract Huntington disease (HD) is a fatal neurodegenerative caused by pathogenic expansion of CAG repeat in the huntingtin (HTT) gene. There are no disease-modifying therapies for HD. Artificial microRNAs targeting HTT transcripts degradation have shown preclinical promise and will soon enter human clinical trials. Here, we examine tolerability efficacy non-selective lowering with an AAV5 encoded miRNA (AAV5-miHTT) humanized Hu128/21 mouse model We show that intrastriatal administration...
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)....
Muscle represents an important tissue target for adeno-associated virus (AAV) vector-mediated gene transfer in muscular, metabolic or blood-related genetic disorders. However, several studies have demonstrated the appearance of immune responses against transgene product after intramuscular AAV vector delivery that resulted a limited efficacy treatment. Use microRNAs are specifically expressed antigen-presenting cells (APCs) is promising approach avoiding those responses. Cellular mir-142-3p,...
The most common pathogenic mutation in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is an intronic GGGGCC (G4C2) repeat the chromosome 9 open reading frame 72 (C9orf72) gene. Cellular toxicity due to RNA foci dipeptide (DPR) proteins produced by sense antisense repeat-containing transcripts thought underlie pathogenesis of both diseases. sequencing (RNA-seq) data C9orf72-ALS patients controls were analyzed better understand sequence conservation C9orf72 patients....
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.
Huntington disease (HD) is a fatal, neurodegenerative genetic disorder with aggregation of mutant Huntingtin protein (mutHTT) in the brain as key pathological mechanism. There are currently no modifying therapies for HD; however, HTT-lowering hold promise. Recombinant adeno-associated virus serotype 5 expressing microRNA that targets HTT mRNA (AAV5-miHTT) development treatment HD promising results rodent and minipig models. To support clinical trial, toxicity studies were performed non-human...
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...
RNAi-based gene therapy is a powerful approach to treat viral infections because of its high efficiency and sequence specificity. The HIV-1-based lentiviral vector system suitable for the delivery RNAi inducers HIV-1 susceptible cells due ability transduce nondividing cells, including hematopoietic stem stable transgene into host cell genome. However, presence anti-HIV short hairpin RNA (shRNA) microRNA (miRNA) cassettes can negatively affect titers. We show that shRNAs, which target genomic...