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PubMed UniQure

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  1. flosz 19 april 2016 17:35

    • flosz

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    701 - Successful In Vivo Re-Administration of AAV with the Use of Two-Step AAV Injection
    Add To Itinerary
    May 6, 2016, 6:00 PM - 8:00 PM

    Authors
    Anna Majowicz, Harald Petry, Valerie Ferreira

    Research, uniQure N.V., Amsterdam, Netherlands
    Disclosures
      A. Majowicz: 1; Commercial Interest i.e. Company X; uniQure. 1; What was received? i.e. Honorarium; Salary. 1; For what role? i.e. Speaker; Employee.
    Abstract
    Introduction: The major challenge for a successful re-administration of AAV vectors is the presence of neutralizing antibodies (NABs) directed against AAV developed after the first administration of AAV vectors. Those serotype-specific neutralizing antibodies directed towards the viral capsid proteins prevent efficient gene transfer with AAV of the same serotype. The generation of a humoral immune response does not permit the use of “vector of choice” more than once which is a concern for life-long disorders for which re-administration has to be considered. Currently different methods are being explored in order to circumvent the presence of anti-AAV NABs at re-administration. One of those methods is based on the principle of antibody adsorption in AAV-based gene delivery. It was first observed in mice by Scallan et al. who reported that the administration of AAV vectors in the presence of empty AAV capsids significantly reduced the neutralization of AAV vectors by anti-AAV circulating NAB (Scallan et al. 2006). Additionally, Mingozzi et al. have also shown in mice and non-human primates that injection of therapeutic AAV vector together with empty AAV capsids allows liver transduction in the presence of high titers of anti-AAV NABs (Mingozzi et al. 2013). Goal: The goal of our study was to decrease the anti-AAV NABs to a level that would allow successful repeated gene delivery with the same AAV serotype. Study design and results: We have designed an approach to decrease the levels of circulating NABs in vivo by mean of anti-AAV NABs adsorption. In our study, for the re-administration of AAV in the presence of anti-AAV NABs, a two-step AAV vector injection was used. The first dose of AAV vector was used as a “decoy” AAV that captured circulating anti-AAV NABs. To allow a proper binding of circulating anti-AAV NABs by “decoy” AAVs, we delayed the second AAV injection. In our proof of concept experiments, mice were initially immunized with AAV5-GFP. Two weeks later the re-administration of AAV5 was performed. The re-administration procedure consisted of a first “decoy” AAV5-GFP injection followed by an injection with AAV5-hSEAP. In a first experiment, mice were injected with a “decoy” AAV5-GFP followed by AAV5-hSEAP at 30, 60 or 120 minutes after the first injection. A significant decrease of total anti-AAV5 antibody levels after injection of the “decoy” AAV5-GFP vector was observed. In the second study, we used a similar procedure with a 30 min time frame between ”decoy” AAV5-GFP and AAV5-hSEAP injection, using three different doses of the “decoy” AAV5-GFP. The decrease of total anti-AAV5 antibodies 30 min after “decoy” AAV5-GFP injection was inversely proportional to the dose of the “decoy” AAV5-GFP used and to the hSEAP activity levels that were achieved after AAV5-hSEAP injection. Conclusions:Based on hSEAP transgene activity levels, we were able to determine a cut-off level of anti-AAV5 antibodies that allow a successful re-administration of the AAV5. Overall, the two-step AAV injection approach as such is promising for AAV re-administration.
    www.abstractsonline.com/pp8/#!/4077/p...
  2. flosz 26 mei 2016 19:06

    • flosz

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    Phase I Open Label Liver-Directed Gene Therapy Clinical Trial for Acute Intermittent Porphyria.
    ac.els-cdn.com/S0168827816301982/1-s2...

    Background & Aims
    Acute intermittent porphyria (AIP) results from porphobilinogen deaminase (PBGD) haploinsufficiency, which leads to hepatic over-production of the neurotoxic heme precursors porphobilinogen (PBG) and delta-aminolevulinic acid (ALA) and the occurrence of neurovisceral attacks. Severe AIP is a devastating disease that can only be corrected by liver transplantation. Gene therapy represents a promising curative option. The objective of this study was to investigate the safety of a recombinant adeno-associated vector expressing PBGD (rAAV2/5-PBGD) administered for the first time in humans for the treatment of AIP.
    Methods
    In this phase I, open label, dose-escalation, multicenter clinical trial, four cohorts of 2 patients each received a single intravenous injection of the vector ranging from 5x1011 to 1.8x1013 genome copies/kg. Adverse events and changes in urinary PBG and ALA and in the clinical course of the disease were periodically evaluated prior and after treatment. Viral shedding, immune response against the vector and vector persistence in the liver were investigated.
    Results
    Treatment was safe in all cases. All patients developed anti-AAV5 neutralizing antibodies but no cellular responses against AAV5 or PBGD were observed. There was a trend towards a reduction of hospitalizations and heme treatments, although ALA and PBG levels remained unchanged. Vector genomes and transgene expression could be detected in the liver one year after therapy.

    Conclusion
    rAAV2/5-PBGD administration is safe but AIP metabolic correction was not achieved at the doses tested in this trial. Notwithstanding, the treatment had a positive impact in clinical outcomes in most patients.

    Lay summary
    Studies in an acute intermittent porphyria (AIP) animal model have shown that gene delivery of PBGD to hepatocytes using an adenoassociated virus vector (rAAV2/5-PBG) prevent mice from suffering porphyria acute attacks. In this phase I, open label, dose-escalation, multicenter clinical trial we show that the administration of rAAV2/5-PBGD to patients with severe AIP is safe but metabolic correction was not achieved at the doses tested; the treatment, however, had a positive but heterogeneous impact on clinical outcomes among treated patients and 2 out of 8 patients have stopped hematin treatment.

    Volledig art.via link.
  3. flosz 23 september 2016 20:10

    • flosz

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    The role of registries in rare genetic lipid disorders: Review and introduction of the first global registry in lipoprotein lipase deficiency www.sciencedirect.com/science/article...

    In vivo proof-of-concept of removal of the huntingtin caspase cleavage motif-encoding exon 12 approach in the YAC128 mouse model of Huntington's disease

    Huntington’s disease (HD) is a progressive autosomal dominant disease, caused by a CAG repeat expansion in the HTT gene, resulting in an expanded polyglutamine stretch at the N-terminal of the huntingtin protein. An important event in HD pathogenesis appears to be the proteolysis of the mutant protein, which forms N-terminal huntingtin fragments. These fragments form insoluble aggregates and are found in nuclei and cytoplasm of affected neurons where they interfere with normal cell functioning. Important cleavage sites are encoded by exon 12 of HTT. A novel approach is Htt protein modification through exon skipping, which has recently been proven effective both in vitro and in vivo. Here we report proof-of-concept of AON 12.1 in vivo using the YAC128 mouse model of HD. Our results support and encourage future longitudinal studies exploring the therapeutic effects of sustained infusions in the YAC128 mouse model.
    www.sciencedirect.com/science/article...

    Adeno-associated virus (AAV) vectors in cancer gene therapy www.cchem.berkeley.edu/schaffer/2016%... David Schaffer
  7. flosz 25 april 2017 19:34

    • flosz

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    #ASGCT17 $QURE abstract 395 - Successful Repeated Hepatic Gene Delivery in Non-Human Primates Achieved with AAV5 by Use of Immune Adsorption
    www.abstractsonline.com/pp8/#!/4399/p...

    #ASGCT17 $QURE Novel AAV Vector Reservoirs: Peripheral Blood Cells and Hematopoietic Progenitors www.abstractsonline.com/pp8/#!/4399/p...

    #ASGCT17 $QURE Circulating Anti-AAV5 Neutralizing Antibody Titers up to 1:1031 Do Not Affect Liver Transduction Efficacy of AAV5 Vectors in Non-Human Primates www.abstractsonline.com/pp8/#!/4399/p...

    #ASGCT17 $QURE AAV5-miHTT Gene Therapy Demonstrates Broad Vector Distribution and Strong Mutant Huntingtin Lowering in a Huntington’s Disease Minipig Model www.abstractsonline.com/pp8/#!/4399/p...

    #ASGCT17 $QURE Detection of AAV Vector DNA and Transgene RNA in Liver Tissue by Fluorescent In Situ Hybridization www.abstractsonline.com/pp8/#!/4399/p...
    Bijlage:
  13. flosz 15 februari 2019 15:44

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    quote:

    flosz schreef op 4 februari 2019 20:03:

    Artificial microRNAs targeting C9ORF72 have the potential to reduce accumulation of the intra-nuclear transcripts in
    ALS (amyotrophic lateral sclerosis) and FTD (frontotemporal dementia) patients ac.els-cdn.com/S2162253119300149/1-s2...
    $QURE
    +

    Targeting RNA-mediated toxicity in C9ORF72 ALS/FTD by RNAi-based gene therapy $QURE www.cell.com/molecular-therapy-family...
  14. flosz 26 april 2019 16:59

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    $QURE #ASGCT19 APRIL29-MAY2,WASHINGTON,D.C. Pre-Existing Anti-Adeno-Associated Virus (AAV) Serotype 5 Neutralizing Antibodies (NABs) Titers in Minipig Serum Do Not Reflect Levels of Anti-AAV5 NABs Titers in Their Cerebrospinal Fluid (CSF)
    AAV-based therapies generated promising pre-clinical results translating into phase I clinical trials for several neurodegenerative diseases. However, it remains unclear whether naturally acquired pre-existing systemic immunity to AAV would affect the therapeutic efficacy of AAV vectors delivery to the Central Nervous System (CNS). To address this question, we investigated the levels of pre-existing anti-AAV5 NABs in serum and in CSF in a cohort of minipigs. Thirty matched serum and CSF samples from wild type minipigs were analyzed for the presence of anti-AAV5 NABs. While serum samples of minipigs had detectable levels of anti-AAV5 NABs that varied between a titer of 2 (negative) to 256 (positive), CSF samples of all the minipigs were found negative for the presence of anti-AAV5 NABs. Hence, no detectable anti-AAV5 NABs were detected in CSF of animals that had systemic pre-existing anti-AAV5 NAB titers up to 256. In order to translate our data to clinic, an anti-AAV5 NABs prevalence study was performed using serum of healthy donors (n=350). In this cohort, 88% of the subjects had anti-AAV5 NABs titers below 256. We have previously reported that serum anti-AAV5 NAB titers up to 340 in humans and as high as 1030 in primates did not interfere with the therapeutic efficacy of intravenously administered AAV5 vector. Combined with the current data, we conclude that the risk for reduced therapeutic efficacy of intrathecal or intraparenchymal administration of therapeutic AAV5 vectors by pre-existing neutralizing AAV5 antibodies is very low. Further studies are needed to determine the local and systemic induction and persistence of anti-AAV5 NABs titers following intrathecal or intraparenchymal administration of AAV5 vectors to assess the possibility of re-administration of AAV5-based gene delivery.
    www.asgct.org/global/documents/asgct1... annualmeeting.asgct.org/UserFiles/fil...

    $QURE #ASGCT19 APRIL29-MAY2,WASHINGTON,D.C. Improving AAV Quality Attributes and Process Robustness Through Molecular Redesign
    The manufacturing of recombinant AAV relies significantly on the underlying production technologies to support the robustness and scalability of clinical grade AAV material. To date two main production platforms are utilized to generate clinical grade rAAV material. One is the chemical transient transfection of HEK293 cells and the other is utilizing the baculovirus expression vectors to deliver genetic material to insect cells. The baculovirus production system has been shown to be capable of large scale rAAV manufacturing (500L) in stirred tank reactors while maintaining the high quality of the rAAV attributes. That said, large scale processes require a significant improvement in process robustness. Process robustness is dependent on the timing, quantity and quality of the precursor substrates where scaling of the processes can lead to difficulty in controlling these key parameters. Here we will highlight the results from molecular biology approaches in attaining higher process stability. Key improvements were obtained for the % full capsids (minimally 70% full, up from 30%), crude lysed bulk titers (2-fold improvement) and a process that is significantly less sensitive to the starting and raw materials used for production. In conclusion, molecular engineering of the BEVS constructs facilitated significant process-related improvements and robustness.
    www.asgct.org/global/documents/asgct1... annualmeeting.asgct.org/UserFiles/fil...
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