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flosz
0
Clin Med. 2014 Dec;14 Suppl 6:s41-4. doi: 10.7861/clinmedicine.14-6-s41.
Dyslipidaemia: what's around the corner?
Wierzbicki AS1, Perera D2, Ewang-Emukowhate M2.

Abstract
Hyperlipidaemia is a major risk factor for the development of atherosclerosis and cardiovascular disease. Statins are the mainstay of therapy and new guidelines focus on the use of these agents without specific targets for low-density lipoprotein (LDL)-cholesterol or non high-density lipoprotein (HDL)-cholesterol. However, patients remain at risk of cardiovascular disease despite statin therapy so new drugs are required. This article reviews therapies in development to further lower LDL-cholesterol (Proprotein convertase subtilisin/kexin-9 (PCSK-9) inhibitors), raise HDL-holesterol (cholesterol ester transfer protein inhibitors (CETPIs)) and reduce triglycerides (novel peroxisome proliferator-activated receptor (PPAR)-agonists and omega-3 fatty acid preparations).

Specialised therapies are in development for treatment of orphan disoders such as homozygous familial hypercholesterolaemia (lomitapide) or familial chylomicroaemia (alipogene tiparvovec). These novel lipid-lowering agents are likely to find uses in treating patients at the highest cardiovascular risk.

www.ncbi.nlm.nih.gov/pubmed/25468918
Volledig art.:
www.clinmed.rcpjournal.org/content/14...
flosz
0
The baculovirus expression vector system: A commercial manufacturing platform for viral vaccines and gene therapy vectors.

Abstract
The baculovirus expression vector system (BEVS) platform has become an established manufacturing platform for the production of viral vaccines and gene therapy vectors. Nine BEVS-derived products have been approved - four for human use (Cervarix®, Provenge®, Glybera® and Flublok®) and five for veterinary use (Porcilis® Pesti, BAYOVAC CSF E2®, Circumvent® PCV, Ingelvac CircoFLEX® and Porcilis® PCV). The BEVS platform offers many advantages, including manufacturing speed, flexible product design, inherent safety and scalability. This combination of features and product approvals has previously attracted interest from academic researchers, and more recently from industry leaders, to utilize BEVS to develop next generation vaccines, vectors for gene therapy, and other biopharmaceutical complex proteins. In this review, we explore the BEVS platform, detailing how it works, platform features and limitations and important considerations for manufacturing and regulatory approval. To underscore the growth in opportunities for BEVS-derived products, we discuss the latest product developments in the gene therapy and influenza vaccine fields that follow in the wake of the recent product approvals of Glybera® and Flublok®, respectively. We anticipate that the utility of the platform will expand even further as new BEVS-derived products attain licensure. Finally, we touch on some of the areas where new BEVS-derived products are likely to emerge.

www.ncbi.nlm.nih.gov/pubmed/25800821
DrMedicalValue
0
Super vondst Flosz!
QURE positioneert zich als productieleider enmogelijk kunen we op basis hiervan beoordelen hoe grott hun competitive advantage is.
rationeel
0
quote:

El Gaucho schreef op 13 apr 2015 om 11:35:


Super vondst Flosz!
QURE positioneert zich als productieleider enmogelijk kunen we op basis hiervan beoordelen hoe grott hun competitive advantage is.



Ze zullen het zelf wel weten toch? Alles wat beter is overnemen en integreren in je eigen bedrijf!
pommeraie
0
Mooi staaltje hoe je ook om kan gaan met je (trouwe)aandeelhouders op dit forum: Galapagos

www.iex.nl/Forum/Topic/1324074/Galapa...

(BTW: van E24 naar E31 in 2 dagen op goed nieuws)
DrMedicalValue
0
Heel mooi voorbeeld.
Toch mensen: ook QURE staat nog steeds op 6 euro winst en we moeten ook leven met de onzekerheden van biotech.
flosz
0


ASGCT New Orleans, May 13-16,2015

[545] Strong Cortico-Spinal Transduction After AAV5 Delivery into the Central Nervous System of Nonhuman Primates

Lluis Samaranch, Bas Blits, John Bringas, Michael Macayan, Foad Green, Waldy San Sebastian, John Forsayeth, Krystof Bankiewicz. Department of Neurological Surgery, University of California San Francisco, San Francisco, CA; UniQure, Amsterdam, Netherlands

Widespread distribution of gene products at clinically relevant levels throughout the central nervous system (CNS) without involving peripheral organs is still a challenge. Previous work demonstrated that infusion of adeno-associated virus (AAV) serotypes 9 (AAV9) and 7 (AAV7) into the cerebrospinal fluid (CSF) via cisterna magna of nonhuman primates (NHP) resulted in widespread transduction throughout cortex and spinal cord. Adeno-associated virus serotype 5 (AAV5) is also a potential candidate for CNS gene therapy when delivered into brain parenchyma but its performance in CSF has not been described. In the present work, we compared transduction patterns after CSF and parenchymal delivery of AAV5-GFP. For CSF delivery, we injected various doses of AAV5 (1E+14, 1E+13 and 1E+12 vg/mL) into CSF via lumbar routes in naïve NHP and studied vector distribution and cellular transduction 4 weeks after CSF delivery. We found a dose-dependent increase in transduction with strong levels of cell transduction and distribution throughout cortex and along the spinal cord at the highest doses and no signal in the low-dose group. These results suggest a dose threshold when delivering into CSF, most likely due to a dilution of the viral particles. Both astrocytes and neurons were transduced by AAV5 when infused either in CSF or directly into brain parenchyma.
Parenchymal delivery of AAV5-GFP was analyzed 8 weeks after surgery. Interestingly, when infused into the thalamus and the contralateral putamen, AAV5 resulted in higher levels of expression in cortical and subcortical structures than those observed in high-dose CSF animals. Surprisingly, thalamic injection directed spinal cord transduction throughout the cortico-bulbar axis. These results suggest not only that smaller volumes of AAV5 infused directly into the thalamus can result in robust and widespread cellular transduction in the brain but also to spinal cord. Our results confirm AAV5 as a powerful viral vector for gene transfer in the CNS and underscore its translational potential for treating neurological disorders of the brain and spinal cord.
Keywords: AAV Vectors; Gene Expression; Neurological Disorders

Session: Poster Session: AAV Vectors III (5:30 PM-7:00 PM)
Date/Time: Friday, May 15, 2015 - 5:30 pm
Room: Elite Hall A
www.abstracts2view.com/asgct/view.php...

[664] Improving AAV Gene Therapy Safety Analysis: Multiplex LAM-PCR Provide New Insights Into AAV Vector Integration

Irene Gil-Farina, Christine Käppel, Stefan Wilkening, Esperanza Lopez-Franco, Maria Astrid Paneda, Jesús Prieto, Lisa Spronck, Christof von Kalle, Harald Petry, Gloria Gonzalez-Aseguinolaza, Manfred Schmidt. Translational Oncology, NCT / DKFZ, Heidelberg, Germany; Gene Therapy and Hepatology, CIMA, Pamplona, Spain; DIGNA Biotech SL, Madrid, Spain; University Hospital of Navarra, Pamplona, Spain; uniQure, Amsterdam, Netherlands

Nowadays, recombinant adeno-associated viruses (rAAV) constitute one of the most successful vectors for human gene therapy. These viral vectors allow a long-term transgene expression mainly due to their ability to form stable concatemeric DNA structures. Interestingly, although it is a rare event, rAAV have been shown to randomly integrate into the host genome.

The inverted terminal repeats (ITR) have been shown to be preferred breakage points within the rAAV vectors. Current analysis of AAV integration are based on the linear amplification mediated (LAM)-PCR technology, here the genomic regions adjacent to the ITRs are amplified and sequenced for the determination of the integration sites (IS). However, recent studies have shown that vector breakage may also occur along the whole vector sequence, thus requiring the development of new methods able to identify the integration of internal vector regions.

We present a novel method for the detection of rAAV integration based on the LAM-PCR technology by employing simultaneously five primer sets covering the whole AAV vector sequence. This multiplex LAM-PCR was used, in parallel with the standard 5' LAM-PCR, in liver, spleen and adrenal gland biopsies from monkeys injected with 1x1013 viral genomes (vg)/kg or 5x1013 vg/kg of the AAV2/5-AAT-coPBGD vector (this vector has been used in a phase I clinical trial for acute intermittent porphyria). Subsequent 454 sequencing and data analysis of ~1 million raw sequences for each tissue allowed the identification of near 800 integration sites (IS). As it has been previously reported, vector integration occurs within different regions of the ITR, although preferentially in the C-region. In addition, multiplex LAM-PCR showed breakage at different positions of the AAV vector genome in all the organs analyzed.

Our data show the increased sensitivity of this method and its suitability for the analysis of viral integration occurring at inner regions of the rAAV vector. Thus, this new method will provide a deeper insight into the interaction of AAV vectors with the host genome and will contribute to increase the thoroughness of the safety studies for the increasing number of gene therapy clinical trials using rAAV vectors.
Keywords: Other-Vector integration, NGS, LAM-PCR; Other-Vector integration, NGS, LAM-PCR; Other-Vector integration, NGS, LAM-PCR

Session: Poster Session: Clinical Translation of Vector Production and Protocol Preparation II (5:30 PM-7:00 PM)
Date/Time: Friday, May 15, 2015 - 5:30 pm
Room: Elite Hall A
www.abstracts2view.com/asgct/view.php...
flosz
0
Moving Forward Toward a Cure for Hemophilia B

Abstract
AAV vectors are among the most promising to treat hereditary diseases by gene therapy. Long-term expression of therapeutic genes has been demonstrated in preclinical models and in clinical trials after AAV delivery in various tissues.

www.nature.com/mt/journal/v23/n5/full...


flosz
0
S100A1 DNA-based inotropic therapy protects against pro-arrhythmogenic ryanodine receptor 2 dysfunction.
Ritterhoff J1, Völkers M1, Seitz A1, Spaich K1, Gao E2, Peppel K3, Pleger ST1, Zimmermann WH4, Friedrich O5, Fink RH6, Koch WJ2, Katus HA7, Most P8.
Author information
Abstract
Restoring expression levels of the EF-hand calcium (Ca2+) sensor protein S100A1 has emerged as a key factor in reconstituting normal Ca2+ handling in failing myocardium. Improved sarcoplasmic reticulum (SR) function with enhanced Ca2+ resequestration appears critical for S100A1's cyclic adenosine monophosphate-independent inotropic effects but raises concerns about potential diastolic SR Ca2+ leakage that might trigger fatal arrhythmias. This study shows for the first time a diminished interaction between S100A1 and RyR2s in experimental HF. Restoring this link in failing cardiomyocytes, engineered heart tissue and mouse hearts, respectively, by means of adenoviral and adeno-associated viral S100A1 cDNA delivery normalizes diastolic RyR2 function and protects against Ca2+- and â-adrenergic receptor-triggered pro-arrhythmogenic SR Ca2+ leakage in vitro and in vivo. S100A1 inhibits diastolic SR Ca2+ leakage despite aberrant RyR2 phosphorylation via protein kinase A and calmodulin-dependent kinase II and stoichiometry with accessory modulators such as calmodulin, FKBP12.6 or sorcin. Our findings demonstrate that S100A1 is a regulator of diastolic RyR2 activity and beneficially modulates diastolic RyR2 dysfunction. S100A1 interaction with the RyR2 is sufficient to protect against basal and catecholamine-triggered arrhythmic SR Ca2+ leak in HF, combining antiarrhythmic potency with chronic inotropic actions.Molecular Therapy (2015); doi:10.1038/mt.2015.93.
www.ncbi.nlm.nih.gov/pubmed/26005840

mobile.twitter.com/ogut_ozgur
Ogut_Ozgur: For those interested in $QURE S100 program
flosz
0
Translational research for Parkinson's disease: The value of pre-clinical primate models www.sciencedirect.com/science/article...
Opm. mbt PD onderzoek Qure.

Bijlage:
flosz
0
First global, longitudinal, pharmaco-epidemiologic, observational registry on gene therapy in the management of lipoprotein lipase deficiency (GENIALL)
www.sciencedirect.com/science/article...
flosz
0
Prof. Dollar
0
quote:

flosz schreef op 12 jan 2016 om 09:25:


Pathogenic classification of LPL gene variants reported to be associated with LPL deficiency www.sciencedirect.com/science/article...

Van belang is dus deze zin:
"The deleterious mutations associated with LPL deficiency will assist in the diagnosis and selection of patients as candidates for the presently approved LPL gene therapy."

Hier verwijst men dus indirect naar Glybera. Hopelijk hebben Chiesi en QURE er profijt van.
flosz
0
Recombinant AAV integration is not associated with hepatic genotoxicity in non-human primates and patients.

Recombinant adeno-associated viral vectors (rAAV) currently constitute a real therapeutic strategy for the sustained correction of diverse genetic conditions. Though a wealth of preclinical and clinical studies have been conducted with rAAV, the oncogenic potential of these vectors is still controversial, particularly when considering liver-directed gene therapy. Few preclinical studies and the recent discovery of incomplete wild-type AAV2 genomes integrated in human hepatocellular carcinoma biopsies have raised concerns on rAAV safety. In the present study we have characterized the integration of both complete and partial rAAV2/5 genomes in non-human primate tissues and clinical liver biopsies from a trial aimed to treat acute intermittent porphyria. We applied a new multiplex linear amplification-mediated PCR assay capable of detecting integration events that are originated throughout the rAAV genome. The integration rate was low both in non-human primates and patient's samples. Importantly, no integration clusters or events were found in genes previously reported to link rAAV integration with hepatocellular carcinoma development, thus showing the absence of genotoxicity of a systemically administered rAAV2/5 in a large animal model and in the clinical context.Molecular Therapy (2016); doi:10.1038/mt.2016.52.

www.ncbi.nlm.nih.gov/pubmed/26948440 twitter.com/floszcrxl/status/70831708...
flosz
0
300 - Changing the Route of Administration to Improve Liver Transduction by Recombinant AAV-Based Vectors
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May 5, 2016, 6:00 PM - 8:00 PM
Authors
Nerea Zabaleta1, David Salas1, Anna Majowicz2, Rubén Hernandez-Alcoceba1, Valerie Sier-Ferreira2, Jesús Prieto1, Ignacio Bilbao1, Gloria González-Aseguinolaza1

1FIMA, Pamplona, Spain,2uniQure, Amsterdam, Netherlands
Disclosures
 N. Zabaleta: None.
Abstract
The liver is a central organ in metabolism and there are numerous inherited metabolic disorders that have their origin in this organ. Gene therapy represents a promising therapeutic approach for this type of diseases. Although in preclinical studies using AAV-based vectors high and long-term hepatic expression has been achieved, there are still some concerns about the expression levels and the percentage of hepatocytes that can be transduced. This is of particular importance for diseases in which the deficiency of an enzymatic activity is associated with the generation of toxic products that require the transduction of a high percentage of hepatocytes. Therefore, the main goal of our study was to improve liver transduction efficacy by an AAV serotype. For this purpose, the vector was administered directly to the liver via suprahepatic veins (SHV) using a catheter and balloon occlusion or via the hepatic artery (HA) with balloon occlusion of the suprahepatic vein. The experiment was performed in Macaca fascicularis, with 8 animals being infected with a dose of 3x1013 gc/kg of an AAV5 expressing the reporter gene hSEAP (human secreted embryonic alkaline phosphatase) under the control of a liver specific promoter (AAV5-AAT-hSEAP). The first group (2 animal) received the virus systemically in the saphenous vein, the second group (3 animals) received the virus via the SHV with 10 minutes of balloon occlusion and the third group (3 animals) via the HA with 10 minutes of balloon occlusion of the SHV. The procedure could only be performed on the right branch of SHV and HA due to the small size of the left SHV and HA branches, reaching only 40% of the liver. hSEAP-specific activity in serum samples of the groups that received the virus directly in the hepatic blood flow was higher compared to the animals receiving the vector by peripheral intravenous injection. This was correlated with the presence of a higher number of viral genomes in the liver of the animals. Moreover, when their distribution was analyzed we found that the animals that had received the virus through the SHV or HA displayed higher infection rates in the right side of the liver, where the administration had been performed. In conclusion, direct administration of the vector AAV5-AAT-hSEAP through the hepatic blood flow with balloon occlusion was associated with higher transgene expression and an increase in vector genomes in the injected area. Studies in bigger animals in order to reach both sides of the liver should be performed in order to explore the potential use of alternative routes of administration in the clinic.
www.abstractsonline.com/pp8/#!/4077/p...
flosz
0
310 - Analysis of AAV5 Biodistribution and Viral Shedding in the Presence or Absence of Neutralizing Antibodies
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May 5, 2016, 6:00 PM - 8:00 PM

Authors
David Salas1, Anna Majowicz2, Nerea Zabaleta1, Estefania Rodríguez-Garcia1, Harald Petry2, Valerie Ferreira2, Gloria Gonzalez Aseguinolaza1

1Gene Therapy and Regulation of Gene Expression Program, FIMA, Pamplona, Spain,2Research Department, uniQure B.V., Amsterdam, Netherlands
Disclosures
 D. Salas: None.
Abstract
Neutralizing antibodies (NAbs) are the main obstacle that must be overcome to achieve a successful delivery of a viral vector to the target organ. NAbs acquisition can be induced naturally after infection with wild type AAV or after the first administration of AAV vector in the course of gene therapy treatment. Therefore, the objective of this project was to evaluate the efficacy and presence of the vector in the organism, as well as the response and vector elimination in the presence and absence of NAbs. We analyzed the presence of the reporter transgene (hFIX), humoral and cellular immune responses against the vector, viral shedding and biodistribution. The administration of AAV2/5 was successful in absence of NAbs. In contrast, vector administration in presence of specific NAbs was unsuccessful, probably due to the vector being completely depleted by anti-AAV2/5 NAbs. Our data demonstrate that while in the absence of antibodies the vector can be detected in serum and in other body fluids for 70 days after vector administration, the presence of antibodies immediately clears the vector from the organism. 24 hours after the AAV-hFIX administration 1X1008 gc/mL are detected in the serum in the absence of NAbs but in the presence of NAbs the concentration is reduced 1000-fold. In both groups the presence of NAbs increased upon infection without a cellular immune response against the vector. Finally, the biodistribution studies showed remarkable differences between the two groups: in the absence of NAbs vector genomes are detected mainly in liver, heart, spleen and inguinal LN, while in the presence of NAbs vector genomes are almost undetectable in all tissues analyzed.
www.abstractsonline.com/pp8/#!/4077/p...
flosz
0
546 - Development of MFP-Inducible System for AAV5 Gene Therapy of Chronic Diseases in the Liver
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May 6, 2016, 6:00 PM - 8:00 PM

Authors
Jolanda Liefhebber1, Raygene Martier2, Richard van Logtenstein1, Harald Petry1, Pavlina Konstantinova1

1uniQure n.v., Amsterdam, Netherlands,2uniQure n.v. and Leiden University, Amsterdam and Leiden, Netherlands
Disclosures
  J. Liefhebber: 1; Commercial Interest i.e. Company X; uniQure NV. 1; What was received? i.e. Honorarium; Salary. 1; For what role? i.e. Speaker; Employee.
Abstract
Introduction: Gene therapy offers long term solutions for chronic diseases, whereby the transgene is continuously expressed upon single vector administration. However in some cases it would be desirable to tightly regulate or switch off transgene expression. Methods: We are investigating regulated gene expression based on the mifepristone (MFP)-inducible GeneSwitch system. The GeneSwitch protein comprises yeast Gal4 DNA-binding domain, a human p65 activation domain and a MFP controlled domain derived from the human progesterone receptor. The classical GeneSwitch system consists of two expression cassettes on two separate vectors; one containing the GeneSwitch sequence and one containing the transgene. We compared this two-vector system to a single-vector system, where the two cassettes were put into one vector for efficacy in vitro and in vivo. Results: We show inducible expression of EPO, IGF and GNDF obtained in vitro upon addition of MFP to cells transfected with plasmids containing GeneSwitch and the gene expression cassette. The kinetics of EPO mRNA and protein expression followed a dose dependent fashion in the range of 0.1 to 10 nM MFP and reached a plateau at higher MFP concentrations. Surprisingly, the GeneSwitch protein expression decreased 48h after MFP induction. The indicibility of the single versus the two-vector system of GeneSwitch-EPO was compared. Both systems were equally inducible based on total amount of EPO produced in the presence of MFP and related to background expression in the absence of MFP. In vivo proof of concept was obtained for EPO in the liver. EPO is characterized by clear expression kinetics in plasma and raises blood hematocrit, hence provides a reliable in-life read-out for gene inducibility. Mice were injected with different doses of AAV5-AAT-GeneSwitch-EPO and gene expression was induced in two separate rounds at 4 and 8 weeks p.i. EPO plasma levels increased approximately 2-logs in the single or two-vector system-injected mice, compared to un-induced groups. Moreover in the absence of MFP background expression of EPO was lower in the single-vector system and hematocrit levels were unaffected. Measurements of MFP in tissue matrices and in plasma by mass spectrometry show the presence of MFP in plasma and liver, validating applicability of the GeneSwitch system in the liver. Conclusion: Overall, our data indicate that transgene expression can be repeatedly regulated in the liver using the GeneSwitch system and provides us with a novel AAV5 vector for further development.
www.abstractsonline.com/pp8/#!/4077/p...
flosz
0
618 - Directional Transduction of AAV-5 Vectors in the NHP Brain
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May 6, 2016, 6:00 PM - 8:00 PM


Authors
Bas Blits1, Lluis Samaranch2, John Bringas2, Waldy San Sebastian2, Krystoff Bankiewicz2, Harald Petry3

1Neurobiology Research, uniQure, Amsterdam, Netherlands,2Neurological Surgery, University of California San Francisco, San Francisco, CA,3Research, uniQure, Amsterdam, Netherlands
Disclosures
 B. Blits: None.
Abstract
This study was performed to investigate the delivery of AAV vectors into the putamen and thalamus of nonhuman primates. The vectors were delivered to the targeted brain regions by MRI-guided convection enhanced delivery. Special attention was given to the analysis of axonal transport and levels of transduction. Recombinant AAV is an excellent candidate for delivery of therapeutic molecules to the central nervous system to target neurodegenerative diseases. UniQure has succeeded in developing a proprietary platform manufacturing technology that allows safe, effective, cGMP-compliant, economically feasible and commercially scalable manufacturing of AAV. UniQure’s novel approach is based on the use of a combination of recombinant baculoviruses and insect cells. Using our production platform, two AAV stocks encoding GDNF or GFP were generated. At eight weeks following infusion into the thalamus, for instance, massive transduction of the thalamus, cortex, striatum and substantia nigra was observed indicating both anterograde and retrograde transduction. At the site of injection, transduction was both glial and neuronal, whereas off site transduction was mainly neuronal. Following injection of a lower AAV volume into the putamen, transduction was limited to areas within the putamen and substantia nigra suggesting only anterograde transport of viral particles. These data indicate a dose dependent anterograde or retrograde transport mechanism. This data set confirms that production of AAV using the (scalable) baculovirus-based platform results in an effective vector that is able to mediate expression patterns that can be used to develop an AAV-mediated therapeutic strategy to treat neurodegenerative diseases.
www.abstractsonline.com/pp8/#!/4077/p...
flosz
0
700 - Successful Repeated Hepatic Gene Delivery in Mice and Non-Human Primates Achieved by Sequential Administration of AAV5 and AAV1 Vector Serotypes
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May 6, 2016, 6:00 PM - 8:00 PM

Authors
Anna Majowicz1, David Salas2, Nerea Zabaleta2, Estefania Rodríguez-Garcia2, Gloria Gonzalez Aseguinolaza2, Harald Petry1, Valerie Ferreira1

1Research, uniQure N.V., Amsterdam, Netherlands,2Gene Therapy and Regulation of Gene Expression Program, CIMA, University of Navarra, Pamplona, Spain
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
The major challenge in AAV-based gene therapy is the presence of circulating neutralizing antibodies (NAB) against AAV vector capsids. NAB can be present in patient’s blood prior to AAV treatment due to naturally acquired infections with the wild type AAV virus (pre-existing NAB). Anti-AAV NABs are also raised after first administration of AAV in the course of gene therapy treatment. There is a need to develop strategies that would permit a repeated AAV gene delivery not only to be able to treat the patients that have pre-existing NAB but also for the patients previously treated with recombinant AAV, that might experience overtime a decrease in therapeutic protein expression due to the natural turnover of transduced cells. To address those issues, we explored the feasibility of using the AAV5 and AAV1 serotypes for repeated, liver-targeted gene delivery in non-human primates (NHPs). Sequential AAV-based gene delivery with AAV5 and AAV1 proved to be successful as an expression of the two reporter transgenes used in the study was observed (hSEAP and hFIX). In contrast, the re-administration of the same serotype (AAV5-hSEAP followed by AAV5-hFIX) was unsuccessful due to the total inhibition of secondary AAV5 transduction by anti-AAV5 NAB. In order to determine the long-term stability of transgenes activity/expression, the NHP cross administration experiment was continued up to 1 year after primary injection (AAV5- hSEAP or PBS). All NHPs cross administered with AAV5-hSEAP followed by AAV1-hFIX showed hSEAP and hFIX protein expression in plasma. In a long-term follow-up, decreases of transgenes activity/expression were observed in 5 out of the 12 NHPs injected. The reductions of transgenes activity/expression were associated with specific immune responses directed against hSEAP or hFIX. Interestingly, DNA and mRNA levels in the animals presenting transgene directed immunity were comparable to those observed in the other animals that did not lose the transgene activity/expression. Additionally, fluorescent in situ hybridization (FISH) was performed on the liver sections of the animals to localize AAV vector DNA and transgene mRNA. In summary, our data demonstrates that a successful re-administration can be achieved in AAV-based gene therapy when combining AAV5 and AAV1 in NHPs.
www.abstractsonline.com/pp8/#!/4077/p...
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