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Huntington’s Disease

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Prof. Dollar schreef op 26 feb 2019 om 11:18:

I don't think that will work because AMT-130 consists of an AAV5 vector carrying an artificial micro-RNA specifically tailored to silence the huntingtin gene. In analogy to SCA-03, AMT-150 must be tailored to silence the ATXN3 gene.

Ok thank you.:-( I followed your advise to follow the AMT-130 also.
Prof. Dollar
You're welcome! Both gene therapies contain very likely the same building blocks, except for one. That is the micro-RNA. If the Huntington program is paying off, it also offers perspective for other similar programs such as SCA3.
The Company is currently performing studies in large animals to demonstrate further safety and efficacy.
Orphan designation EMA/FDA.
IND(investigational new drug) filing.

Hoi Yvonne,
M.a.w., dit proces gaat nog jaren duren, onderzoek staat nog in de kinderschoenen.
Misschien is het mogelijk je arts(en) contact op te laten nemen met M.b.t. informatie en toegang tot mogelijk geschikte behandelopties. Als er momenteel geen mogelijkheden zijn is men misschien wel in staat e.e.a. voor je uit te zoeken, te concretiseren, e.o. je op weg te helpen in de enorme wirwar van geneesmiddelen in ontwikkeling en informatie over klinische studies.
Veel geluk en sterkte!

flosz schreef op 21 feb 2019 om 15:00:

+ Draadje:

14th Annual Huntington's Disease Therapeutics Conference: A Forum for Drug Discovery & Development.Monday, February 25, 2019 - Thursday, February 28, 2019

AMT-130 Shows Restoration of Brain Cell Function and Reversal of Neuropathology in #HuntingtonsDisease Mouse Model $QURE

AMT-130 Shows Restoration of Brain Cell Function and Reversal of Neuropathology in Huntington’s Disease Mouse Model ~
LEXINGTON, Mass. and AMSTERDAM, the Netherlands, Feb. 27, 2019 (GLOBE NEWSWIRE) -- uniQure N.V. (NASDAQ: QURE), a leading gene therapy company advancing transformative therapies for patients with severe medical needs, today presented new preclinical data on AMT-130, its gene therapy candidate for the treatment of Huntington’s disease (HD) at the 14th Annual CHDI Huntington’s disease Therapeutics Conference in Palm Springs, California.
“Findings from our preclinical studies illustrate the therapeutic potential of AMT-130 in restoring function to damaged brain cells in Huntington’s disease and providing a safe and sustained reduction of mutant huntingtin protein with a gene therapy candidate that could be applicable to a broad patient population,” stated Sander van Deventer, M.D., Ph.D., chief scientific officer at uniQure.
Five scientific abstracts submitted by uniQure researchers were accepted for presentation at the conference.  Among these abstracts are the following poster presentations featuring new data on AMT-130:    
Magnetic resonance spectroscopy (MRS) shows restoration of neuronal function in a HD mouse model treated with AMT-130.
In this study, a non-invasive technique called MRS was used to measure biomarkers for the health of brain cells in HD mice after treatment with AMT-130 by direct injection in the striatum. At 3 months after administration, significant levels of vector were present in the treated areas resulting in robust expression of microRNA and a significant knock down of the mutant huntingtin protein (mHTT). The MRS analyses showed improvement in brain cell function, a reversal in HD neuropathology, and a partial reversal of volume loss in a key brain region involved in memory called the hippocampus.
Pre-existing serum antibodies to AAV5 Neutralizing Antibodies (NABs) are not found in the cerebrospinal fluid (CSF).
The presence of pre-existing neutralizing antibodies (NABs) can reduce the efficacy of gene therapy. Thirty matched serum and CSF samples from wild-type minipigs were analyzed for NABs. Serum samples showed detectable levels of anti-AAV5 NABs in the range of titers 2 to 256.  All paired CSF samples were negative for the presence of anti-AAV5 NABs.
For comparison, a prevalence study in 350 healthy donors showed serum anti-AAV5 NABs titers below 256 in 88% of the subjects’ serum. The Company has previously reported data that show anti-AAV5 NAB titers up to 340 in humans, and as high as 1,030 in primates, did not interfere with the therapeutic effect of AAV5 gene therapies.  Therefore, this study suggests the risk of reduced efficacy due to anti-AAV5 NABs is low when AAV5 vectors are administered into the brain or spinal fluid.
Virtual neurosurgical planning demonstrates the safety of deep brain gene delivery in patients with early manifest HD. 
High-resolution magnetic resonance imaging (MRI) scans from 20 patients with early manifest HD were analyzed to simulate the neurosurgical insertion of micro-catheters by a specialized technique called convection-enhanced delivery. The results identify specific micro-catheter trajectories that are projected to safely deliver gene therapy and provide enough coverage to efficiently transduce the brain regions involved in HD.
“uniQure’s neuroimaging translational studies in non-human primates and Huntington’s disease patients shows the importance of careful, individualized neurosurgical planning and meticulous dosing parameters in delivering gene therapy products to the brain,” added Joseph J. Higgins, M.D., F.A.A.N., vice president, clinical development.   “We are excited about the AMT-130 clinical development program and look forward to treating the first patient in the second half of this year and announcing initial safety data by year-end.”
Additional data presented at the CHDI conference include:
• Oral Session II: “Gene Therapy for Huntington’s Disease: Silencing the Villain.” Pavlina Konstantinova, Ph.D., vice president, new therapeutic target discovery at uniQure, participated in the featured session “HTT Lowering” on Tuesday, February 26 delivering an oral presentation.
• Poster #7: Transfer of therapeutic miRNAs within extracellular vesicles secreted from Huntington’s disease iPSC-derived neurons.
• Poster #5: Sustained mutant huntingtin lowering in the brain and cerebrospinal fluid of Huntington disease minipigs mediated by AAV5-miHTT gene therapy.
Transfer of therapeutic miRNAs within extracellular vesicles secreted from Huntington’s disease iPSC-derived neurons.
$QURE #CHDI #HuntingtonsDisease

Sustained mutant huntingtin lowering in the brain and cerebrospinal fluid of Huntington disease minipigs mediated by AAV5-miHTT gene therapy.

Exploring the effects of intrastriatal AAV5-miHTT lowering therapy on MRS signal and mutant huntingtin levels in the Q175FDN mouse model of HD

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)

MRI Volumetric Analysis of 20 Early Manifest Huntington Disease Patients to Determine the Safety of Delivering Gene Therapy to the Striatum
Sinds gist. nieuwe volger op twitter, petje af voor Kait!
28 jaar en dan maar zien Huntington’s Disease “hanteerbaar” te krijgen, om stil van te worden.

#HuntingtonsDisease :Kait introducing the monster
$QURE #HuntingtonsDisease CHDI 2019 - Oral Presentation: Changing treatment paradigms with AMT-130, a gene therapy for #HD
Dr Joseph Higgins from $QURE shares their exciting #HuntingtonsDisease research gene therapy treatment coming to trials this year
$QURE AAV5-miHTT gene therapy demonstrates sustained huntingtin lowering and functional improvement in Huntington disease mouse models,%202019%20-%20Sustained%20huntingtin%20lowering%20in%20HD%20mice.pdf
Link via:
$QURE #ASGCT19 APRIL29-MAY2,WASHINGTON,D.C. Transfer of Therapeutic miRNAs within Extracellular Vesicles Secreted from Huntington’s Disease iPSC-Derived Neurons
Huntington’s disease (HD) is a neurodegenerative disorder caused by an autosomal dominant mutation in the huntingtin gene (HTT), which leads to mutant protein aggregation, toxicity and neuronal cell death. microRNA (miRNA)-based gene therapies have emerged as a potential approach to lower the disease-causing protein in HD. We have developed an engineered microRNA targeting human huntingtin (miHTT), delivered via adeno-associated serotype 5 (AAV5) virus. AAV5-miHTT have demonstrated an efficient lowering in vitro and in vivo in the brain in different HD animal models. For adequate efficacy in HD, brain-wide biodistribution (striatum, cortex) of the therapeutic miRNA is of crucial importance. Recently, extracellular vesicles (EVs), and in particular exosomes and microvesicles, have been identified as carriers of RNA species. Therefore, understanding how therapeutic miRNAs are transferred between neuronal cells might be relevant for delivery, translational studies and biomarker discovery in gene therapies for brain disorders. The aim of this study was to investigate the presence of miHTT molecules within EVs secreted from AAV5-miHTT-treated neuronal cultures originating from an HD patient. For this purpose, we developed an in vitro model based on the differentiation of induced pluripotent stem cells (iPSCs) from HD patients to mature neuronal cells. iPSC-derived neuronal cultures were transduced with AAV5-miHTT and the cultured medium was collected for the precipitation of EVs. We observed a dose-dependent transduction of neuronal cells and a dose-dependent expression of miHTT in the cells measured by TaqMan qPCR. At 5 days and 12 days after transduction we detected mature miHTT molecules within EVs enriched for exosomes and microvesicles secreted from AAV-transduced iPSC-derived neurons. EV-associated miHTT levels strongly correlated with AAV dose and miHTT expression in neuronal cells. Moreover, isolated EVs were taken up by other naïve neuronal cells resulting in a concentration-dependent transfer of miHTT molecules to recipient cells. This study indicates a contribution of EVs to the transfer of therapeutic molecules for miRNA-based gene therapies for HD. EV-containing therapeutic miRNAs can thus be regarded as novel mediators of cell-cell communication and as potential source of biomarkers in neurodegenerative disorders.

$QURE #ASGCT19 APRIL29-MAY2,WASHINGTON,D.C. Sustained Mutant Huntingtin Lowering in the Brain and Cerebrospinal Fluid of Huntington Disease Minipigs Mediated by AAV5-miHTT Gene Therapy
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 to efficient HTT-lowering in vitro and in vivo in rodent models. Here, we have used transgenic HD (tgHD) minipigs to assess the translatability of our approach in a large animal model. Animals were injected with AAV5-miHTT (1.2x1013 gc/brain), bilaterally into striatum (caudate and putamen) and sacrificed 6 months post-treatment. Widespread brain biodistribution of vector DNA was observed, with the highest levels in target (striatal) regions but also in thalamus and cortical regions, in both grey and white matter. Expression of miHTT was highly correlated with vector DNA in all brain areas. Corresponding to the vector DNA and miHTT expression, a reduction of mutant HTT (mHTT) mRNA and protein was observed in AAV5-miHTT treated animals with respect to controls. mHTT protein lowering was on average more than 75% in the injected areas, and between 3050% in most of the distal regions. Translational pharmacokinetic and pharmacodynamic measures in the cerebrospinal fluid (CSF) were in line with the effects observed in the brain. We detected miHTT in the CSF, and CSF mHTT protein lowering up to 50% at 3 and 70% at 6 months post-dosing. This study demonstrates widespread biodistribution and durable efficiency of AAV5-miHTT in diseaserelevant regions in a large brain, and the potential of CSF translational measures to follow-up efficacy
HD Patient Day uniQure Amsterdam, 15 mei 2019

Zoals eerder al aangegeven met een 'save-the-date' bericht is er op woensdag 15 mei een 'HD patient Day' bij het biotech bedrijf uniQure in Amsterdam. UniQure heeft recentelijk toestemming gekregen van de Amerikaanse FDA om een trial op te zetten, volgend op succesvolle experimenten in laboratoria waarin ze met behulp van een virus de aanmaak van het Huntington eiwit in de hersenen verlagen. Een van de verschillen met de bekende IONIS/Roche trial is dat er geen herhaalde injecties via een ruggenprik toegediend worden, maar het eenmalig wordt toegediend direct in de hersenen.

UniQure wil graag de Nederlandse Huntington families informeren over het onderzoek en het verdere verloop, met veel ruimte voor vragen en discussie. Er zijn ook betrokkenen vanuit het Campagneteam Huntington en de Vereniging van Huntington aanwezig. De dag is NIET bedoeld voor hulpverleners en deskundigen, maar juist voor iedereen die (zelf) te maken heeft met de ziekte, dus patiënten, risicodragers, familie, partners enz. Juist ook in de internationale 'HD Awareness Month'.

De open dag is in het gebouw van uniQure in Amsterdam op de Paasheuvelweg 25a, 1105 BP Amsterdam. Het duurt van 10.00 tot 15.00 uur en er wordt voor een lunch gezorgd. Parkeren kan lastig zijn, je kan parkeren rondom het AMC Ziekenhuis (P1 ligt voor het AMC, tegenover uniQure, de parkeergarage P2 is iets verder en dan ongeveer een kwartier lopen). Het station Amsterdam Holendrecht ligt op 500 meter afstand, met treinverbinding (sprinter) en metroverbinding met bijvoorbeeld Duivendrecht, Amsterdam Bijlmer, Amstel en Centraal Station.

Je kan je aanmelden door een e-mail te sturen naar

Reageer graag per ommegaande, want er zijn 100 plekken en het gaat op volgorde van inschrijving!
Prof. Dollar
@Vitavita Dank voor het delen! Mooi dat QURE in een vroege fase aan 'klantenbinding' doet.
Weet iemand wanneer Uniqure de eerste patienten met amt-130 wil gaan behandelen? Ik meen dat ik ergens gelezen/gehoord had dat het plan was om in de eerste helft van 2019 te starten, maar ik weet het niet meer zo zeker...
Prof. Dollar
"The Company expects to begin dosing patients in the second half of this year in its dose-escalating, randomized and controlled Phase I/II clinical study to assess the safety, tolerability and efficacy of a one-time treatment of AMT-130 in patients with Huntington’s disease, and is planning to announce initial safety data on the surgical procedure before the end of this year."
Thanks prof! Ohja dat was het, voor het einde van het jaar de eerste safety data =)
Issued Patents in the U.S. and EU Cover RNA Construct Specifically Designed to Target Highly Toxic Exon1 Protein
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