MEET THE COMPANY: uniQure

18588 2,527

VITAL SIGNS

NAME: uniQure

STOCK SYMBOL: QURE   

SHARE PRICE AS OF 2/17/17: $6.31

52-WEEEK RANGE AS OF 2/17/17: $5.25-$16.40

MARKET CAPITALIZATION: $152 million

U.S. HEADQUARTERS: Lexington, MA

Dr. Pavlina Konstantinova, a research scientist at uniQure, spoke with HD Insights about the company’s program to develop a gene therapy treatment for HD, using micro RNAs expressed from a DNA cassette delivered via an adeno-associated viral vector. The following is an edited transcript of the conversation.

HD INSIGHTS: Tell us about uniQure.

KONSTANTINOVA: uniQure is in a unique position because we have established a scalable manufacturing platform for adeno-associated virus (AAV) vector delivered gene therapies for commercial use. We started this a number of years ago when we were developing our first product, Glybera® (alipogene tiparvovec), which was developed in the mammalian system that a lot of other researchers are using.

However, during the Glybera® development period, we recognized that the process that we were using was not scalable and was also not really stable for commercial use. So we switched from a mammalian production system to an insect-based production system a number of years ago. At the moment, we think we are in a unique position, and we are the first company that has invested in developing this large-scale manufacturing platform for AAV vector delivered gene therapies that have commercial market potential.

Glybera® has been approved by the European drug regulatory agencies for treatment of familial lipoprotein lipase deficiencies. It is not available on the American market at the moment.

HD INSIGHTS: What are uniQure’s plans for HD therapeutics?

KONSTANTINOVA: uniQure started the HD program about six years ago. We combined our expert experience with AAV production and delivery with the micro RNA-based silencing approach. Prior to HD, we worked successfully to prove the concept of our gene silencing technology for liver disease, and we published a number of articles in peer-reviewed journals. After that initial work, HD seemed to be a good candidate for the gene silencing approach.

HD is a monogenetic disease with a very well-defined nature of the primary gene mutation that results in production of mutant huntingtin. But besides that, I think HD is a devastating disease, and no treatment is currently available. We saw an opportunity to try to develop a disease-modifying therapy that can eventually be a game-changer in management of HD. Reducing mutant huntingtin expression seems to us to be the most logical step to take because doing so can be expected to significantly contribute to slowing down disease progression.

At the moment, we are developing an RNA interferencebased approach. We have engineered small molecule RNAs known as micro RNAs (miRNAs) that target human huntingtin messenger RNA, expressed from a DNA cassette incorporated into AAV vector particles. This expression cassette will be delivered to the patient, with the aim of reducing the expression of the mutant gene that results in HD.

HD INSIGHTS: Other companies are also investigating gene silencing therapies for HD. Can you tell us how your approach is different or similar to theirs?

KONSTANTINOVA: First of all, companies that are silencing the mutant gene that causes HD are trying to lower the amount of mutant huntingtin. What distinguishes us from other companies is that we are proposing to use a single-time gene therapy, while the other approaches would require multiple administrations. Also, with the gene therapy approach using AAV, we can select the vector serotype to refine the targeting and safety of the delivery system, and we have been working on refining the administration procedure in order to have a very safe and efficacious profile. I think that is really our strength the combination of the mechanism of action, the vector serotype, production platform and the administration procedure that we have selected.

HD INSIGHTS: How and where would the therapy be administered?

KONSTANTINOVA: At the moment, we envision targeting the striatal structure in the brain. This would involve intraparenchymal injection using the convection-enhanced diffusion delivery method.

HD INSIGHTS: How is your preclinical work going? Have you applied this therapy to animal models, for example?

KONSTANTINOVA: We collaborate with others in our preclinical work. We have tested the therapy in a wide range of HD animal models. A number of years ago, we started a collaboration with Dr. Nicole Déglon from CHUV Lausanne, Switzerland, who has developed an HD rat model. The first proof-of-concept experiment was performed in this model, which typically displays very acute pathology. Neurodegeneration occurs very quickly, with very severe mutant huntingtin aggregate formation.

After these experiments, we moved to the humanized mouse model, working with Dr. Amber Southwell from University of British Columbia in Dr. Michael Hayden’s lab, and we performed a number of dose escalation studies in this model. The model is unique because it has two copies of the human huntingtin gene, one mutated, one wild-type, and no murine background huntingtin.

That makes it very suitable for a gene therapy approach like ours, where the huntingtin gene would be lowered, as well as looking at the tolerability of total huntingtin lowering. We also collaborated with Charles River Laboratories, where we are testing the functional improvement in the more standardized HD rodent models.

In the last two years, most of our experiments have been in large animals. We started our HD mini-pig experiments in collaboration with Dr. Jan Motlik from IAPG, Libechov, Czech Republic. This model was developed together with CHDI. In these experiments, we deliver our gene silencing therapy in a similar manner to how we envision delivery in our clinical program. We have obtained the first data from this HD mini-pig model, showing substantial total huntingtin knock-down, as well as very good vector distribution and miRNA expression. I think that so far, we have seen an adequate safety profile. And finally, we have performed tests in healthy non-human primates to refine the delivery procedure. We have injected different brain regions with increasing vector doses and looked at vector distribution, inflammation and neurodegeneration. Based on the outcome of those experiments, we are defining our therapeutic dose in patients aiming at approximately 50% huntingtin knock-down and no associated adverse events. As you can see, we have used several animal models of HD as well as healthy non-human primates to propel our preclinical program toward the development stage.

HD INSIGHTS: Can you tell us about the clinical effect you saw from your trials in the pig model?

KONSTANTINOVA: At the moment the pig model does not show clinical symptoms of HD, so the only parameters we could assess were mutant huntingtin lowering in the CNS, as well as vector distribution and safety. We looked at huntingtin lowering in the CSF at three months and saw a trend of reduction in the treated animals. In the blood, we looked mainly at markers for immune system activation, because this is a very important safety readout for our therapy. We found transient increase in some cytokines and interleukins in the treatment groups.  The study has not yet been published, but we are hoping to submit it for publication before the CHDI meeting.

HD INSIGHTS: Do you think it is feasible in humans to be able to look at huntingtin levels or to look for huntingtin-lowering effects in either the blood or CSF?

KONSTANTINOVA: I think if it were at all possible to have a positive readout for mutant huntingtin, it would be in the CSF. Because our therapy would be administered directly into the CNS, we do not expect leakage of the gene-silencing agent into the periphery, so all the changes in mutant huntingtin that we expect would be in the CSF. I am not aware of positive measurements of mutant huntingtin in the blood or in serum at the moment. We can envisage measuring mutant huntingtin levels in the CSF as it is a biomarker for therapeutic efficacy.

HD INSIGHTS: Researchers take both allele-specific and non-allele-specific approaches to gene silencing in HD. What is uniQure currently working on and why?

KONSTANTINOVA: We published a paper in Molecular Therapy – Nucleic Acids about our evaluation of both approaches, allele-specific and total silencing;1 however, our program development within the company has focused on total huntingtin silencing. Of course, we are working on the allele-specific approach as well, but the first therapy that we would like to bring to patients would be based on total huntingtin silencing.

HD INSIGHTS: When do you plan to start testing your therapy in humans?

KONSTANTINOVA: The program is progressing very well and we are working toward a company goal to begin a clinical trial in 2018.  At the moment, we are initiating our IND-enabling studies, and we are defining our regulatory pathway. To support our clinical program, we are creating a clinical network of key opinion-leaders in the HD field, but also neurosurgeons, experts in gene therapy delivery to the brain, and brain anatomy specialists who can help us and advise us on the development of our program.

HD INSIGHTS: Do you have early thoughts on the population of individuals affected by HD that you would see as most appropriate for initial investigations?

KONSTANTINOVA: We have talked about it a lot with our key opinion-leaders. As is well-known, brain atrophy in HD patients starts years before the onset of symptoms, and neuronal degeneration precedes decline in neuronal function. If we start from this standpoint, we think that to have a high likelihood of therapeutic efficacy, we would need to treat patients as early as possible, either at the time of diagnosis or shortly after the start of manifestation of symptoms. So I think for the first trial we would aim to go as early as possible in the course of the disease. To achieve maximum therapeutic benefit, we would need to go to patients at the time of genetic diagnosis.

HD INSIGHTS: Are there other things that you would like the community to know about your approach and your gene silencing therapies?

KONSTANTINOVA: Yes, I think we already have very promising results. Combined with the production platform that we have developed, I think we can make HD gene therapy a reality in the near future. So, I think that gene silencing as a disease-modifying treatment can really be a game-changer for HD patients.

HD INSIGHTS: Thank you and your colleagues at uniQure very much for all your efforts seeking and hopefully finding treatments that will make a huge difference for HD.


1Miniarikova J, Zanella I, Huseinovic A, et al. Design, Characterization, and Lead Selection of Therapeutic miRNAs Targeting Huntingtin for Development of Gene Therapy for Huntington’s Disease. Mol Ther Nucleic acids. 2016;5(3):e297.

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    However, after Raphael Varane’s header rattled the crossbar, Ajax raced into an early lead through Hakim Ziyech before Dusan Tadic set up David Neres for a second in the 18th minute.
    tinyurl
    Real Madrid were forced into two changes when Lucas Vazquez and Vinicius Junior went off injured, with substitute Gareth Bale hitting the post just before half-time.

    Ajax looked to have put the tie to bed when Tadic swept in a brilliant third goal just after the hour – which was eventually given following an extensive Video Assistant Referee review to check if the ball had gone out of play in the build-up.

  70. Inter Rapid Wien live score (and video online live stream*) starts on 21.2.2019. at 20:00 UTC time at San Siro/Giuseppe Meazza stadium, Milan, Italy in UEFA Europa League, Knockout stage – Europe. Here on SofaScore livescore you can find all Inter vs Rapid Wien previous results sorted by their H2H matches. Links to Inter vs. Rapid Wien video highlights are collected in the Media tab for the most popular matches as soon as video appear on video hosting sites like Youtube or Dailymotion. We’re not responsible for any video content, please contact video file owners or hosters for any legal complaints tinyurl.

  71. Inter Rapid Wien live score (and video online live stream*) starts on 21.2.2019. at 20:00 UTC time at San Siro/Giuseppe Meazza stadium, Milan, Italy in UEFA Europa League, Knockout stage – Europe. Here on SofaScore livescore you can find all Inter vs Rapid Wien previous results sorted by their H2H matches. Links to Inter vs. Rapid Wien video highlights are collected in the Media tab for the most popular matches as soon as video appear on video hosting sites like Youtube or Dailymotion. We’re not responsible for any video content, please contact video file owners or hosters for any legal complaints tinyurl.

  72. Ernest Quintana, 78, was at Kaiser Permanente Medical Center in Fremont when a doctor – appearing on the robot’s screen – informed him that he would die within a few days.

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    Mr Quintana died the next day.

  73. Theresa May says she has secured “legally binding” changes to her Brexit deal, a day ahead of MPs voting on it.

    But European Commission President Jean-Claude Juncker” warned if the deal was voted down there was “no third chance”.

    They spoke at a joint press conference in Strasbourg after a late meeting.

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  75. These three figures — William Rick Singer, Mark Riddell and Rudolph Meredith, respectively — are at the center of the nationwide scandal in which 33 parents are accused of using their wealth and means to help their children game the college admissions system.
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  76. Trump was surrounded at Friday’s event by officials from Customs and Border Protection as well as surviving family members of those who have loved ones killed by undocumented immigrants. Attorney General William Barr was also at the President’s veto event.
    While some lawmakers including some Republicans — have argued against the President’s use of national emergency powers in this instance, the Justice Department set forth a robust defense of the President’s authority to do so in a letter to Senate Majority Leader Mitch McConnell earlier this month, according to a copy obtained by CNN on Friday.
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  77. Christina was born in the royal castle Tre Kronor on 18 December S. 8 December] 1626. Her parents were the Swedish king Gustavus Adolphus and his German wife, Maria Eleonora, had already had two daughters—a stillborn princess in 1620, and then the first Princess Christina, who was born in 1623 and died the following year.3] Excited expectation surrounded Maria Eleonora’s third pregnancy in 1626. When the baby was born, it was first thought to be a boy as it was “hairy” and screamed “with a strong, hoarse voice.”she later wrote in her autobiography that, “Deep embarrassment spread among the women when they discovered their mistake.” The king, though, was very happy, stating, “She’ll be clever, she has made fools of us all!”6] From most accounts, Gustav Adolf appears to have been closely attached to his daughter, and she appears to have admired him greatly.