Category Archives: Gene Medicine

Researchers from the University of Texas Health Science Center in San Antonio have found a way to cure type 1 diabetes in mice. It is hoped that the novel technique - which boosts insulin secretion in the pancreas - will reach human clinical trials in the next 3 years.

Study co-author Dr. Bruno Doiron, Ph.D., of the Division of Diabetes, and colleagues recently reported their findings in the journal Current Pharmaceutical Biotechnology.

Type 1 diabetes is estimated to affect around 1.25 million children and adults in the United States. Onset of the condition is most common in childhood, but it can arise at any age.

In type 1 diabetes, the immune system destroys the insulin-producing beta cells of the pancreas. Insulin is the hormone that regulates blood glucose levels. As a result, blood glucose levels become too high.

There is currently no cure for type 1 diabetes; the condition is managed through diet and insulin therapy. However, in recent years, researchers have investigated replacing beta cells as a means of eradicating type 1 diabetes once and for all.

Dr. Doiron and colleagues have taken a different approach with their new study. The team reveals how they used a method called gene transfer to coax other pancreatic cells into producing insulin.

Using this technique, the researchers have managed to cure type 1 diabetes in mice, bringing us one step closer to curing the condition in humans.

The gene transfer technique - called Cellular Networking, Integration and Processing - involves introducing specific genes into the pancreas using a virus as a vector.

The team notes that beta cells are rejected in patients with type 1 diabetes. With the gene transfer method, the newly introduced genes encourage non-beta cells to produce insulin, without any side effects.

"The pancreas has many other cell types besides beta cells, and our approach is to alter these cells so that they start to secrete insulin, but only in response to glucose [sugar]," says study co-author Dr. Ralph DeFronzo, chief of the Division of Diabetes. "This is basically just like beta cells."

Upon testing their technique on mouse models of type 1 diabetes, the researchers found that they were able to induce long-term insulin secretion and blood glucose regulation, with no adverse side effects.

"It worked perfectly. We cured mice for 1 year without any side effects. That's never been seen. But it's a mouse model, so caution is needed. We want to bring this to large animals that are closer to humans in physiology of the endocrine system."

Dr. Bruno Doiron, Ph.D.

Importantly, the researchers point out that the gene transfer therapy only releases insulin in response to blood sugar, so it has the potential to transform current treatments for type 1 diabetes.

"A major problem we have in the field of type 1 diabetes is hypoglycemia (low blood sugar)," says Dr. Doiron. "The gene transfer we propose is remarkable because the altered cells match the characteristics of beta cells. Insulin is only released in response to glucose."

Not only could the novel strategy yield a cure for type 1 diabetes, but the researchers say that it may also eliminate the need for insulin therapy in patients with type 2 diabetes, which arises when the body is unable to use insulin effectively.

It will cost around $5 million to test their technique in large animal models, but the researchers are confident that this can be achieved. They hope to reach human clinical trials within the next 3 years.

Learn how maternal omega-3 intake may influence the risk of type 1 diabetes in infants.

See the article here:
Type 1 diabetes cured in mice using gene therapy - Medical News ... - Medical News Today

The high number of deaths related to cancer demonstrates the need for the continued development of new treatments. For example, gene therapy has been employed for treatment of different forms of cancer and in the past few years has been proven effective in certain situations. In China the use of an adenovirus vector expressing the tumor suppressor p53 (rAd-p53/ Gendicine) was approved almost 15 years ago for the treatment of head and neck cancer.1

P53 is an obvious choice as the therapeutic gene since it is one of the most important tumor suppressors and has long been considered the guardian of the genome.2 Except for Gendicine, progress in the field of p53 gene therapy has been limited. As applied to prostate carcinoma (PCa), p53 gene transfer has not been tested clinically even though its application in PCa cell lines was first reported more than 20 years ago 3, 4. Though many factors may have contributed to this situation, one central issue is the reliability of the gene transfer system at both the transductional and transcriptional levels.

Our group has developed adenoviral vectors that feature improvements that should facilitate virus entry as well as promote high levels of expression of the gene of interest. We developed a p53-responsive promoter (called PG), which directs the transgene expression in the presence of p53, and have shown the utility of the PG promoter in several vector platforms.5, 6, 7 When the PG promoter is employed to direct the expression of p53, a positive feed-back loop is established that induces high levels of p53.8 We introduced this expression cassette into an adenoviral vector and observed high levels of p53 expression in prostate carcinoma cell lines whereas a vector similar to Gendicine was quite limited in its ability to express p53.9 Our improved vector with autoregulated expression of p53 (AdPG-p53) was also superior in killing PC3 prostate carcinoma cells in vitro and in vivo as compared to the traditional rAd-p53 vector. However, PC3 cells were quite difficult to transduce. With this study we achieved high-level expression of p53, but were frustrated by the limited tropism of this adenoviral vector.

In order to surpass this limitation we have employed a fiber modified adenoviral vector (AdRGD), with the insertion of an RGD motif, directing the viral particle to the ubiquitous integrin receptor. In our recent study, we showed increased transduction efficiency and high levels of transgene expression in prostate carcinoma cell lines when using the AdRGD platform.10 We then showed that the adenoviral vector with improved transduction efficiency and autoregulated expression of p53 (AdRGD-PGp53) conferred even higher levels of p53 protein as compared to our AdPG-p53 vector. The new AdRGD-PGp53 vector was also shown to be superior for the induction of cell death as compared to the AdPG-p53 vector in PC3 cells.

We then explored the possible mechanisms responsible for the cell killing associated with the exceptionally high levels of p53 expression. Since many cell death mechanisms converge on the generation of oxidants, especially radical oxygen species (ROS) that damage DNA, we looked for these indicators of the cellular response upon treatment with the new AdRGD-PGp53 vector. Indeed, we observed accumulation of superoxide and peroxide only when PC3 cells were treated with the new vector, yet treatment with catalase or an inhibitor of NOX1 reduced cell killing, revealing the importance of ROS in the response to our gene therapy approach. Upon treatment with AdRGD-PGp53, the induction of oxidants correlated with reduced mitochondrial membrane potential and accumulation of phosphorylated H2AX.

We then explored the impact of gene therapy on the expression of key cellular genes. Strikingly, expression of the NOX-1 gene, an important factor in the production of ROS, was markedly increased only in the presence of AdRGD-PGp53 in PC3 cells. Note that NOX1 is not a known p53 target, a point that may be further explored in future studies. We also showed that the new, improved vector was especially effective for the induction of known p53 target genes (p21, Sestrin2, NOXA and PIG3).

When applied in a xenograft mouse model of in situ gene therapy, our vector retarded tumor progression and increased overall survival significantly. Upon treatment with AdRGD-PGp53, cell death was induced and was correlated with signs of DNA damage (phosphorylated H2AX) induced, presumably, by oxidative stress. These assays indicate that our new vector has a superior capacity to kill prostate cancer cells in vitro and in vivo by a mechanism that involves the production of oxidants.

While AdRGD-PGp53 maximizes transductional and transcriptional mechanisms, overcoming limitations associated with other p53-expressing adenoviral vectors, it did not halt tumor progression. Thus, further refinements, such as alteration of the treatment regime and association with chemotherapeutics, may offer even better control over tumor progression. Clearly, additional work is required before proposing pre-clinical evaluation of our approach. However, we have made a considerable advance in the design and study of virus-mediated gene therapy in a model of prostate carcinoma.

Written by: Rodrigo E. Tamura and Bryan E. Strauss

References: 1. Ma G, Shimada H, Hiroshima K, Tada Y, Suzuki N, Tagawa M. Gene medicine for cancer treatment: commercially available medicine and accumulated clinical data in China. Drug Des Devel Ther 2009, 2: 115-122.

2. Lane DP. Cancer. p53, guardian of the genome. Nature 1992, 358(6381): 15-16.

3. Yang C, Cirielli C, Capogrossi MC, Passaniti A. Adenovirus-mediated wild-type p53 expression induces apoptosis and suppresses tumorigenesis of prostatic tumor cells. Cancer Res 1995, 55(19): 4210-4213.

4. Eastham JA, Hall SJ, Sehgal I, Wang J, Timme TL, Yang G, et al. In vivo gene therapy with p53 or p21 adenovirus for prostate cancer. Cancer Res 1995, 55(22): 5151-5155.

5. Strauss BE, Costanzi-Strauss E. pCLPG: a p53-driven retroviral system. Virology 2004, 321(2): 165-172.

6. Bajgelman MC, Medrano RF, Carvalho AC, Strauss BE. AAVPG: A vigilant vector where transgene expression is induced by p53. Virology 2013, 447(1-2): 166-171.

7. Bajgelman MC, Strauss BE. Development of an adenoviral vector with robust expression driven by p53. Virology 2008, 371(1): 8-13.

8. Strauss BE, Bajgelman MC, Costanzi-Strauss E. A novel gene transfer strategy that combines promoter and transgene activities for improved tumor cell inhibition. Cancer Gene Ther 2005, 12(12): 935-946.

9. Tamura RE, da Silva Soares RB, Costanzi-Strauss E, Strauss BE. Autoregulated expression of p53 from an adenoviral vector confers superior tumor inhibition in a model of prostate carcinoma gene therapy. Cancer Biol Ther 2016, 17(12): 1221-1230.

10. Tamura RE, Hunger A, Fernandes D, Laurindo F, Costanzi-Strauss E, Strauss BE. Induction of oxidants distinguishes susceptibility of prostate carcinoma cell lines to p53 gene transfer mediated by an improved adenoviral vector. Hum Gene Ther 2017

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Induction of oxidants distinguishes susceptibility of prostate carcinoma cell lines to p53 gene transfer mediated by ... - UroToday

May 10, 2017 Modified ECO nanoparticles bind to interphotoreceptor retinoid-binding protein (IRBP), which transports them to the target cells in the retinal pigment epithelium (RPE.) The ECO is taken up by the cell through endocytosis but the nanoparticles escape endosomes and release the RPE 65 DNA into the nucleus. The RPE65 gene is then expressed by the RPE call, protecting the photoreceptor cells and preserving vision. Credit: Zheng-Rong Lu

Researchers at Case Western Reserve University have developed gene-carrying nanoparticles that home in on target cells and prevent vision loss in mice with a human form of Leber congenital amaurosis.

The condition is one of the most common causes of blindness in children, according to the National Institutes of Health, affecting two to three of every 100,000 newborns.

Though this research focused on the form of the disease called Leber congenital amaurosis 2, or LCA2, the scientists and engineers involved in the study believe the technology holds promise for other forms of LCA as well as other inherited diseases that lead to severe vision loss or blindness.

"We believe this technology can deliver almost any type of gene to tackle inherited visual disorders," said Zheng-Rong Lu, the M. Frank and Margaret Domiter Rudy Professor of Biomedical Engineering at Case Western Reserve and leader of the research.

The research team's study is published in the June 16 issue of Molecular Therapy - Nucleic Acids.

Those with LAC2 carry a mutated RPE65 gene and suffer from profound vision loss from birth. The mutated gene fails to produce RPE65 protein in the retinal pigment epithelium (RPE), a cell layer critical for protecting photoreceptors (rods and cones). The protein is an essential constituent of the visual cycle that converts light to electrical signals to the brain.

Reaching target cells

Lu and colleagues designed a lipid-based nanoparticle called ECO to deliver healthy RPE65 genes to RPE cells.

"The promise of this technology is it localizes the drug to the photoreceptor cells, sparing the liver and kidney from exposure," said Krzysztof Palczewski, chairman of the Department of Pharmacology at the Case Western Reserve School of Medicine. Palczewski, a vision scientist, and Lu, who studies drug delivery, have worked together on this research for six years.

"He had a clever idea," Palczewski said. "The nanoparticle uses a protein present in the eye to serve as an anchor, and the gene is delivered when bound."

While other researchers focus on using modified viruses to deliver genes for therapy, sometimes the genes are too large for viruses to carry, Lu said. The ECO can be tailored to fit the cargo.

The exterior of the nanoparticle is coated with nucleic acids that act as targeting agents, drawing the delivery system to the retina and facilitating uptake by RPE cells. To track activity, Lu's team included a fluorescent marker

Treating LCA and more

Following injection into the retina of mice, the researchers could see fluorescent green concentrating in RPE cells. Testing showed a significant increase in light-induced electrical activity from the eyes to the brain, indicating the rods and cones were operating as they should in the visual cycle.

The therapeutic effect lasted 120 days in treated mice. No improvements were observed in untreated mice.

"This work is important beyond one disease," Palczewski said. "The loss of photoreceptor cells affects virtually all of us."

As people age, they lose about 30 percent of their photoreceptors, he explained. Disease or an injury to the retina also can cause the loss of protective proteins in the cells, resulting in additional cell death. The technology potentially could be applied to protect these aged or damaged cells.

The researchers are now investigating whether the ECO system is effective against other visual disorders, including Stargardt disease, which is a form of inherited juvenile macular degeneration, primarily affecting the central portion of the visual field. They are also studying whether the nanoparticles can be used with the CRISPR/Cas9 gene-editing technique to treat genetic lesions related to retinal degenerative diseases.

Explore further: Fish eyes to help understand human inherited blindness

Newborns babies can be at risk of congenital blindness, presenting sight defects due to lesions or to genetic mutations in their genome. Among the latter, Leber Congenital Amaurosisor LCAis one of the most widespread ...

Silencing a gene called Nrl in mice prevents the loss of cells from degenerative diseases of the retina, according to a new study. The findings could lead to novel therapies for preventing vision loss from human diseases ...

Scientists from the Florida campus of The Scripps Research Institute (TSRI) have discovered how a protein called 24 establishes proper vision. Their research helps explain why mutations in the gene encoding 24 lead ...

A new gene therapy has restored some sight in people born with an inherited, progressive form of blindness. The technique replaces a defective gene in the eye with a normal working copy of the gene using a single injection.

A new research report published in The FASEB Journal will help ophthalmologists and scientists better understand a rare genetic disease that causes increased susceptibility to blue light, night blindness, and decreased vision ...

Research led by Minghao Jin, PhD, Assistant Professor of Ophthalmology and Neuroscience at the LSU Health Sciences Center New Orleans Neuroscience Center of Excellence, has found a protein that protects retinal photoreceptor ...

Researchers at Case Western Reserve University have developed gene-carrying nanoparticles that home in on target cells and prevent vision loss in mice with a human form of Leber congenital amaurosis.

Monthly eye injections of Avastin (bevacizumab) are as effective as the more expensive drug Eylea (aflibercept) for the treatment of central retinal vein occlusion (CRVO), according to a clinical trial funded by the National ...

Researchers comparing leading treatment approaches for patients with severe uveitis have discovered that systemic therapy with oral corticosteroids and immunosuppression can preserve or improve vision in the long term better ...

A synthetic, soft tissue retina developed by an Oxford University student could offer fresh hope to visually impaired people.

Glaucoma, a leading cause of blindness worldwide, most often is diagnosed during a routine eye exam. Over time, elevated pressure inside the eye damages the optic nerve, leading to vision loss. Unfortunately, there's no way ...

The tip of our optic nerve is typically the first place injured by glaucoma.

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Gene-delivery system prevents vision loss from inherited eye disease - Medical Xpress

Aevi Genomic Medicine, Inc . (NASDAQ:GNMX)

Q1 2017 Earnings Conference Call

May 10, 2017 8:30 AM ET

Executives

Michael Cola President and Chief Executive Officer

Brian Piper Chief Financial Officer

Garry Neil Chief Scientific Officer

Analysts

Jason Butler JMP Securities

Brian Marks Zacks Investment Research

Operator

Good day and welcome to the Aevi Genomic Medicine First Quarter Conference Call and Business Update. Todays conference is being recorded. At this time, I would like to turn the conference over to Mr. Brian Piper, Chief Financial Officer. Please go ahead sir.

Brian Piper

Thank you, Gina. Good morning everyone and welcome to the conference call. As a reminder, a copy of todays presentation can be found on the Aevi Genomics website. Participants on todays call are Chief Executive Officer, Mike Cola; Chief Scientific Officer, Garry Neil; and myself Chief Financial Officer, Brian Piper.

Before we begin, I would like to direct your attention to Slide two and remind you that todays discussion will include statements about the companys future expectations, plans, and prospects that constitute forward-looking statements for purposes of the Safe Harbor provisions under the Private Securities Litigation Reform Act of 1995.

And with that, I would now like to turn the call over to Aevi Genomic Medicines CEO, Mike Cola. Mike?

Michael Cola

Thank you, Brian and welcome everyone to our corporate update. Im on slide three. We have a fairly tight agenda today, mostly focused on 001. We will take you through the SAGA trial summary, although we missed our primary endpoint, were very excited by the genetics subset of responders that weve been working on over the last six weeks. Garry will take you through that analysis and our steps forward. I will also readdress the market potential. We do have a reduced set of genes, but we still think its a very significant and compelling business story moving forward its a very significant portion of the ADHD market.

I will briefly touch on 002 as were just getting that trial off the ground and Brian will take you through the Q1 results of operation. As you know, our mission is focused on translating genetic discoveries into novel therapies to improve the life of children and adults with pediatric onset life altering diseases. We do that through our collaboration with Childrens Hospital of Philadelphia and that collaboration over the last 2.5 years has yielded two programs on slide five; that is 001 which well spend the bulk of the time on today and AEVI-002 or anti-LIGHT program.

Garry will take you through our plans for studying the genetic subset within ADHD that weve identified as responders. We expect that data to be out mid-2018 at the latest. It will explain the trial design and why we think we have some opportunity to do better than what we did in the SAGA trial as far as timing. 22q Deletion Syndrome, as you know, weve had struggles to recruit into that trial. These patients have been physically very fragile. Parents have not been really that excited about taking any chances with their child as far as changing therapy. We will talk about two patients in the coming months in top-line data.

Garry will also walk you through the story around contactin-4 or CNTN4, in autism spectrum disorder. We have an unusual finding, a novel finding in ADHD as far as the prevalence of that particular gene that causes disease in ADHD, we think its a very important gene in autism. And we are doing work with CHOP today to understand its phenotype and prevalence in autism. Hope to have discussions with the agency in the middle of the year.

And then as I mentioned earlier, well talk through Severe Pediatric Crohns Disease, as that program is just getting off the ground with initial data the second half of 2017. This will be open label data and will be based on some end points that are harder than what were currently working with.

And with that, Ill turn it over to Garry.

Garry Neil

Thanks, Mike. Im now on slide seven. So this is a high level schematic of our AEVI-001 ADHD development plan and youll notice that the plan is very similar to our original plan but has been updated to include a new Phase 2 trial shown here in dark blue on the right. And Ill describe this new study in more detail a little later. Our plan remains otherwise very similar to the previous plan, in that we expect to ultimately perform two pivotal Phase 3 trials in a genetically selected subset of ADHD patients, one in 6 to 12 year olds and the other in 6 to 17 year olds along with a longer term safety trial for first approval in ADHD. Phase 3 will now be delayed until we confirm the findings that our post-hoc analysis in the new Phase 2 trial.

Now also as a reminder, we began our development program last year with an ADHD Phenotype/Genotype study shown in the upper left corner in children aged 6 to 17. And this recently completed non-interventional study has several objectives mainly one; confirm the prevalence of mGluR CMV mutations and individual genes in U.S. children with ADHD; two, better characterize the mGluR CMV mutation positive phenotype; and three, to find suitable patients for our clinical interventional study, and we did all of that. We ultimately enrolled 1,876 kids from sites across the country, all of them had ADHD. We genotyped them, analyzed their phenotype drug use and so on. And this patient pool was of course used to recruit the patients for SAGA.

The Phenotype/Genotype study taught us a lot about how to recruit these types of patients, about mGluR gene distribution and the phenotype in ADHD. For example, we learned that the genes are not evenly distributed across the 273 gene network. In fact, 75% of the patients had a CMV in just 1 of 25 genes. And one gene contacted four, well talk about that later, accounted for 20% of all the mutation positive kids with ADHD. We also saw differences in the ADHD phenotype at the gene level and were still understanding that. Ill provide more details on this on subsequent slides. In these analysis, theyve all been critical for the interpretation of our responder analyses and setting the path forward.

Slide eight. As I mentioned, the Phenotype/Genotype study was the source of patients for the SAGA trial which is showed here schematically. As a brief reminder, the trial was a multi-center 24 site, six week randomized placebo controlled parallel design study to assess the efficacy and safety of AVEI-001 in adolescents with genetic mutations impacting the mGluR network in ADHD. It was a one-to-one randomization design, either drug or placebo, we enrolled 96 patients; 46 randomized to drugs, 50 to placebo.

There were two phases to the trial, a four week dose optimization phase where subjects received AVEI-001 or placebo, initiated at 100 milligrams twice daily and - weekly up to 400 twice weekly based on clinical response and tolerability. Then at the end of week four, there was a second two week maintenance phase and subjects in that phase continued with their optimized dose for an additional two weeks. The large majority of subjects reached the highest 400 milligram twice daily dose. The primary endpoint in this trial, as youll recall, was improvement in the ADHD-RS and the key secondary endpoint was reduction in the Clinical Global Impression of Improvement, CGI-I.

Slide nine. So, as you also know, and as weve previously reported, the SAGA trial did not meet its primary endpoint. There was numerical superiority favoring the drug with an absolute reduction of about 15 points in ADHD-RS on active treatment and about 12 on placebo, but that was not significant. Interestingly, when we looked at the response on the inattention subscale of the ADHD-RS, there was a nearly significant trends favoring patients on drug, but that also just fell slightly short of significant. But we also pre-specified two responder analyses in our analysis plan.

And as I mentioned last time, responder analysis provide several benefits in assessing and interpreting clinical trial data, particularly in trials that rely on rating scale endpoints and those may have a high placebo or variable response. But the main reason for doing this was because we suspected that not all of the genes in the mGluR network would predict response to AEVI-001, even though they are highly predictive of the disease. Not knowing what genes might respond, we did not pre-specify individual response apriori.

Now in these analyses, these responder analyses, a significant high proportion of AEVI-001 patients responded by both ADHD-RS and CGI-I, 70% on drug versus placebo, 42% for ADHD-RS and 57% on drug versus 33% on placebo for CGI-I both of those were highly significant. So take it together, we felt these findings strongly suggest that there must be a responding population and we were able to very quickly exclude factors such as gender and weight, and the most likely explanation that remained and the one that we had foreseen was a genetic responder sub-population. We plan to do such an analysis in any event, although we had hoped to do it in the context of a positive result overall.

Lets move on to slide 11 and talk about the additional post-hoc analyses that we did. So, again, we wanted to focus on genetic responders. We approached the analysis in the following way; we knew that we had CMV in the total of 44 genes from the 273 gene network in the SAGA study. We also knew that responding patients on drug had a very robust response with an ADHD-RS reduction of over 20 versus only about 0.5 on average for the non-responders. So we decided to focus on genes that were sufficiently prevalent for analysis, had at least one patient on drug and one on placebo, and that showed a meaningful response to AEVI-001. We included some GRM genes and contactin-4 because these were both prevalent and showed a good response to the drug but we also included some other neurodevelopmental genes.

Now doing it this way, we knew that we would miss some responding genes because the numbers were too small for analysis in this study, but we felt it would be best at this stage to focus on those genes that we thought would give the best likelihood of clinical response. Taking this approach, we identified a 9-gene subset which comprises, as Mike said, about 10% of the pediatric ADHD population or about 40% to 50% of all of the mGluR positive ADHD patients which is a very substantial and study-able population. As Ill show you in the subsequent slides, this responder sub-population had a very robust response to drug.

Lets go to slide 12. So heres the frequency of the responder genes to 001. At this point, as we file IP, we are only revealing the identity of one of these genes, contactin-4 which is shown on the left, most prevalent one. As I mentioned earlier, about three quarters of the population seems to express the CMV in one of only, in this case 24 genes, and you can see here that our analysis identified the responders 8 of the 15 most frequent genes. And then the SAGA trial list accounted for about 40% of all of the mGluR patients that were studied.

Slide 13. Once again the most prevalent CMV in both the Phenotype/Genotype and the SAGA trial was contactin-4 which accounted for about 22% of the entire mGluR CMV positive population and about 5% of trials of ADHD all by itself. Interestingly, patients with this CMV may also have a more severe phenotype.

Lets go to slide 14. Here is an analysis of ADHD-RS reduction in the SAGA trial, limiting the analysis to the nine genes of interest that I just mentioned. As you can see, this analysis is highly statistically significant and has a placebo subtracted reduction in ADHD-RS of nearly 12 in week six. And as noted on the slide, you can see that 43% of patients in this subset had a contactin-4 CMV 14% were one of the GRMs and 42% were under neurodevelopmental genes.

Lets go to slide 15 and put this in some context. I wanted to show you here the change in ADHD-RS, the primary endpoint in SAGA in three adolescent trials. Were comparing SAGA now to two additional adolescent ADHD trials. We limit the comparison to adolescent trials because adolescents typically have a higher placebo response and lower treatment effect size than pediatric patients do.

So we wanted to make this an apples-to-apples comparison. When we compare AEVI-001 in the 9-gene subset that I just showed you to these two highly effective and successful ADHD medications Vyvanse and Adderall XR, we can see that AEVI-001 had a much greater placebo subtracted reduction total ADHD-RS and in both the inattention hyperactivity subscales that either of those drugs. Of course, its not a head to head comparison, but we were struck by the fact that the magnitude of the treatment effect didnt, in our subset, exceeded that of or even high dose Vyvanse with respect to overall change with ADHD-RS and both the inattention and hyperactivity subscale. So we think we were pretty struck by that finding.

Lets go to slide 16. We also looked at the responder analysis in the 9-gene subset. As a reminder, we used standard response definitions namely, an ADHD-RS reduction of 30% or more and a CGI improvement rather, to 1 very much improved or 2, much improved on the 7 point Likert scale. And as you can see, the response rate of the 9-gene subset were 89% and 72% respectively ADHD-RS CGI-I compared to only 21% and 13% of placebo, both very significantly superior to placebo.

Lets go on to slide 17. Now I want to talk a little bit about contactin-4. Again, we were particularly intrigued by the discovery that contactin-4 was so prevalent in our ADHD population, both in the Phenotype/Genotype study and the SAGA trial and the gene is very interesting. It encodes an anchored neuronal membrane protein that functions as a cell adhesion molecule. The developing nervous system requires the formation of many complex interconnections and network and contactin-4 appears to play a key role in the formation of axon connections and synapses in developing the nervous system.

Mutations in this gene have been previously with a variety of neurological conditions, including neurodevelopmental delay, autism spectrum, bipolar disease and schizophrenia and we also had seen those associations in the network more broadly. Now the CHOP team was the first to identify an association between ADHD and CMV affecting this gene, but because we use the higher resolution technology, namely the Illumina Omni 2.5 chip in our genotyping, we were able to detect smaller CMVs in this gene and this is probably why we detected a higher frequency of the gene than the CHOP team originally did. Consequently, we estimate, as I said earlier, the frequency of the CMV to be 5% of the overall ADHD population.

Next slide, slide 18. Equally interesting, when you look at the phenotype associated with contactin-4 mutated, it gets with the mutation in contactin-4 with ADHD, the observation that these kids seem to have a higher substantially and significantly higher prevalence of emotional dysregulation symptoms including disruptive behavior, anger control, risk taking, inappropriate movements and sounds as compared to the non-mGluR CMV positive ADHD kids. And we previously reported this in a broad population but were now seeing it as contactin-4 drives the substantial part of this. So were doing more work to better understand this phenotype. We do know though that the emotional dysregulation phenotype and ADHD often predicts worst life outcomes for the patients.

Next slide, slide 19. So given the high prevalence and the unique features of this gene, we chose to analyze it independent of the other genes in the selected nine gene subset. So we looked at it alone. And we observed that the AEVI-001 response in patients with CMV associated with this gene was higher than with any other. In fact, all six patients who were randomized to receive AEVI-001 responded vigorously as compared to 3 in 12 patients randomized to placebo. And the magnitude of response was the highest seen with any gene, so even with data on only 18 patients, the reduction in the primary endpoint of ADHD-RS, SAGA was statistically significant.

And going to slide 20, again, when we do responder analyses using just patients with the mutation in this gene, you will see that we have a very statistically and clinically significant difference between placebo and drug for both ADHD-RS and CGI, 100% and 83% respectively.

Lets go to slide 21 and just to summarize, we were able to identify our responder subset of patients who bear a CMV in one of nine genes. Taken together, this subset accounted for about 40% of all mGluR CMV positive ADHD patients and about 10% ADHD patients overall. So this was a very substantial population. Response rates in patients in this subset were very high, but were noticeably higher in patients with a CMV in one particular gene, contactin-4. All patients with a CMV and contactin-4 in the SAGA trial responded to AEVI-001. The prevalence of contactin-4, CMV in our population of ADHD patients was greater than 20% of the overall mGluR positive patients and accounts for 5% of all ADHD patients.

So by itself, this is a very substantial and study-able population. Moreover, preliminary data suggests that these patients may have a more severe disease phenotype characterized by higher prevalence of emotional dysregulation. So we believe that the best path forward for the development of AEVI-001 in ADHD lies in enrichment of patients with CMV in these genes in future study. Not to say that other genes in the mGluR network could also not predict or could predict response to AEVI-001, these can also be elucidated in future studies, but we feel its necessary to first concentrate on patients with mutations that have been observed in patients who did show response. I want to emphasize that not all genes predict response to AEVI-001, we remain convinced that the 273 gene mGluR network is highly predicted for the disease ADHD.

Slide 22, we talk about the next steps for AEVI-001 in ADHD and autism. Were currently finalizing the design of the new Phase 2 trial I mentioned to confirm our post-hoc analyses in the SAGA trial. Right now we plan a multi-center randomized placebo controlled trial in patients aged 6 to 17, use of younger patients which should now be enabled by our juvi talks and pediatric pk studies should result in better effect size and lower placebo response. We plan to use the stage adaptive design with the initial focus on patients with contactin-4 CMV. The N should be around 40 to 70 patients.

Subsequent stages will enroll patients with a CMV in the remaining genes in the 9-gene subset. We expect to get this study underway in the second half of this year, 2017, with top-line data expected mid-2018. As I noted, contactin-4 looks particularly interesting in autism spectrum disease, its prevalence maybe even higher in that population than it is in ADHD. Were currently genotyping ASD patients at CHOP with the Omni 2.5 chip and studying their phenotype in more detail. Depending on the data, we plan a discussion later this year with FDA regarding a potential orphan indication for contactin-4 related autism.

So with that, Ill turn it back to Mike.

Michael Cola

Thank you, Garry. Were on slide 23. As I mentioned earlier, with the 9-gene subset, we have a reduced set of patients that were looking at approximately 10% of the market. So we still think its a very significant and compelling business case for the 9-gene subset. Looking at current sales of about $11 billion, growing slowly and about 90% of this sales are stimulant, we still think there is a very high unmet need for a non-stimulant that is effective. We have about 6 million patients in the 6 to 17 category and about 10 million adult patients.

If you take 10% of that, there are about 1.6 million patients total using current premium pricing of about $15 a day and current compliance and adherence which we think we can improve on, about five to seven scripts per year, still end up with a total addressable market of $2 billion to $3 billion which is obviously sizeable. As we understand more about other diseases with these genes, particularly ASD, we think there is a lifecycle opportunities in those diseases as well.

And with that Ill move on 002 in Severe Pediatric Onset Crohns Disease. This is the program that we licensed in the middle of last year in 2016. Its based on a discovery at Childrens Hospital of Philadelphia that in very severe early onset Crohns disease and IBD in general, you have a loss of function indicated by genetic mutation in decoy receptor 3. Decoy receptor 3 is a buffer protein that reduces inflammatory cytokines particularly light that are causal in IBD. And when you have left DcR3 and have more light, you have these severe pediatric onset symptoms. We think that comprises anywhere from 10% to 15% of those patients.

We did begin our search looking for a DcR3 analog, we couldnt find one with an appropriate profile, particularly for children and so we moved on to monoclonal antibodies that known down light. And we were lucky to find one from Kyowa Hakko Kirin which was just coming back from a collaboration with Sanofi Aventis. We were able to get that deal done in the middle of last year and weve made great progress over the last nine months to get us toward the clinical trial. Obviously, we successfully reinitiated and transferred the IND with a new protocol.

We have re-qualified the clinical trial material which was the major part of the work over the last nine months and we are cleared by the FDA to start a trial, still have some administrative work at CHOP to get this thing up and running, but were moving through that quite rapidly and we expect this study starts at the end of this month, beginning of June. And initial data in the second half of 2017 with endoscopic - in Crohns Disease Activity Index as our primary endpoints.

And with that, Im going to turn it over to Brian for the quarterly financial update.

Brian Piper

Thanks, Mike and Ill walk us through the results of operations from Q1. R&D expenses for the quarter were $7.9 million, increasing from $7 million for the same period in 2016. Not surprisingly, this is mainly due to increased spend on clinical activities related to completion of the SAGA for AEVI-001 and to a lesser extent, initial cost start-up cost for the AEVI-002 program. We do anticipate clinical spend should decrease going forward as the majority of clinical activities related to the SAGA trial have ceded.

G&A expenses for Q1 17 were $3 million decreasing from $4.2 million for the same period in 2016. This is mainly due to severance benefits recorded in 2016. Cash we recorded at the end of March 31, $29.2 million, importantly, we do feel that these cash resources will be sufficient to fund operations through Q2 2018 which would in course include delivering top-line data by mid-2018 in the Phase 2 trial to confirm the genetic responders to AEVI-001 that Mike and Garry described earlier as well as initial data by the second half of this year from the signal finding trial of AEVI-002 in Severe Pediatric Onset Crohns Disease.

And with that, I will turn it back to Mike for any final comments and Q&A.

Michael Cola

Thank you, Brian. On slide 28, you see our upcoming events on our pipeline chart again, very busy time ahead of us, getting a trial up and running in the mGluR positive genetic subset, particularly with the Crohns program starting as well, with initial data in the second half of the year. We expect success in these trials and we continue to be very confident in our ability to execute again with this plan.

And with that, Ill turn it back to the moderator. Thank you.

Question-and-Answer Session

Operator

Thank you. [Operator Instructions]. And well take our first question from Jason Butler from JMP Securities.

Jason Butler

Hi. Thanks for taking my questions and thanks for going through all the details in the prepared comments. Just first question, you mentioned that in the CNTN4 patients, there are more disruptive behaviors. Can you talk about whether the severity of ADHD symptoms as a whole is, is worse than the patient population or what their response to current ADHD treatment option is relative to the border ADHD population?

Garry Neil

Thats still something that were analyzing. I mean we see this with a much higher odds ratio of these symptoms which are prevalent to begin with, in ADHD patients. So it is a source of considerable morbidity in those patients.

Michael Cola

But we do, in the phenotypic data that Garry showed on slide 18, know that approximately two-thirds of the patients that were in the phenotypic study were on stimulants at the time of the questionnaire or had been on stimulants. So, although we are doing actual EMR work with Childrens Hospital now to understand how theyre responding to therapy, the increased odds ratio for these more severe symptoms you would expect they are not responding to stimulant therapy very well, but we have to clarify that going forward.

Jason Butler

Okay, great. And then from the next Phase 2 trial, when we see results mid-18, will that be from just the first cohort of CNTN4 patients or will that be from old patients in the trial?

Garry Neil

Yeah, our approach Jason is to win on contactin-4 first and I dont have an answer for that because were going to do it as an adaptive design. Once we go on CNTN4, well go to the other eight genes. So our hope is to do it as quickly as possible, were working through the details of that study right now, its kind of coming together real-time, but obviously our goal would be to provide much data as we possibly can, as quickly as we possibly can.

Jason Butler

Okay, great. And then just last question from me, can you just give us an idea of how many patients well see from the 002 trial later this year?

Garry Neil

So there are cohorts of four patients. We do have a fairly lengthy washout requirement than we have to do the first patient sequentially, but were hoping were going to get us as many of that first cohort done as we can this year.

Jason Butler

Okay, great. Thanks for taking the questions.

Michael Cola

If you remember Jason, its also an open label trial. So we will report that data as it comes in, we dont necessarily have to wait for the first four patients.

Jason Butler

Great. Thanks.

Operator

And we will take our next question from Brian Marks from Zacks Investment Research.

Brian Marks

Hi. Good morning guys. Among the children that fit into the CNTN4 cohort, is there much comorbidity with ADHD and autism or any other disorders such that it might present challenges in designing in ADHD study just with the CNTN4 cohort?

Garry Neil

Well, we had no problem enrolling them with our enrollment criteria in the SAGA trial. But were interested in the fact that, as Mike said, were really looking at a phenotype that appears to have more emotional dysregulation. Were also looking to find better ways to be able to evaluate the response to therapy on those specific symptoms which arent always perfectly evaluated by the existing scales. Were going to be thinking about some supplemental scales to use in those patients. But no, I dont think it will be a problem getting patients in the study, but we are very interested, as I said, were doing much more deep phenotyping looking at autism and other comorbidities associated with this gene and there may be a spectrum of neurodevelopmental disorders which would provide a lot of opportunity for us for AEVI-001.

Brian Marks

Okay. In terms of endpoints in the study, will they be similar to SAGA?

Garry Neil

ADHD trials are fairly stereotypical in that everybody uses the regulatory gold standards which are ADHD-RS and CGI-I as their primary endpoints. But we also, as I said, well also be using some additional endpoints that are more specifically targeted in some of the symptoms of interest that weve already mentioned

Brian Marks

I think you guys said, when you talked about the SAGA top-line results indicated that there could be potential to increase the dose or increase the treatment duration. Is that potentially still in the cards maybe not with this upcoming CNTN4 study but potentially with the follow-on 9-gene study?

Garry Neil

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Aevi Genomic Medicine's (GNMX) CEO Michael Cola on Q1 2017 Results - Earnings Call Transcript - Seeking Alpha

Our next group of correspondents stood out due to their vocations: In one way or another, their chosen careers brought them into the subculture of scientific thinking. These readers tended to be more favorably disposed to gene editing than others.

Take this reader, a semi-retired school psychologist and a lover of science whose daughter plans to become a clinical geneticist:

I agree with the premise of your article [that prophylactic gene editing could soon be mandatory] and am not frightened by it at all. Scientific advances have not, cannot, and should not be stopped. Since the first civilizations science has been dragging religion and society reluctantly along into a more technologically advanced future. What we gain from this seems always to be more than what we have lost.

A medical student who hopes one day to do gene editing was likewise eager for a future where it is used to cure diseaseand even to direct the way that humans evolve:

Modern medicine, in its current form, is basically the answer to the question: What is the best way to treat diseases whose cures cannot and will not ever be found? Treating someone with cystic fibrosis, for instance, is an admirable thing to do, but its also an exercise in futility: That patient will undoubtedly die prematurely. Anything besides excising the mutant gene and replacing it with a normal copy is treading water and delaying the inevitable (though, obviously, the patients must still be treated).

In modern societies, infectious diseases and trauma are more or less under control (relative to developing countries and bygone eras). Curing genetic diseases (cancer loosely being included in this category) are currently a dead end. So, logically, addressing this head-on is the only next step.

I view gene therapy and editing as the way of the future, not only of medicine but also of humanity in general. It will start as the means for cures of currently incurable diseases. Eventually, it will be a means by which we can continue to evolve ourselves as a species. If 3.5 billion years of evolution churned our species out through the natural selection of random mutations, how much better can we do with logic and molecular precision? In my opinion, anything that can widely (and, potentially, permanently) change mankind and society for the better should be done.

I wish I shared the correspondents confidence that logic and molecular precision will serve humanity better in this realm than the decentralized systems of dating and mating have done so far. Reflecting on the decisions that literally every bygone generation might have made if able to edit genes, I fear that our choices will prove as imprudent in hindsightand thats not even accounting for unintended consequences.

The next reader is working to earn his Masters degree in Biochemistry:

It is not unreasonable to imagine that in the near future gene editing will be a safe and effective means of preventing genetic diseases. It is also not unreasonable to imagine that in the case of many diseases, such as sickle-cell anemia or cystic fibrosis, which are caused by small mutations in a single gene coding for a functionally important protein, gene editing would be likely to prevent the disease without affecting the child in any other way. For these diseases, once it is demonstrated that gene editing works the way that it is supposed to, I think parents should be punished for failing to employ gene editing. I think that if it had been demonstrated that gene editing was safe, effective, and selective, refusal to use this technique to prevent disease would essentially amount to fear and mistrust of the scientific and medical communities. I really dont think thats a valid reason to allow another person to be afflicted by a preventable disease.

However, I draw a distinction here between expecting parents to make edits that will definitely prevent a debilitating disease, and expecting edits that reduce the risk of a disease that the child may or may not have ended up getting. I certainly wouldnt be opposed to parents editing genes to reduce the chance of cancer, but I wouldnt really expect it. There are a number of behaviors that we know reduce cancer risk which we dont really expect parents to push on their kids. For example, parents could probably reduce cancer risk in their children by some small fraction by giving them grape juice every day or something like that. I dont really expect parents to do that. If you cant blame parents for not giving their kids grape juice you really cant blame them for not editing the kids genome.

At the same time, he adds, we can really only justify using gene editing for medical purposes:

We are a long way from understanding our biology well enough to be able to make genome modifications to enhance intelligence or beauty or athleticism without risking horrible unforeseen side effects. But even if we did have the ability to do that, I still dont think it would be justified because I dont think we can tie these traits to an increased sense of happiness or fulfillment.

I am short and scrawny, and Im perfectly happy with that. I know plenty of people who are perfectly content with being as dumb as rocks. I know plenty of smart people who are miserable. So, Ill grant that I am basing my opinion here on a biased personal experience, but I really dont think that we can say that it really is in the best interests of the child to alter superficial traits.

When discussing a childs future, people often talk as if the parents preference is the most important thing. But parents dont own their children. Parents are stewards of their children. I think that making designer babies would be an example of parents making self-serving decisions, rather than making decisions in the best interests of the child. I dont think that is justifiable.

The next correspondent is a biochemistry grad student who works in a research group that specializes in genome-editing technology, and cautions against its near-term limits:

If gene therapy with Cas9 were at some future time as cheap, easy, and safe as an antibiotic treatment, then yes, I would support punishments for parents who forewent a cure for their children. In some cases, a genetic disorder is very similar to other macro-level disorders, e.g. genes can be broken in the same sense that a wrist is broken. While wrists can come in many healthy shapes and sizes and colors, broken in two is not one of them; likewise, while genetic diversity is important and natural and cant always be cleanly mapped to disease, some genetic mutations are incontrovertibly damaging and lead to illness and suffering. Refusing a simple medical treatment for a disorder with a clear singular genetic root cause (of which there are fewer than one might think) would be as unethical as refusing to set a broken wrist.

But I dont think gene therapy will be as cheap, easy, or safe as antibiotics in our lifetimerather, my opinion is that gene therapy will be expensive, invasive, and risky (at least relative to an antibiotic pill) for the foreseeable future. I dont expect gene therapy to become routine in the same way that oral therapies are, and so choosing not to subject your child to gene editing cannot be chalked up to negligence. (A contemporary example: Sovaldi is a drug that essentially cures Hepatitis C, but it costs $200,000 and there are other treatmentscould you imagine a parent being prosecuted for refusing to pay for Sovaldi?)

Why am I so down on gene therapy?

First of all, regarding cost, the clamor surrounding the Cas9 patent dispute should give you an idea of how profitable the players in this field expect gene therapy to be. Gene therapy will always be more expensive than an oral antibiotic because the treatment requires many more steps (each of which is far costlier), is much lower throughput, and will require specialized care and oversight. For similar reasons, it will not be nearly as convenient for patients as filling a prescription. And as Ive written elsewhere, our current early-generation gene-therapy tools and limited understanding of the link between genetics and disease means that gene therapy carries unprecedented safety risks. (For example, no currently approved therapy could cause permanent heritable genetic changes.)

These risks shouldnt disqualify gene therapy as a possible future treatment, but they could certainly give the most informed and adventurous patient pause. In short, I believe technical limitations and cost and safety concerns will delay the debate over mandatory gene editing for decades at least. More pressing to discuss are the multitude of other ways that gene editing and GMOs affect modern life and medicine.

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Thoughts on Gene Editing From the Science Community - The Atlantic

May 09, 2017 09:13 ET | Source: Admera Health, LLC

SOUTH PLAINFIELD, N.J. and ROCHESTER, N.Y., May 09, 2017 (GLOBE NEWSWIRE) -- Today, the University of Rochester School of Medicine and Dentistry and Admera Health announced that enrollment had commenced in a randomized clinical study evaluating the use of pharmacogenomics to guide pain management decisions related to acute dental surgery. Specifically, the study is seeking to determine if a preoperative chair-side pharmacogenomic algorithm can significantly enhance the efficacy of surgical pain management and to characterize the association between gene-drug interactions and clinical outcomes.

Admera Health, a molecular diagnostic company, will extract and sequence DNA samples provided by the University of Rochester. Sequencing will utilize Admeras PGxOne Plus test, a 50 gene Next Generation Sequencing panel that interrogates nearly 200 different variants and provides recommendations for over 220 drugs based on an individuals unique genetic makeup.

It is well understood in the medical community that most acute surgical pain methods have shown inconsistent effects on pain relief and rely excessively on opioid use, which has associated dependency issues, as stated by Admera CEO and President Guanghui Hu. With the implementation of our PGxOne Plus test, we are confident that this study will demonstrate improved patient outcomes, similar to the way pharmacogenomics has been clinically validated in other therapeutic areas such as cardiovascular health, oncology, and psychiatric care. That is why we are excited to be working with the University of Rochester for this study.

According to the CDC, opioid-involved deaths continue to increase and have reached epidemic status. In March, a United States Senate committee opened a probe into the practices of the top manufacturers of opioid drugs.

About Admera Health

Admera Health is a CLIA-certified and CAP-accredited advanced molecular diagnostics company focused on personalized medicine, non-invasive cancer testing, digital health, and providing research use only services. Research and development efforts are dedicated to developing cutting-edge diagnostics that span the continuum of care. Utilizing next generation technology platforms and advanced bioinformatics, Admera Health seeks to redefine disease screening, diagnosis, treatment, monitoring, and management through its innovative, personalized solutions. It is our mission to deliver transformative, valuable solutions for patients, physicians, and clinical researchers. We are committed to improving the health and well-being of our global community through the direct delivery of personalized, medically actionable results.

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University of Rochester School of Medicine and Dentistry Collaborate with Admera Health in a Clinical Study ... - GlobeNewswire (press release)