BARCELONA Researchers have obtained the first signs of clinical benefit in an early-stage gene therapy trial for Tay-Sachs disease, according to a presentation at the European Society of Gene & Cell Therapy (ESGCT) annual conference last week.

Terence R. Flotte, MD, executive deputy chancellor, provost, and dean of the University of Massachusetts (UMass) School of Medicine, presented the results in Barcelona. Flotte is also the editor-in-chief of Human Gene Therapy (a sister journal of GEN).

Buckle your seatbelts, commented Fyodor Urnov, PhD, a gene therapy expert at the Innovative Genomics Institute, UC Berkeley, on Twitter. A gene therapy early-stage success for Tay-Sachs!!!

Urnov said: Flotte has long been an inspiration and a leader for the field, and this is just MAGNIFICENT. Tay-Sachs is devastatingbut perhaps for not much longer?

Tay-Sachs is an incurable recessively inherited pediatric genetic disease, a member of a group of lysosomal storage diseases, which is particularly common in individuals of Ashkenazi Jewish descent. Patients have a median life expectancy of approximately three to four years.

Flotte presented preliminary data on two infants in the Phase I trial, which is designed to ascertain safety rather than efficacy. But Flotte said there are early signs that the therapy, which in 2018 was licensed to Axovant Gene Therapies, has the potential to modify the rate of disease progression.

Flotte said that the adeno-associated virus (AAV) gene therapyAXO-AAV-GM2had been successfully administered in both children and has been well tolerated so far, with no serious adverse events or clinical abnormalities related to the therapy. The route of therapy is significant: it involves bilateral intrathalamic and intrathecal injection of the virus in an effort to deliver widespread distribution of the replacement enzymehexosaminidase A (HexA) throughout the brain and central nervous system.

This innovative delivery could overcome one of the primary challenges for developing treatments for Tay-Sachs, Sandhoff, and many other severe pediatric genetic disorders, providing much needed hope for these families, Flotte said.

Flotte said there had been a very modest increase in HexA bioactivity in both patients (less than two percent). More encouragingly, the second patient treated showed signs of increased myelination and a plateau in disease development.

The data presented by Flotte marked the first reported evidence for potential disease modification in Tay-Sachs disease, and suggest an opportunity for gene replacement therapy to improve outcomes for children with this devastating condition, said Gavin Corcoran, MD, Axovants chief research and development officer, in a statement.

Myelination is an important component of healthy brain development in infants and is often abnormal in children with Tay-Sachs disease. We were encouraged to see MRI evidence of preserved brain architecture and improved myelination in the early symptomatic child treated at 10 months of age, Corcoran said.

Flotte presented the preliminary trial findings on behalf of his UMass colleagues including Miguel Sena-Esteves, PhD, associate professor of neurology; Heather Gray-Edwards, PhD, DVM, assistant professor of radiology; and Douglas Martin, PhD, professor of anatomy, physiology, and pharmacology in the College of Veterinary Medicine at Auburn University.

A Phase II trial is being planned.

Flottes report was one of several highlights delivered at the ESGCT annual congress, which attracted a record attendance of more than 2,000 scientists last week. Flotte was one of many leading plenary speakers, including Carl June, MD (University of Pennsylvania) and Michel Sadelain, MD (Memorial Sloan Kettering) on CAR-T therapy; David Williams, MD (Boston Childrens Hospital), Matthew Porteus, MD (Stanford University), and Donald Kohn, MD (UCLA) on gene therapy for sickle-cell disease and beta-thalassemia; Fulvio Mulvilio, MD (Audentes Therapeutics) on X-linked myotubular myopathy; and James Wilson, MD (University of Pennsylvania) on safety of gene-editing nucleases.

The conference also marked the third public presentation of prime editing, the novel genome editing technology developed by David Liu, PhD (Broad Institute/HHMI) and colleagues, which was published last week in Nature. The method offers the possibility of engineering any base substitution by using an RNA intermediate.

Despite recent protests in Barcelona, the conference proceeded without incident. The 2020 ESGCT congress will be held in Edinburgh, Scotland, on October 20-23, in collaboration with the British Society for Gene and Cell Therapy.

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Promising Results Reported in Tay-Sachs Gene Therapy Trial - Genetic Engineering & Biotechnology News

Sickle cell anemia, a common form of sickle cell disease, is caused by a particular mutation in the HBB gene. This mutation results in the production of an abnormal version of beta-globin called hemoglobin S or HbS. In this condition, hemoglobin S replaces both beta-globin subunits in hemoglobin. The mutation changes a single protein building block (amino acid) in beta-globin. Specifically, the amino acid glutamic acid is replaced with the amino acid valine at position 6 in beta-globin, written as Glu6Val or E6V. Replacing glutamic acid with valine causes the abnormal hemoglobin S subunits to stick together and form long, rigid molecules that bend red blood cells into a sickle (crescent) shape. The sickle-shaped cells die prematurely, which can lead to a shortage of red blood cells (anemia). The sickle-shaped cells are rigid and can block small blood vessels, causing severe pain and organ damage.

Mutations in the HBB gene can also cause other abnormalities in beta-globin, leading to other types of sickle cell disease. These abnormal forms of beta-globin are often designated by letters of the alphabet or sometimes by a name. In these other types of sickle cell disease, just one beta-globin subunit is replaced with hemoglobin S. The other beta-globin subunit is replaced with a different abnormal variant, such as hemoglobin C or hemoglobin E.

In hemoglobin SC (HbSC) disease, the beta-globin subunits are replaced by hemoglobin S and hemoglobin C. Hemoglobin C results when the amino acid lysine replaces the amino acid glutamic acid at position 6 in beta-globin (written Glu6Lys or E6K). The severity of hemoglobin SC disease is variable, but it can be as severe as sickle cell anemia. Hemoglobin E (HbE) is caused when the amino acid glutamic acid is replaced with the amino acid lysine at position 26 in beta-globin (written Glu26Lys or E26K). In some cases, the hemoglobin E mutation is present with hemoglobin S. In these cases, a person may have more severe signs and symptoms associated with sickle cell anemia, such as episodes of pain, anemia, and abnormal spleen function.

Other conditions, known as hemoglobin sickle-beta thalassemias (HbSBetaThal), are caused when mutations that produce hemoglobin S and beta thalassemia occur together. Mutations that combine sickle cell disease with beta-zero (B0) thalassemia lead to severe disease, while sickle cell disease combined with beta-plus (B+) thalassemia is milder.

Originally posted here:
HBB gene - Genetics Home Reference

Gene therapy is an experimental method of fighting disease that involves correcting or replacing a persons mutated or malfunctioning genes. This promising research is now being used in clinical trials and may lead to improved health outcomes for patients with inherited bleeding and immune disorders as well as some forms of blood cancer and other diseases.

What Is Gene Therapy?

Genes carry the DNA information needed to make proteins that are the building blocks of the human body. Some of these genes can become damaged through mutation, which can lead to disease conditions. Gene therapy is a scientific technique that uses genes to prevent or treat disease in a number of different ways:

Finding the Keys to Alter Body Chemistry

Currently, gene therapy can be used for conditions in which a change in the genetic coding of somatic cells can alter the course of a disease. For example, to correct a disease in which a specific enzyme is missing, the addition of a necessary gene component for production of the enzyme would fix the underlying problem of the disease. In many cases, harmless viruses are employed to serve as packets to carry the new gene to where it is needed. When used this way, the viruses are called vectors, and their own genes may be removed and replaced with the working human gene. Once the gene is correctly placed, it can be switched on to provide the working instructions for correct function.

Conditions Being Treated with Gene Therapy

Although much of this may still sound like the realm of mad scientists tinkering with the human body, gene therapy is an accepted experimental technique that is currently being used to help patients with certain types of cancer to target specific antibodies that can be used to fight the disease. Gene therapy is also being used to correct deficiencies in the production of dopamine, such as in Parkinsons disease, correct some immune system problems, and restore components needed for normal blood cell function in those with certain blood diseases, such hemophilia and beta-Thalassemia. Gene therapy holds promise for treating a wide range of diseases, including cancer, cystic fibrosis, heart disease, diabetes, hemophilia and AIDS.

Potential Risks

Gene therapy does come with some potential risks, all of which, researchers are hoping to overcome. Because the genes have to be delivered using a carrier or vector, the bodys immune system may see the newly introduced viruses as intruders and attack them. Its also possible that the altered viruses may infect additional cells, not just the targeted cells containing mutated genes. There may also be some concern that the viruses may recover their original ability to cause disease, or that the new genes get inserted in the wrong spot in a patients DNA, leading to tumor formation.

Hope for the Future

Gene therapy holds promise as an effective treatment option for a variety of diseases at some point in the near future. An estimated 4,000 medical conditions are a result of gene disorders. If some of these genetic problems can be corrected through gene replacement or manipulation, individuals suffering from these diseases may enjoy longer, healthier lives, free of symptoms and the associated medical expenses.

More here:
Gene Therapy The Future of Medicine? | Science Care

By KIMBERLY HOUGHTONUnion Leader CorrespondentAugust 14. 2017 11:06PM

This sequence of images shows the development of embryos after being injected with a biological kit to edit their DNA, removing a genetic mutation known to cause hypertrophic cardiomyopathy.(Oregon Health & Science University)

Bryan Luikart, an associate professor of molecular and systems biology at Geisel School of Medicine at Dartmouth College.

It is pretty amazing. It is a super-exciting time to be a scientist right now, said Bryan Luikart, an associate professor of molecular and systems biology at Geisel School of Medicine at Dartmouth College.

The study, which was published in the journal Nature, was detailed in a New York Times report. According to the article, Oregon researchers reported they repaired dozens of human embryos, fixing a mutation that causes a common heart condition that can lead to sudden death later in life.

The way they have dodged some ethical considerations is that they didnt go on to have that embryo grow into a person, said Luikart, explaining that if the embryos with the repaired mutation did have the opportunity to develop, they would be free of the heart condition.

At the Geisel School of Medicine at Dartmouth, Luikart and his colleagues have already been using this concept with mouse embryos, focusing specifically on autism.

Researchers are using the gene-editing method called CRISPR-Cas9 in hopes of trying to more fully understand autism, which he said is the most critical step in eventually finding a cure.

I think the CRISPR is a tremendous breakthrough. The question really is where and when do you want to use it, Luikart said. I have no ethical concerns using it as a tool to better understand biology.

The new milestone, an example of human genetic engineering, does carry ethical concerns that Luikart said will trigger some debates. He acknowledged that while the advancement of gene-editing technology could eventually stop unwanted hereditary conditions, it also allows for creating babies with smarter, stronger or more attractive traits.

The ability to do that is now within our grasp more than it has ever been, he said.

More importantly, the breakthrough could ultimately eliminate diseases, Luikart said. As the technology advances, he said, genetic diseases that are passed down to children may be corrected before the child receives them.

He used another example of a brain tumor, which often returns after it is surgically removed. Now, once the brain tumor is removed, there is the possibility of placing something in the space to edit and fix the mutation that causes the brain tumor in the first place if physicians are able to find the right cell to edit, Luikart said.

People are definitely thinking along those lines, or cutting the HIV genome, said Luikart, who predicts that those advancements will occur in mice within the next decade, and the ability to do that in humans is definitely there.

The big question is whether that can occur without some sort of side effect that was not predicted, he said.

Columbia University Medical Center posted an article earlier this year warning that CRISPR gene editing can cause hundreds of unintended mutations, based on a study published recently in Nature Methods.

This past May, MilliporeSigma announced it has developed a new genome editing tool that makes CRISPR more efficient, flexible and specific, giving researchers more experimental options and faster results that can accelerate drug development and access to new therapies, according to a release.

CRISPR genome editing technology is advancing treatment options for some of the toughest medical conditions faced today, including chronic illnesses and cancers for which there are limited or no treatment options, states the release, adding the applications of CRISPR are far ranging from identifying genes associated with cancer to reversing mutations that cause blindness.

It is pretty big news, Luikart said.

khoughton@newstote.com

HealthHanover

The rest is here:
New Hampshire biologist reacts to gene-editing discovery - The Union Leader

Two gene-editing companies are hitting back at a scientific publication that caused their stocks to plummet, calling it wrong, filled with errors, and saying it shouldnt have been published.

In separate letters sent to Nature Methods, scientists from Intellia Therapeutics and Editas Medicine criticized a report in the journal that claimed the gene-editing tool CRISPR had caused unexpected mutations in the genomes of mice and which cast a shadow over efforts to initiate human studies using the technique.

A spokesperson at Springer Nature, which publishes Nature Methods, said the organization had received a number of communications already about the paper. We are carefully considering all concerns that have been raised with us and are discussing them with the authors, the journal said.

On Twitter and elsewhere, other scientists quickly pointed out basic mistakes in the paper, including misidentifying genes, the small number of animals involved and, most seriously, that it had mislabeled normal genetic differences between animals as the result of CRISPR editing.

In our opinion the conclusions drawn from this study are unsubstantiated by the disclosed experiments, wrote Vic Myer, chief technology officer of Editas, in a letter signed by 11 other company scientists.

The GLP aggregated and excerpted this blog/article to reflect the diversity of news, opinion, and analysis. Read full, original post:Gene Editing Companies Hit Back at Paper That Criticized CRISPR

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Controversial CRISPR paper blasted by gene-editing companies Editas Medicine, Intellia Therapeutics - Genetic Literacy Project

June 13, 2017 UNC scientists discovered how the enzyme Set2 keeps gene transcription working properly when cells are under stress. Credit: Christ-claude Mowandza-ndinga

UNC School of Medicine researchers have cracked a long-standing mystery about an important enzyme found in virtually all organisms other than bacteria. The basic science finding may have implications for understanding cancer development and how to halt it.

Researchers have known that the enzyme Set2 is important for transcribing genes - the process of making strands of RNA from the DNA. Transcription is critical for making proteins and other functional molecules. But Set2's precise role in transcription hasn't been clear. Now, UNC scientists discovered that the enzyme is particularly important for keeping transcription working properly when cells are under stress. Without Set2, cells that become stressed through the lack of nutrients begin mis-transcribing genes in a way that prevents cells from adapting properly to the stress.

"We think this solves a mystery about the purpose of Set2, and we now understand much better how gene transcription is prevented from happening at the wrong place and time," said study senior author Brian Strahl, PhD, professor of biochemistry and biophysics and member of the UNC Lineberger Comprehensive Cancer Center.

Set2 enzymes in yeast and other lower organisms have close relatives in all animal species and plants. Its human cousin SETD2 is often found mutated in cancerous cells.

"These fundamental findings may help explain how SETD2 mutations could lead to inappropriate transcription within genes, which might then promote cancer initiation or progression," Strahl said. His team's research on SETD2 is ongoing.

The research, published in Cell Reports, involved collaboration between Strahl's laboratory and that of Ian J. Davis, MD, PhD, associate professor of pediatrics and genetics at the UNC School of Medicine and member of the UNC Lineberger Comprehensive Cancer Center.

The discovery comes 15 years after the first studies of Set2 by Strahl and others, who found that the enzyme works by attaching molecules known as methyl groups to a support protein - or histone - around which DNA is spooled.

This methyl-attaching process is called methylation. Research has shown in recent years that the particular histone methylation performed by Set2 serves as a quality control check on gene transcription.

Transcription of a gene should start at a precise spot at the beginning of a gene and then continue until the end in order to fully transcribe the RNA. But in the absence of histone methylation laid down by Set2, transcription begins at the wrong places in the middle of a gene instead of at the beginning. If that is allowed to happen, the production of "cryptic" RNA transcripts can then interfere with the normal expression of a gene. The mis-expression of our genetic material can result in diseases such as cancer.

Strahl's team thought Set2 might have something to do with these cryptic transcripts arising during stress. Previously, it was shown that Set2's histone-methylating activity has the effect of attracting another enzyme to clear away chemical tags in the middle of a gene that, otherwise, can lead to inappropriate new transcription from within that gene.

"But under typical laboratory conditions, the deletion of Set2 and the subsequent increase in cryptic transcripts didn't seem to harm cells very much," Strahl said.

Strahl's team then thought about cells under stress, which is what cells are like in disease states. His team conducted experiments to observe what happens in cells that don't have Set2 when vital nutrients are removed. In this stressed state, cells normally activate a complex set of gene expression programs to help cope with the reduced nutrient resources.

"Nutrient depletion more accurately mimics what yeast cells experience in the wild," Strahl said.

The scientists examined yeast cells that were deprived of nutrients, or were exposed to chemicals that reliably trigger the low-nutrient response. In these cells, not having Set2 proved to have major consequences.

"We found that this inappropriate transcription at the wrong place in genes exploded to high levels in stressed cells, and often interfered with the normal genes," Strahl said. "As a result, the normal changes in genes that help cells survive under low-nutrient conditions did not happen correctly, and the cells became extremely sick."

To Strahl and colleagues, the finding suggests that Set2 evolved to guard against harmful abnormal transcription in times of stress, when cells seem particularly vulnerable to this type of error. Why would cells be so vulnerable to cryptic transcription during the nutrient stress response? Strahl isn't sure. But his team suspects that when there's a sudden and widespread rearrangement of the molecular machinery of gene transcription, genes across the genome are left relatively open to inappropriate transcription.

"We found that a lot of the genes that show this crazy jump in cryptic transcription were not even related to the nutrient stress response," Strahl said. "It's as if there are genes throughout the genome that are just predisposed to this error, especially at this time when transcription is shifting dramatically."

Strahl and Davis and their colleagues plan further research to determine why cryptic transcription rises so dramatically during nutrient stress. They also intend to find out whether Set2 is important for safeguarding transcription during other types of cellular stress.

In addition, the scientists are now studying Set2's human counterpart, SETD2, which for unknown reasons is often mutated in tumor cells, especially in kidney cancers.

"It's possible that SETD2 normally works as a major tumor suppressor by preventing inappropriate transcription," Strahl said.

Explore further: Study pinpoints new role for enzyme in DNA repair, kidney cancer

More information: Cell Reports (2017). DOI: 10.1016/j.celrep.2017.05.057

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Researchers show how a cancer gene protects genome organization - Phys.Org

It may still seem like science fiction, but the ability to nip-and-tuck problematic genomes to cure disease is easier than ever and will soon be getting easier.

At the HIMSS Precision Medicine Summit on Monday, Ross Wilson, principal investigator at UC Berkeley's California Institute for Quantitative Biosciences, explained how tools such as CRISPR-Cas9 are set to transcend the confines of the lab to fundamentally change clinical care.

While there have been some intriguing recent strides made with gene editing technology, Wilson admits that so far, at least CRISPR's "hype eclipses early success stories."

But five to 10 years from now, he said, it "will come into its own and be safe and effective."

The process of fixing certain inheritable diseases by accessing the genome and fixing the root cause is clearly far more complex than the "cut-and-paste" analogies Wilson used to explain advanced precision medicine techniques to non-scientists.

But CRISPR-Cas9 is a "readily programmable genome-editing tool" that makes the process more intuitive and usable for researchers and clinicians than ever before.

[Also:How precision medicine can fix a broken healthcare system]

For an analogy, Wilson likened the use of similar techniques known as zinc-finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs) as wheeling in an '80s-era arcade game to play Frogger or Pac-Man. CRISPR-Cas9, he said, was more akin to an easy and agile Playstation.

That said, the "future of medicine" is still some way off from full fruition. There are three key hurdles to overcome, said Wilson:

Efficacy. Although cutting out a gene can be done reliably, it's still not easy or efficient to "paste" the corrected gene.

Delivery. Researchers still lack robust and reliable technology for sending genome-editing enzymes to the cells in need of repair.

Genetic understanding. Clinicians' ability to cure disease remains hamstrung by an impressive but still too limited knowledge of the underlying genetic causes, said Wilson.

"The total scope of genome editing will be defined by our genetic understanding," he said.

There are currently three conceivable approaches to genome-editing, in order of prevalence, said Wilson: ex vivo, in vivo (systemic), in vivo (targeted).

The "earliest success stories will be ex vivo" enabling clinicians to snip and edit genomes in a petri dish with a "high-efficiency that will let you do the 'pasting' of the effective gene that's hard to do in the host," he said.

In vivo delivery essentially allowing gene editing to be done by injection, whether into the body as a whole or "compartmentalized" to specific places such as the brain or the eye is the "holy grail," said Wilson. The challenge, of course, is that it's hard to distribute effectively to the correct areas of the body.

[Also:Eric Dishman wants precision medicine to move from personal to universal]

Taken as a whole, gene editing has come a long way in recent years. Early trials have been promising for diseases such as cancer, sickle cell anemia and eye disease, he said. Soon after, "I expect to see good progress on" cystic fibrosis, Duchenne muscular dystrophy, Huntington's disease and hemophilia.

Then there are areas where "I think we'll be able to see genome editing applied to things that might be a bit more elective, but could have huge impact, since they're so common," said Wilson, such as Alzheimer's, diabetes, osteoporosis, HIV risk and cholesterol.

Still, he cautioned, "we have to wait a few years to see how safe effective this could be."

One complication for therapeutic genome editing is simply the existence of such a dizzying array of genetic diversity.

Wilson notes that it's "kind of incredible" that, of 3 billion bases in the human genome, just 3 million bases ("a fraction of a percent") of are responsible for all human diversity." Moreover, 100 to 200 bases worth of new changes arise per generation.

That means that close attention must be paid to genetic diversity and novel mutations in order to minimize the serious risks of off-target genomic editing.

Still, Wilson is convinced that genome sequencing will "come to the forefront" of primary care in the near future, with these techniques more commonly identifying genetic risk factors.

That comes with big responsibilities. Clinicians will have to design sequences to minimize off-target risks something that demands whole-genome analysis and "an established gene target will have several validated flavors of enzyme, and the appropriate one will be administered based on the patients genetic profile," he said.

Twitter: @MikeMiliardHITN

Link:
Genome editing tools set to bring monumental change to healthcare - Healthcare IT News

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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When to Tell Daughters About a Genetic Breast Cancer Risk New York Times In genetic medicine, minors typically are not tested for BRCA mutations, which increase the risk of adult-onset breast and ovarian cancers. The worry is that children often lack the maturity to fully understand the implications of a genetic risk, and ...

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When to Tell Daughters About a Genetic Breast Cancer Risk - New York Times

05 May 2017

A paper in the May 3 Science Translational Medicine identifies a potential new risk gene for amyotrophic lateral sclerosis (ALS). Mutations in ANXA11, which encodes the phospholipid binding protein annexin A11, turned up in people with both familial and sporadic forms of the disease, report scientists led by Christopher Shaw of Kings College London, Vincenzo Silani of the University of Milan, and John Landers of the University of Massachusetts Medical School, Worcester. Mutant proteins strayed from their normal binding partner, the calcyclin protein, and instead aggregated in the nucleus and cytoplasm. Annexin A11 appears to aid in vesicletransport.

This falls in line with themes we are seeing in all ALS mutations, which are impairments in proteostasis, autophagy, vesicular trafficking, and aggregation, said Matthew Harms, Columbia University, New York. It adds some genetic firepower to our interest in thosepathways.

Mutant annexin A11 inclusions take varied forms, including an ordered series of parallel tubules seen from the side (left) and top. [Courtesy of Science TranslationalMedicine/AAAS.]

This paper lists a handful of co-first authors: Bradley Smith, Simon Topp, and Han-Jou Chen of Kings College, with Claudia Fallini of UMass Worcester, and Hideki Shibata, Nagoya University, Japan. On their hunt for new ALS-associated genes, they analyzed whole exome sequences from 751 patients with familial disease and from 180 with sporadic ALS. They found six rare mutations in annexin A11 in 13 people, including a p.D40G amino acid substitution that segregated with disease in two families. These mutations were absent from 70,000 healthy controls. They clustered at the N-terminal tip of the protein. Previous studies suggest that annexin A11 aids in vesicular transport between the endoplasmic reticulum and Golgi apparatus (Shibata et al., 2015).

Carriers developed ALS at an average age of 67, with a classic ALS phenotype and primarily bulbar-onset disease, meaning they first had trouble speaking and swallowing. One patient who had the p.D40G mutation donated tissue for postmortem analysis. As is typical in ALS, neuron loss, astrogliosis, and phosphorylated TDP-43 inclusions pervaded their spinal cords; the latter also appeared in the medulla, temporal neocortex, andhippocampus.

The surprise came when the researchers stained for annexin A11. We saw the most extraordinary inclusions, Shaw told Alzforum. The skein-like patterns and tubular structures in motor neurons of the spinal cord were a far cry from the disordered blobs of TDP-43 that are typical of ALS neuropathology. They were unlike anything the scientists had ever seen, Shaw said (see image above). Add to that the torpedo-shaped structures in axons of the motor cortex, temporal neocortex, and hippocampus, and Shaw knew they were onto something. This mutant protein is actually aggregating in our patients, he said. That gave me 100 percent confidence that we had found a real gene causingpathology.

To find out how ANXA11 causes disease, the authors expressed several of the disease-associated variants or the wild-type protein in mouse primary motor neurons. Wild-type annexin A11 appeared in the nucleus, and in large, vesicle-like structures throughout the cytoplasm of the axons, soma, and dendrites. By contrast, the mutant proteins largely stayed out of vesicles; they aggregated instead. Their inclusions trapped functional, wild-type annexin A11 protein, implying they robbed the cell of the function of the normalprotein.

The variants also appeared to disrupt Annexin A11 binding to calcylin. Computer modeling predicted that the N-terminus of annexin A11 forms two helices, one in and the other next to the calcyclin binding site. Two of the six mutations appeared to disrupt formation of one of those helices. Immunoprecipitation assays revealed that while wild-type annexin A11 bound calcyclin, those mutants did not. The authors suggested that when annexin A11 cannot bind calcyclin, annexin A11 builds up in the cytoplasm and accumulates. As controls, the authors expressed non-pathogenic annexin A11 variants that appear in the general population; these variants left calcyclin bindingintact.

That last step was important, and provides a model for how these assays should be done in the future, said Harms, adding, It demonstrated that the ALS-specific functional defect was coming from mutations that they found in the patients. In general, researchers should always compare suspected pathogenic mutations to non-pathogenic ones to avoid assays picking up on nonspecific effects. Harms agreed this paper offers clear evidence that the p.D40G mutationwhich segregates with disease and leads to those unusual inclusionsis causative of ALS. More work needs to be done to see if the other five mutations are pathogenic, hesaid.

Shaw said his collaborators are now making transgenic zebrafish and mouse models with the mutations so they can study them in whole organisms.Gwyneth DickeyZakaib

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Potential New ALS Gene Leads to Extraordinary Aggregates - Alzforum

Outside contributors' opinions and analysis of the most important issues in politics, science, and culture.

Labs across our country are a source of American optimism advancing knowledge, technologies, and cures. And yet, as citizens in 500 cities worldwide prepare to march this weekend in support of science, many American scientific practitioners are afraid. They worry that American science as we know it would be hobbled if President Trumps proposed 18 percent cut to the National Institutes of Health, Americas premier medical research funder, becomes reality.

We hope Congress will hear historys call and re-assert American leadership in advancing humanitys scientific knowledge.

Call us nave, but we believe as an immunologist and biochemist attempting to perfect and deploy gene-editing advances to cure disease that Democrats and Republicans alike can be united by a shared drive for scientific exploration and life-saving discoveries.

Science is not the property of any political party or region of the country. In red states and blues states, daughters and sons ask their first scientific questions when they come to us and wonder how the human body grows, how genes are inherited, and how a medicine works. Over the past century, American political leaders have encouraged young people to ask these fundamental questions, invested in their training to become scientists, and given them tools to translate questions into innovation.

The rewards of breakthroughs are felt most acutely when our families experience illness. Many of us know the pain of a loved one discovering a lump that turns out to be cancer or showing signs of neurological decline. In these moments, whatever our politics, we all hope to reach for the most powerful medicines, which continue to result from the relentless pursuit of scientific knowledge.

As we write, biomedical progress is accelerating, changing how we understand and fight disease. One example is CRISPR, a tool that can edit specific sequences in human DNA, which one of us helped invent and the other uses in research to understand and control the human immune system. Targeted at the building blocks of life, CRISPR could induce immune cells to fight disease or neutralize predisposition to one.

The combination of CRISPR and new therapies has raised hopes for a new generation of powerful cancer treatments. Across the US, our colleagues are teaming up and racing to apply similar approaches to dementia, heart disease, and countless other conditions.

A growing number of Americans have heard of CRISPR and its medical potential. Far fewer realize that the transformative applications of CRISPR genome editing would never have occurred without robust funding for basic scientific research. Inquiry into unusual genes in unglamorous bacteria before we even knew the gene-altering power they contained, laid the foundation for CRISPR technology. Now that same technology is driving a revolution in biomedicine and rapidly advancing towards clinical trials.

We certainly have not charted the breadth of microorganisms that will inspire the invention of future drugs, nor fathomed the full complexity of the inner workings of human cells. Thats the work of basic scientific research. The next revolution in biology is currently an idea in a scientists head, or being hashed out in a late night lab conversation among graduate students, or sitting in a grant application to the NIH asking for a chance.

Our research represents just a sliver of the vital projects that more than 300,000 researchers are undertaking in 50 states with NIH support. Unfortunately, the presidents proposed budget threatens that research. Among the deep cuts to science support he seeks is a nearly $6 billion reduction for NIH, representing nearly a fifth of the agencys funding. (For context, thats more than its entire current cancer budget.) The proposal has prompted justifiable concern among scientists and patient advocates. Funding cuts would deter tomorrows scientists from the field, or at least from pursuing careers in the US.

Curtailing the NIH budget, a significant chunk of Americas biomedical research funding, would cripple our capacity to lead on pressing health challenges. The vast majority of NIH funds go to funding scientific research and training, both within the agency and externally. For decades, America has been at the forefront of scientific innovation. Slashing funding would destroy long-term projects and threaten American primacy in medical research. More importantly, underfunding NIH will hamstring efforts to fight disease.

Some might argue that private industry will fill the void, given the economic benefits of scientific breakthroughs,. But the truth, surprising to many, is that while private investment can indeed lead to the discovery of profitable new drugs and therapies, its focus on the bottom line tends to short-change basic as opposed to applied research. In weighing a projects anticipated earnings and costs, businesses seek a probable path to profit.

Transformative science requires a different mold than the one found in industry. CRISPR grew not out of a race to develop disease treatments, but out of basic scientific research into bacteria. The boldest innovations stem from unlikely collaborations or quixotic investigations in other words, exploration driven by discovery rather than profit. Occasionally, these projects do become profitable, but only through a scientists persistent drive to show that an idea, a hope, a hunch, is not so crazy after all. While stockholders may not want a corporation to make bets that are unlikely to have an immediate payoff, as citizens we must demand our government does so.

And thats precisely why the National Institutes of Health exists: It ensures that, though we may not know what the next CRISPR will be, there are bright and dedicated American scientists pursuing many roads of inquiry, even if the path to profit isnt immediately clear.

As Congress considers the presidents budget, we have a simple request: Please give Americas scientists the tools we need to succeed.

Supporting NIH will position American scientists to continue the open-ended explorations at which they excel. Government funding is critical to encourage our scientists to pursue not just the challenges that are relatively easy, or obviously profitable, but the ones that are fiendishly hard yet crucial.

NIH funding is a down payment on discovery, the seed money to fund a critical step toward ending Alzheimers or curing cancer. What could be a bigger win for America than that?

Jennifer Doudna is a professor of chemistry, and molecular and cell biology, at the University of California, Berkeley. Alex Marson is an assistant professor of microbiology and immunology at UC San Francisco.

The Big Idea is Voxs home for smart discussion of the most important issues and ideas in politics, science, and culture typically by outside contributors. If you have an idea for a piece, pitch us at thebigidea@vox.com

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Federal funding for basic research led to the gene-editing revolution. Don't cut it. - Vox

Synpromics Ltd, the leading synthetic promoter and gene control company, is pleased to announce that it has completed a financing round of 5.2M. Participants included existing investors Calculus Capital, the Scottish Investment Bank, the investment arm of Scottish Enterprise and private shareholders.

Synpromics has grown rapidly over the past two years as it expanded its portfolio of international customers. These include leading gene therapy companies and multinational technology corporations, most recently GE Healthcare.

The majority of the new investment will be used to further develop and exemplify Synpromics proprietary PromPT synthetic promoter design platform. PromPT enables the design of unique synthetic promoters which give precise control of gene function in many areas of gene medicine including gene therapy, cell therapy and gene editing. The Company is also preparing to move into a larger, new purpose built, facility.

David Venables, CEO of Synpromics, commented Since our last fundraising round 18 months ago the business has grown rapidly as weve signed more commercial partnerships with companies in the US and Europe. We see an exciting opportunity to fund further rapid expansion of our business, supported by our innovative science and novel capabilities.

Alexandra Lindsay, Investment Director at Calculus Capital, added We have been delighted with the progress which Synpromics has made since we made our first investment some 18 months ago. They have a very strong team and the technology has been clearly validated through partnerships with some of the worlds leading gene medicine companies.

Kerry Sharp, Head of the Scottish Investment Bank, said Having supported Synpromics from an early stage it is great to see the progress that has been achieved to develop and grow the business in the highly dynamic synthetic biology industry. We look forward to continuing to work with the company, both from an investment perspective and through our account management support, to deliver its long term growth ambition.

This article has been republished frommaterialsprovided bySynpromics Ltd. Note: material may have been edited for length and content. For further information, please contact the cited source.

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Synpromics Raise 5.2m in its Latest Fundraising Round ... - Technology Networks

April 21, 2017 by Jane Butler Cancer Histopathologic image of colonic carcinoid. Credit: Wikipedia/CC BY-SA 3.0

Researchers from RCSI (Royal College of Surgeons in Ireland) and the University of Nice, France, have discovered the function of a gene called KCNQ1 that is directly related to the survival of colon cancer patients. The gene produces pore-forming proteins in cell membranes, known as ion channels. The finding is an important breakthrough towards the development of more effective therapies for colon cancer and new diagnostics that will provide a more accurate prognosis for colon cancer patients. The research is published this week in the prestigious journal Proceedings of the National Academy of Sciences (PNAS).

This is the first study of its kind to work out the molecular mechanisms of how the KCNQ1 ion channel gene suppresses the growth and spread of colon cancer tumours.

Worldwide, there are 774,000 deaths from colorectal cancer each year and it is the third leading cause of death from cancer globally. In Ireland, almost 2,500 Irish people are diagnosed with bowel cancer annually and it is the second most common cause of cancer death.

The research team, led by Professor Brian Harvey, Department of Molecular Medicine, RCSI, have identified the molecular mechanisms by which the KCNQ1 gene suppresses the growth and spread of colon cancer cells. The KCNQ1 gene works by producing an ion channel protein which traps a tumour promoting protein called beta-catenin in the cell membranes before it can enter the nucleus of the cell causing more cancer cells to grow.

The study looked at the relationship between the expression of the KCNQ1 gene and patient survival from more than 300 colon cancer patients. Patients who had high expression of the KCNQ1 gene were found to have a longer survival and less chance of relapse.

Commenting on the significance of the discovery Professor Harvey said: "This study has demonstrated the ability of an ion channel gene to block the growth of colon cancer cells. This is an exciting discovery as it opens up the possibility of a new kind of therapy that will target the KCNQ1 gene with drugs and also as a biomarker to improve diagnostics of colon cancer onset and development in patients. This information will help clinicians to identify the most effective treatment for the individual patient."

"In the future, when we understand more about the KCNQ1 gene through further research, it will open up the possibility of developing new drug treatments that will be able harness the suppressive properties of the gene to target the colon specifically, without exposing other tissues in the body to unnecessary chemotherapy. The development of more targeted treatments for colon cancer is vital to improve the prognosis and quality of life for colon cancer patients."

Explore further: Among colon cancer patients, smokers have worse outcomes than non-smokers

More information: Raphael Rapetti-Mauss et al. Bidirectional KCNQ1:-catenin interaction drives colorectal cancer cell differentiation, Proceedings of the National Academy of Sciences (2017). DOI: 10.1073/pnas.1702913114

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Many types of cancer are caused by gene mutations in the signalling pathways that control cell growth, such as the hedgehog signalling pathway. A new study from the Karolinska Institutet, published in the journal Nature Communications, ...

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Researchers from RCSI (Royal College of Surgeons in Ireland) and the University of Nice, France, have discovered the function of a gene called KCNQ1 that is directly related to the survival of colon cancer patients. The ...

The activity of cancer drugs changes depending on the types of microbes living in the gut, according to a UCL-led study into how nematode worms and their microbes process drugs and nutrients.

A new laboratory technique developed by researchers at Baylor College of Medicine and other institutions can rapidly test the effectiveness of treatments for life-threatening breast cancer metastases in bone. The study appears ...

A drug created from a malaria protein stopped tumour growth of chemotherapy-resistant bladder cancer, offering hope for cancer patients not responding to standard treatments.

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Scientists discover gene that blocks spread of colon cancer - Medical Xpress

Alain Mrieux, founder of BioMrieux.

Latest update: April 1, 2020, at 4:47 pm ET.

Businesses around the world are shifting into overdrive to help battle the coronavirus, providing everything from rubber gloves and ventilators to diagnostic tools and, hopefully soon, vaccines. While the pandemic continues to wreak havoc, large corporations and small businesses are developing creative solutions to halt the spread of the virus.

Just as automakers famously shifted to make tanks and planes during World War II, todays global giants LVMH, Ford and GE to name a few are retooling their production lines to help make everything from hand sanitizers to respirators. On the medical front, there are more than three dozen COVID-19 vaccines under development, a smart move considering that two out of every three vaccines for infectious diseases fail, according to a study by the Massachusetts Institute of Technology.

Forbes will continue to update this list of private companies and how they are stepping up to fight the COVID-19 pandemic:

Testing:

Abbott Laboratories: Abbott Park, Illinois healthcare firm obtained emergency FDA authorization for its 5-minute coronavirus testing kit on March 27, with plans to start manufacturing 50,000 kits a day.

Alphabet: Through its healthcare arm Verily, Googles parent company launched a website where users can find nearby testing sites in four California counties.

Jeff Bezos.

Amazon: Jeff Bezos retail behemoth invested $20 million in the Amazon Web Services Diagnostic Initiative, which aims to speed up delivery of COVID-19 tests to the market.

BioMrieux: French biotech company, founded by billionaire Alain Mrieux,received emergency FDA approval for its subsidiarys new testing kit, which cuts testing times for the virus down to 45 minutes.

Carbon: California-based 3D printing unicorn backed by Russian tech investor Yuri Milner will soon be distributing testing swabs and face shields to hospitals in the Bay Area.

Cepheid: Sunnyvale, California molecular diagnostics company gained emergency FDA authorization for its new 45-minute COVID-19 testing kit.

Copan Diagnostics: Family-owned company located at the heart of Italys hard-hit Lombardy region makes diagnostic swabs for testing, airlifting 500,000 swabs to the U.S.

DiaSorin: Italian biotech company owned by billionaire Gustavo Denegri obtained emergency authorization from the FDA for its new 60-minute testing kit for COVID-19.

Mammoth Biosciences: South San Francisco-based biotech startup, founded by three 30 Under 30 alums, prototyped a rapid test by using the gene-editing tool Crispr to detect the disease.

Mesa Biotech: San Diego biotech business obtained FDA approval for its new 30-minute testing kit for COVID-19.

Puritan Medical Products: Maine-based diagnostic maker, one of the worlds largest makers of diagnostic swabs along with Italys Copan Diagnostics, is reportedly increasing production to make one million COVID-19 testing swabs a week.

Treatments:

AbbVie: North Chicago-based, publicly traded pharma firm is collaborating with authorities in the EU, the U.S. and China on experimental use of its HIV drug lopinavir/ritonavir to treat COVID-19.

AIM Immunotech: Florida-based pharmaceutical company announced on March 9 it would begin experimental testing of its chronic fatigue syndrome drug rintatolimod as a treatment for COVID-19 in Japan, at the National Institute of Infectious Diseases and the University of Tokyo.

Algernon Pharmaceuticals: Vancouver-based pharmaceutical firm is requesting FDA approval to begin trials of its chronic cough medication ifenprodil as a treatment for COVID-19.

AlloVir: Houston-based cell and gene therapy company is collaborating with Baylor College of Medicine to discover and develop T-cell therapies to fight COVID-19.

Apeiron Biologics: Vienna-based biotech firm started small-scale trials of its immunotherapy treatment on COVID-19 in China in February.

Ascletis: Hangzhou, China pharmaceutical company announced results of clinical trials of its antiviral drug danoprevir on COVID-19 patients in China; the small-scale study found that danoprevir combined with ritonavir is safe and well tolerated in all patients.

Bioxytran: Boston-based biotech outfit is developing a viral inhibitor to treat COVID-19.

Celltrion: South Korean healthcare firm is developing an antiviral treatment for COVID-19 as well as rapid self-testing kits that would provide results within fifteen to twenty minutes.

Cocrystal Pharma: Bothell, Washington pharma outfit is developing antivirals to treat COVID-19 using patents it recently acquired from the Kansas State University Research Foundation.

CytoDyn: Vancouver, Washington biotech firm announced preliminary results from three days of testing its antiviral drug leronlimab on COVID-19 patients in New York; the company stated in a press release that test results from the first four patients suggests immunological benefit within three days following treatment with leronlimab.

Eli Lilly: Indianapolis pharma company is partnering with Vancouver-based biotech outfit AbCellera to develop antibody-based treatments for COVID-19.

Emergent BioSolutions: Maryland drugmaker is developing treatments derived from the antibodies found in the blood of people who tested positive for the disease.

EUSA Pharma: British pharmaceutical firm initiated trials of its siltuximab antibody treatment on COVID-19 patients at the Papa Giovanni XXIII hospital in Bergamo, Italy; the company released initial data on April 1 showing that one third of patients experienced clinical improvement with reduced need for oxygen support and a further 43% saw their disease stabilise.

Fujifilm Toyama Chemical: Tokyo-based conglomerates flu drug favipiravir has shown promising results in early clinical trials on COVID-19 patients in China, and the company is investing $83 million in its biological manufacturing capabilities.

Gilead: The Californian biotech giant initiated clinical trials in March for its antiviral drug remdesivir on patients in the U.S.

Harbour BioMed: Cambridge, Massachusetts biomedical firm announced a collaboration with New Yorks Mount Sinai Health System to develop new human antibodies to treat COVID-19.

I-Mab Biopharma: Shanghai-based biopharma outfit announced it would begin clinical trials of its TJM2 antibody treatment on COVID-19 patients in the United States, with plans to expand to other countries affected by the pandemic.

ImmunoPrecise: Canadian life sciences company is teaming up with New York-based AI startup EVQLV Inc on researching antibody-based therapies and a vaccine for COVID-19.

Innovation Pharmaceuticals: Wakefield, Massachusetts biopharma firm is researching the use of its drug brilacidin part of a category of investigational new drugs called defensin mimetics, which could have antimicrobial effects as both a treatment and a vaccine for COVID-19, in separate efforts with a major U.S. university and with the Department of Health and Human Services.

ISR Immune System Regulation: Swedish immunotherapy firms subsidiary, ISR HBV, is conducting toxicological studies to determine whether its Immunolid ISR50 treatment could be used against COVID-19.

Kamada: Israeli pharmaceutical company is working on an antibody-based treatment for COVID-19 using the blood plasma of patients who recovered from the disease.

Mateon Therapeutics: Californian biopharma firm is testing a number of antiviral drugs as potential treatments for COVID-19 and is preparing to submit an application to the FDA in order to begin clinical trials on patients.

Merck KGaA: Darmstadt, Germany-based pharma multinational donated a supply of its multiple sclerosis drug interferon beta-1a to the French National Institute of Health and Medical Research in Paris for clinical trials on COVID-19 patients. The companys North American life sciences arm, MilliporeSigma, is supplying several vaccine efforts with reagents and other essential raw products for vaccine development.

Mesoblast: Australian medical firm is working with authorities in the U.S., Australia, China and Europe to evaluate the use of its remestemcel-L drug to treat COVID-19.

Mylan: Pennsylvania-based pharmaceutical firm restarted production of hydroxychloroquine, a drug used to fight lupus, malaria and arthritis, at its West Virginia factory; the drug is being tested as a treatment for COVID-19 in human trials in New York.

Pluristem Therapeutics: Haifa, Israel-based medical company is developing a cell-based therapy to treat COVID-19, announcing on March 30 it had dosed three Israeli patients under a compassionate use program, with plans to enroll more.

Leonard Schleifer.

Regeneron Pharmaceuticals: Westchester, New York biotech outfit, run by billionaires Leonard Schleifer and George Yancopoulos, is conducting clinical trials of its rheumatoid arthritis drug sarilumab, developed with French firm Sanofi, on patients in New York.

Roche: Swiss pharma titan, part-owned by billionaire Maja Oeri, is testing its arthritis drug tocilizumab to treat patients in China and received FDA approval to begin U.S. trials.

Roivant Sciences: Swiss pharma company is working with U.S. authorities to begin trials of its antibody treatment, gimsilumab, on COVID-19 patients.

Takeda: Japanese medical firm is working on hyperimmune therapy using blood plasma from previously infected patients.

Vir Biotechnology: The San Francisco-based firm is collaborating with Biogen and Chinese medical firm WuXi Biologics to manufacture antibodies that could treat the virus.

Vaccines:

AJ Vaccines: Danish vaccine developer is working on a COVID-19 vaccine that could hit the market in 2021.

Altimmune: The company is developing a novel intranasal vaccine for the coronavirus, making it one of three firms based in Gaithersburg, Maryland along with Emergent Biosolutions and Novavax thats working on treatments and vaccines for COVID-19.

Arcturus Therapeutics: San Diego-based vaccine maker is developing a COVID-19 vaccine with researchers at the Duke-National University of Singapore medical school in Singapore.

Biocad: Russian drug developer is researching a COVID-19 vaccine, with animal trials scheduled for late April.

Thomas and Andreas Struengmann.

BioNTech: German biotech firm backed by billionaire twins Thomas and Andreas Struengmann is working to develop a coronavirus vaccine in partnership with Pfizer and Fosun Pharma, chaired by billionaire Guo Guangchang.

CanSino Biologics: Tianjin, China-based pharma company isstarting clinical trials for its COVID-19 vaccine, using the vaccine technology deployed to develop the Ebola vaccine.

Codagenix: Melville, New York biotech firm is teaming up with the Serum Institute of India to develop a live-attenuated COVID-19 vaccine, which uses a live but weakened form of the virus.

Dietmar Hopp.

CureVac: German firm, funded by billionaire Dietmar Hopp and the Bill and Melinda Gates Foundation, received $87 million from the European Commission to scale up development of its coronavirus vaccine.

Dyadic: Jupiter, Florida company is collaborating with the Israel Institute for Biological Research on both treatment and a vaccine against COVID-19, using the firms gene expression platform.

Dynavax: Emeryville, California vaccine maker is working with the Coalition for Epidemic Preparedness Innovations (CEPI) and the University of Queensland to develop a COVID-19 vaccine.

EpiVax: Providence-based immunology firm is working with the University of Georgia and Miramar, Florida biotech outfit Generex on separate COVID-19 vaccine efforts.

ExpreS2ion: Danish biotech company received a grant of nearly $1 million from the European Union to develop a vaccine for COVID-19.

GeoVax: Atlanta-based medical company is collaborating with Wuhan-based BioVax to jointly produce a COVID-19 vaccine.

GlaxoSmithKline: British pharma titan is partnering with CEPI and Chengdu, China-based Clover Pharmaceuticals to use its pandemic vaccine adjuvant platform which boosts the immune response in patients receiving a shot to speed up development of COVID-19 vaccines.

Greffex: Houston-based genetic engineering firm is preparing to begin animal trials for its COVID-19 vaccine.

Heat Biologics: North Carolina biopharma company is developing a COVID-19 vaccine with the University of Miami.

iBio: Newark, Delaware biotech upstart is collaborating with Beijing-based CC-Pharming on the rapid development of a COVID-19 vaccine.

Inovio: Plymouth Meeting, Pennsylvania biotech business received $11.9 million in funding from the Department of Defense to rapidly produce a DNA vaccine for COVID-19 with drugmaker Ology Bioservices.

Johnson & Johnson: The companys pharma unit, Janssen, will start manufacturing its vaccine developed with the Department of Health and Human Services this month, with human trials set to begin by September and a public rollout hoped for early 2021. The company and the federal government are investing more than $1 billion in the vaccine effort.

Medicago: Quebec City-based biotech company received more than $7 million from the Canadian and Quebec governments to fund development of its COVID-19 vaccine.

Moderna: Massachusetts biotech company was the first tobegin human trials of its vaccine on March 16 in Seattle and could deploy it to health workers for emergency use by the fall.

Novavax: Maryland-based vaccine maker received $4 million in funding from CEPI to accelerate development of its vaccine candidates, with clinical trials expected in the late spring.

Sanofi: French medical firm is working with the federal government and Massachusetts-based Translate Bio to expedite its coronavirus vaccine, using technology previously used to develop one for SARS.

Sorrento Therapeutics: San Diego-based biotech firm is teaming up with Cambridge, MA gene therapy company SmartPharm Therapeutics to develop a gene-encoded COVID-19 vaccine; its also working with Chinese drugmaker Mabpharm on a fusion protein treatment for the disease.

Takis Biotech: Italian startup with just 25 employees is developing a vaccine with Stony Brook-based Applied DNA Sciences, with plans to begin human trials before the end of the year.

Themis Bioscience: Austrian biotech firm is part of a group, with the Institut Pasteur and the University of Pittsburgh, which received $4.9 million in initial funding from CEPI to build a COVID-19 vaccine modeled on the vaccine for measles.

Tonix Pharmaceuticals: New York-based pharma outfit is researching a potential COVID-19 vaccine based on the virus that causes horsepox.

Vaxart: San Francisco vaccine manufacturer Vaxart is working with Emergent Biosolutions to develop and manufacture an oral vaccine that can be taken as a tablet.

Vaxil: Israeli biotech startup began preclinical trials for its COVID-19 vaccine candidate.

Zydus Cadila: Indian pharma company announced it would fast-track development of a COVID-19 vaccine in February.

Protective Equipment And Sanitizer:

Anheuser-Busch InBev: The worlds largest beer company is making more than one million bottles of hand sanitizer from surplus alcohol at its breweries around the world.

Giorgio Armani.

Armani: Billionaire Giorgio Armanis luxury fashion brand converted all production at its Italian factories to manufacture single-use medical overalls on March 26.

Bacardi: The Bermuda-based spirits giant converted production at nine production facilities in Mexico, France, England, Italy, Scotland, Puerto Rico and the continental U.S. to make hand sanitizer.

BrewDog: Independent beermaker is making hand sanitizer at its distillery in Scotland.

Bulgari: The Italian luxury jeweler is manufacturing hand sanitizer with its fragrances partner, ICR, with plans to make hundreds of thousands of bottles by May.

Sandro Veronesi.

Calzedonia Group: Italian retail clothing group, owned by billionaire Sandro Veronesi, converted production at several plants in Italy and Croatia to manufacture masks and medical gowns, with initial production of 10,000 masks a day.

Cantabria Labs: Spanish health products and cosmetics firm converted production at one of its factories to make hand sanitizer.

Consomed: Tunisian mask and medical equipment maker put all of its workers, more than 70% of which are reportedly women, on quarantine inside the companys Kairouan factory to maximize production of protective gear.

Decathlon: Sporting goods empire founded by French billionaire Michel Leclercq partnered with Isinnova, a small engineering and design firm based in Italy, to convert snorkeling masks into respirators.

Diageo: The maker of Johnnie Walker whisky and Smirnoff vodka donated two million liters of ethyl alcohol, a byproduct of the distillation process, to hand sanitizer manufacturers.

Fanatics: Billionaire Michael Rubins online sportswear retailer converted its baseball jersey factory in Pennsylvania to make masks and gowns for medical workers.

Fiat Chrysler Automobiles: The multinational automaker announced on March 23 it would begin installing capacity to produce masks, which will be initially distributed in the U.S., Canada and Mexico.

Fippi: Italian diapers producer worked with the Lombardy region and the Polytechnic University of Milan to convert its factory to make up to 900,000 masks a day, which will go to frontline health workers facing a devastating outbreak in the region.

Original post:
Coronavirus Business Tracker: How The Private Sector Is Fighting The COVID-19 Pandemic - Forbes

The Broad Foundation brings together stem cell scientists, engineers and physicians at USC and beyond

Developing new stem cell therapies requires more than a solo biologist having a eureka moment alone in the lab. Real progress relies on collaborations between biologists, engineers and physicians. Thats why The Eli and Edythe Broad Foundation has continued its support of two strategic initiatives: innovation awards bringing together teams of engineers and scientists from USC and Caltech, and clinical research fellowships for physician-scientists.

Engineering new approaches: The Broad Innovation Awards

For the fifth consecutive year, the Broad Innovation Awards are providing critical funding to USC-affiliated faculty members pursuing multi-investigator research collaborations related to stem cells. For the first year, these collaborations are also drawing on the expertise of biomedical engineers from Caltech. Each award provides $200,000 of funding for a one-year project.

Were very excited to be joining our colleagues at USC in pioneering new approaches to advancing stem cell research, said Stephen L. Mayo, chair of the Division of Biology and Biological Engineering at Caltech. Were thankful to The Broad Foundation for supporting cross-town collaborations between scientists with different expertise but common goals.

With support from a Broad Innovation Award, Andy McMahon, the director of the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, is collaborating with Caltech biomedical engineer Long Cai to leverage a new technology for understanding chronic kidney disease. The technology, called seqFISH, provides information about genetic activity taking place in intact tissueenabling the study of the interactions between cells in their native environments.

Dr. Cais seqFISH technology will provide an unprecedented insight into the cellular interplay underlying chronic kidney disease caused by a maladaptive response to acute kidney injury, said McMahon, who is the W.M. Keck Provost and University Professor of Stem Cell Biology and Regenerative Medicine, and Biological Sciences, as well as the chair of the Department of Stem Cell Biology and Regenerative Medicine at USC. We aim to better understand this maladaptive responsewhich is more common in malesin order to find new targets for preventing the progression to chronic kidney disease.

A second Broad Innovation Award brings together USC Stem Cell scientist Rong Lu and Caltech synthetic biologist Michael Elowitz. Their team will study the spatial organization of blood-forming stem and progenitor cells, also called hematopoietic stem and progenitor cells (HSPCs), which reside in the bone marrow. By pinpointing the locations of specific HSPCs, the scientists may find clues to explain why certain HSPCs are so dominantreplenishing the majority of the bodys blood and immune cells after a disruption such as a bone marrow transplantation.

Spatial advantages may be the primary drivers of what we refer to as the clonal dominance of certain HSPCs, said Lu, a Richard N. Merkin Assistant Professor of Stem Cell Biology and Regenerative Medicine, Biomedical Engineering, Medicine, and Gerontology at USC. Understanding the spatial competition between HSPCs could help improve bone marrow transplantation and provide new insights into aging and the development of diseases such as leukemiawhich are associated with clonal dominance.

Elowitz added: Thanks to the Broad Innovation Award and this exciting collaboration with Rong Lu, we will be able to bring a new, synthetic biology approach to record cell histories and read them out in individual cells within their native spatial context, providing new insights into fundamental questions in blood stem cell development.

A third Broad Innovation Award brings together three collaborators at USC: Michael Bonaguidi, an assistant professor of stem cell biology and regenerative medicine, biomedical engineering, and gerontology; Robert Chow, a professor of physiology and neuroscience, and biomedical engineering; and Jonathan Russin, an assistant professor of neurological surgery and associate surgical director for the USC Neurorestoration Center. Their project focuses on finding new approaches to treating epilepsy by studying neural cells called astroglia. These cells perform a variety of key functions that support the health of neurons in the brain, and they may also play a role in modulating epileptic seizures.

Although adults dont tend to generate many new brain cells, humans do produce a limited number of new astroglia, said Bonaguidi. We will examine these newborn astroglia at the single-cell level to better understand their role in epileptic patients, and to lay the groundwork for identifying new treatments.

The doctors are in: The Broad Clinical Research Fellowships

The Broad Clinical Research Fellowships are also entering their fifth consecutive year. These fellowships support stem cell research by physician-scientists and residents who intend to practice medicine in California.

These fellowships provide a very special opportunity for our medical residents to engage deeply in laboratory research, as a complement to their extensive training in patient care, said Laura Mosqueda, Dean of the Keck School of Medicine of USC. This valuable research experience gives them a much more complete perspective on how to meet the challenges of finding the best possible treatments for their patients.

A USC resident physician in general surgery, Kemp Anderson will spend his fellowship studying necrotizing enterocolitis, a very serious intestinal infection that affects nearly 10 percent of premature infants. Specifically, he will explore how a molecule involved in cellular communication, called farnesoid X receptor, or FXR, might contribute to this disease.

If FXR plays a role in compromising intestinal barrier function in these premature infants, then altering the activity of FXR could potentially yield treatment modalities for necrotizing enterocolitis, avoiding the morbidity and mortality associated with surgical intervention, said Anderson, who is performing the research under the mentorship of Christopher Gayer and Mark Frey at Childrens Hospital Los Angeles (CHLA). Im deeply appreciative of the benefactors and the selection committee for awarding me the Broad Clinical Fellowship, as it is allowing me devoted time to focus on this important project, and to become a more well-rounded physician through this academic pursuit.

Brittany Rocque, a resident physician in general surgery, will use her fellowship to seek better ways to predict, detect and diagnose immune rejection in patients who have undergone liver transplantation. Nearly 60 percent of pediatric patients and at least 15 percent of adult patients reject their liver transplants, and this can currently only be confirmed through an invasive surgical biopsy. Rocque is utilizing the technology Imaging Mass Cytometry to identify and analyze the types of immune cells involved in rejection.

My project has the potential to provide a noninvasive option to assess rejection in transplanted patients, and to expand our understanding of immune rejection, said Rocque, who is being co-mentored by Juliet Emamaullee and Shahab Asgharzadeh at CHLA. Im greatly looking forward to applying my passion for transplantation surgery in the context of basic science, and enhancing my appreciation for the nuances of research, thanks to the Broad Clinical Research Fellowship.

A hematology-oncology fellow who will be transitioning to a junior faculty position at USC next year, Caitlin ONeill will study a condition known as clonal hematopoiesis or CH, a phenomenon common in the aging population. CH involves genetic mutations that cause the expansion of a particular population of blood cells without leukemia or related malignancies. CH increases risks for certain health conditions including heart disease.

During her Broad Clinical Research Fellowship, ONeill will look at one mutation seen in patients with CH: a mutation to the gene called Tet methylcytosine dioxygenase 2, or TET2. ONeill will explore if this mutation promotes blood clots, inflammation and heart disease.

The goal is to inform therapies to prevent heart disease and leukemic progression in aging patients with CH, said ONeill, who is working with co-mentors Casey OConnell and Rong Lu at USC. Im very happy to be working on this project, with support from the Broad Clinical Research Fellowship, during my transition to becoming a faculty member at USC.

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Broad Foundation brings together stem cell scientists, engineers and physicians at University of Southern - Mirage News

Researchers from the University of British Columbia (UBC) and the Central South University (CSU) in China have for the first time identified a gene that increases the risk of Alzheimers disease.

Dr. Weihong Song

In the study, published recently in the journal JCI Insight, the researchers found two mutations in the gene endothelin-converting enzyme 2 (ECE2) which impaired its ability to break down amyloid beta protein. These mutations were present significantly more often in people with Alzheimers than in controlssuggesting that the genetic variants in ECE2 could be causing, or at least contributing to, Alzheimers symptoms.

Since amyloid beta protein is unique to Alzheimers disease, the majority of drug development was targeted here, says Dr. Weihong Song, who is the Canada Research Chair in Alzheimers disease, professor in the faculty of medicines department of psychiatry, Jack Brown and Family Professor, and director of UBCs Townsend Family Laboratories. If we can prevent amyloid beta protein build up or at least find a way to get rid of some of it, we could prevent and treat the disease.

Dr. Songs laboratory at UBC collaborated with Dr. Lu Shens team at Xiangya Hospital at CSU for the study. The studys lead author is Dr. Xinxin Lio who completed a joint PhD at UBC and CSU.

The scientists looked at 741 people with late-onset Alzheimers and compared them to controls. Unlike early-onset which affects people as young as 30, late-onset Alzheimers is the most common form of this disease, generally affecting individuals after the age of 65.

Dr. Xinxin Lio

Dr. Songs lab focuses their efforts on looking at the role amyloid beta protein plays in Alzheimers. Its well established that increased production (or reduced degradation) of amyloid beta protein results in the formation of neuritic plaques in the brain, which is a hallmark of Alzheimers disease neuropathology.

The team injected the mutated forms of the ECE2 gene into mice. They found mice with the mutation had increased levels of amyloid beta protein and plaque formation, and also exhibited some signs of Alzheimers such as memory loss. When they expressed the wildtype form of the gene in the mice (i.e. the non-mutated form), amyloid beta protein levels decreased and the mice recovered some of their learning and memory deficits.

These findings mean that ECE2 is a risk gene for people to develop Alzheimers later in life, says Dr. Song. Moving forward, we can try to target this gene and increase its expression as a way to treat Alzheimers.

Moving forward, we can try to target this gene and increase its expression as a way to treat Alzheimers.Dr. Weihong Song, Canada Research Chair in Alzheimers Disease

The researchers are now screening further for genetic mutations in a larger dataset as a way to validate these findings and to search for other variants in the ECE2 gene that could be contributing to Alzheimers symptoms.

Read more here:
Scientists discover gene that increases risk of Alzheimer's disease - UBC Faculty of Medicine

But this virus infected only bats, not humans. The researchers named it RaTG13 and then promptly forgot about it.

At the same time, other research groups noted these bat coronaviruses regularly seemed to jump from animals to humans, and posed a significant pandemic threat.

In 2013, in the province of Yunnan, about 2000 kilometres west of Wuhan, a horseshoe bat was caught in a trap.

And then ... the world moved on. We had bigger things to worry about than Chinese bat coronaviruses.

It is now clear we made a mistake.

The virus that is causing the first pandemic in 100 years it will likely kill millions before this is all over, and mean that life may never be the same again shares 96 per cent of its genetic code with RaTG13.

We have been monitoring these coronaviruses. Theyve been jumping species boundaries, says Professor Edward Holmes. We knew this was going to happen.

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RaTG13, or another very similar bat virus, has managed to pick up two tiny genetic tweaks that turned it from a bat disease into a virus perfectly adapted to make humans sick.

Then it had the unbelievable misfortune to emerge in exactly the wrong place at exactly the wrong time.

Its got this beautifully adapted set of mutations, says Holmes. In his published work, he calls it a perfect epidemiological storm.

A crown of spikes

Holmes, a researcher based at the University of Sydney, is among the worlds leading experts on the genetics and evolution of SARS-CoV-2, the virus that causes COVID-19.

He was on the team that first sequenced the genes of the virus from one of the first patients in Wuhan. The

ir article on the possible origins of the virus is now the most-publicised Nature study in the history of that venerable journal.

He has visited the Huanan seafood and wildlife market where the Wuhan outbreak began. He has visited caves in China, searching for bats so he can survey the viruses they contain.

CoV-2 is a coronavirus, just like SARS and MERS. These viruses get their name from how they look under a microscope: a tiny bubble of fat surrounded by a crown of spikes which are used to penetrate cells.

An electron-microscope image of the COVID-19 virus, isolated from the first Australian coronavirus case.Note the bubble in the centre surrounded by spikes.Credit:CSIRO

Animals have many different types of viruses. But coronaviruses seem uniquely able to jump from animal to human. They just have this ability, says Holmes. We dont know why.

The emergence of SARS in 2003, killing 774 people, should have been a warning: these viruses jumped, and when they did lots of humans died.

We should have started building broad-based vaccines and antivirals that target all coronaviruses.

Instead, SARS was defeated largely by enhanced hygiene measures. Several drugs and vaccine candidates for SARS were developed and then largely abandoned.

CSIRO comparative immunologist Michelle Baker. Credit:CSIRO

We have been completely complacent, says Dr Michelle Baker, the CSIROs leading bat virus researcher.

It gets really difficult to get funding when there is not an outbreak. People feel a sense of security. They dont feel its relevant anymore.

Why this virus?

The virus pulled from bats in 2013 could not infect humans. SARS-CoV-2 can. Why?

It appears that two tiny tweaks to the virus genetic code have made a huge difference.

CoV-2 wants to do two things: bind to a human cell and then get inside it. The virus binds to a cellular receptor think of them as little antennae that stick off the side of human cells called ACE2.

ACE2 receptors are designed to listen for signals that change our blood pressure. Fine adjustments to blood pressure are really important in our lungs, so our lung cells are covered in ACE2 receptors.

SARS was able to bind to ACE2. But small genetic changes mean CoV-2 binds almost perfectly, at least 10 times more tightly than SARS. Its beautifully adapted to do that, says Holmes.

But thats not enough. Once CoV-2 is stuck on a cell, it needs to get in. Thats where the second tweak comes in.

CoV-2 is covered in spikes. They act like tiny harpoons. The virus needs to stick to the cell and then fire a harpoon. The harpoon pulls the surface of the cell and the virus together, allowing them to fuse. Thats how the virus gets inside.

A 3D map of the virus's spike protein, which it uses to 'harpoon' human cells. Credit:Science

But you dont want the harpoon firing off randomly, says Professor Stephen Turner, head of microbiology at Monash University. You only want it to fire when its ready to infect the cell. If its going off too early or too late, the virus would not be able to infect us.

To trigger the harpoon at just the right time, viruses rely on human enzymes, little proteins in our blood. Some enzymes trigger the harpoon too early, others trigger it too late. Among the best enzyme triggers the one that fires the harpoon at exactly the right time is an enzyme called furin. Our bodies produce heaps of furin.

Basically, you can work out if a virus is going to be highly pathogenic or not if it is activated by furin, says Turner.

Bird flu is triggered by furin. We got lucky, though, because it wasnt very good at sticking to our cells. CoV-2 is great at sticking to our cells. And its triggered by furin, among the best triggers a virus can have.

The combination is what makes it so infectious, says Turner.

The birth of a virus

How does a bat virus pick up these tricks?

Bats live essentially symbiotic relationships with their viruses. The viruses dont want to kill the bats, because then theyd have nowhere to live.

When scientists test bats, they find lots of different viruses but at very low levels. Often its really difficult to find a virus in a bat, says Baker.

And these viruses are, in evolutionary terms, very stable. They dont change much. It is unlikely RaTG13 turned into SARS-CoV-2 within a bat, Baker says.

But things change when a bat virus jumps to another animal.

Heres one potential scenario.

RaTG13 has the ability to bind to ACE2. But it did not have the furin tweak which makes the virus so infectious.

It is possible RaTG13, or a similar virus, jumped from a bat into a pangolin a small, scaly anteater common to Asia and highly valued in traditional Chinese medicine.

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Pangolins also have the ACE2 receptor, as do other animals like ferrets.

Either of these animals, or many others, could have been the middle animal between bats and humans.But in this particular origin story, the pangolin was infected at the same time with another bat coronavirus. This virus possessed the furin tweak.

When two viruses infect the same host, they can recombine swapping their genes.

This may have created a virus that could both stick to ACE2 and use furin to quickly get inside human cells. That could have been how SARS-CoV-2 was born. Then it jumped to humans in the close confines of the Wuhan wet market.

An image of a bamboo rat caged on top of a deer allegedly sold at the Wuhan seafood market has circulated online. Credit:Weibo

And Wuhan is the perfect spot for a virus to jump. The city is home to millions. It is an international travel hub. The virus appeared just before the biggest travel period of the year: the Chinese Spring festival.

That story is neat. But it is no certainty. The first documented COVID-19 patient had no exposure to the wet market.

It is possible, although unlikely, this virus was circulating in humans for years before breaking out into a pandemic.

It could have spread silently, causing only mild cold-like symptoms, before suddenly acquiring a key mutation or two that made it much more contagious - and much more dangerous. You cannot rule that out, says Holmes.

Whether that market was involved or not, its really unclear at the moment. We may never answer that question.

We need to change the way we live

Holmes is shocked at how fast SARS-CoV-2 has spread. But hes not shocked it was a bat coronavirus that caused a worldwide pandemic.

Environmental damage, illegal wildlife trading (pangolins in particular are heavily traded), wet markets and the climate crisis are all combining to push humans and bats closer than ever before.

It is blindingly obvious that we as humans have to change the way we interact with the animal world. There is no doubt about that, he says. And its not the animals' fault.

Bats have been carrying these viruses for millennia. Its not them thats changed, its us the way we interact with them.

The whole world is now set up for a pandemic - we live in megacities, there is transport. Its an accident waiting to happen, and it happened.

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When the world eventually starts to recover from the pandemic, steps need to be put in place to widen the gap between bats and humans so this cannot happen again, Holmes says.

We have to cut our exposure. Those markets have to go, he says. The illegal trade in wildlife has to end. We have to cut our exposure. Thats very very clear.

Liam is The Age and Sydney Morning Herald's science reporter

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The perfect virus: two gene tweaks that turned COVID-19 into a killer - Sydney Morning Herald

Spurred by promising clinical results in an important trial, each of the three major CRISPR stocks had a great performance in the second half of 2019. Unfortunately, they didn't keep the momentum going in the first month of 2020.

Shares of Intellia Therapeutics (NASDAQ:NTLA) fell 18.8% in January, according to data provided by S&P Global Market Intelligence. That was followed by a 14.7% loss for shares of CRISPR Therapeutics (NASDAQ:CRSP) and a 10.7% tumble for shares of Editas Medicine (NASDAQ:EDIT).

While each has recovered some ground in the first week of February, this trio of pharma stocks is no stranger to volatility. Investors should probably expect that to continue as clinical programs advance in 2020.

Image source: Getty Images.

In November, CRISPR Therapeutics reported data for the first two individuals in the trial, one with sickle cell disease (SCD) and one with transfusion-dependent beta thalassemia (TDT), treated with its lead drug candidate CTX001. Both enjoyed significant benefits in their standard of living, which investors interpreted as a sign that CRISPR gene editing might actually live up to the hype.

That fueled annual gains of 113% for CRISPR Therapeutics last year. While Editas Medicine and Intellia Therapeutics gained only 30% and 7%, respectively, each had been sitting at a year-to-date loss in October.

What relevance does that have for the tumbles taken in January? First, it's not unusual for stocks to regress to the mean. Stocks that are red hot eventually cool off, while those that tumble without good reason eventually recover some ground.

Second, and the more important consideration for investors, is that the early stage results for CTX001 mean relatively little for the industry's pipeline of CRISPR-based gene editing drug candidates.

Consider that CTX001 is an ex vivo tool. Researchers harvest bone marrow from patients, extract specific types of stem cells, and engineer those with CTX001. The engineered stem cells are then grown in the lab before being reinjected into the patient.

Many other CRISPR-based drug candidates are designed as in vivo tools. That means the gene editing payloads are designed to engineer a patient's DNA while inside the body. An in vivo approach is inherently more complex and will be more difficult to control compared to an ex vivo approach.

Put another way, investors cannot take the promising, early stage results from CTX001 and extrapolate it broadly across all first-generation CRISPR tools. Wall Street certainly isn't, if the correlation between technical approach and stock performance is any guide.

Consider that the two most advanced drug candidates from CRISPR Therapeutics rely on ex vivo engineering. By contrast, the lead drug candidate from Editas Medicine relies on in vivo methods.

The lead pipeline asset from Intellia Therapeutics is also an in vivo tool, though unlike the lead assets from its peers, it has yet to advance to clinical trials.

Investors should expect 2020 to be a busy year for these CRISPR stocks. CRISPR Therapeutics will have more clinical data from CTX001 and the first set of data for its lead oncology asset CTX110.

Similarly, Editas Medicine should have results for EDIT101 and progress additional assets, while Intellia Therapeutics is preparing to finally enter the clinic with NTLA-2001 in the second half of the year.

Investors cannot know if the next batch of results will be as rosy as the initial data for CTX001, but they can probably expect another year of volatile stock movements.

See the article here:
Here's Why CRISPR Stocks Fell in January - The Motley Fool

Xiao-Min Wu,1,* Cheng Jin,2,* Yuan-Long Gu,2 Wu-Qiang Chen,2 Mao-Qun Zhu,2 Shuo Zhang,2 Zhen Zhang1

1Department of Integrated Traditional Chinese and Western Medicine Oncology, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062, Peoples Republic of China; 2Department of Hepatobiliary Surgery, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214041, Peoples Republic of China

*These authors contributed equally to this work

Correspondence: Cheng JinDepartment of Hepatobiliary Surgery, Affiliated Hospital of Jiangnan University, 585 Xingyuan Road, Wuxi, Peoples Republic of ChinaTel +8613338770679Email jingcheng1008@163.com

Purpose: Hepatocellular carcinoma (HCC) is one of the deadliest cancers globally with a poor prognosis. Breakthroughs in the treatment of HCC are urgently needed. This study explored the role of IDNK in the development and progression of HCC.Methods: IDNK expression was suppressed using short hairpin (shRNA) in BEL-7404 and Huh-7 cells. The expression of IDNK in HCC cells after IDNK knockdown was evaluated by real-time quantitative RT-PCR analysis and Western blot. After IDNK silencing, the proliferation and apoptosis of HCC cells were evaluated by Celigo cell counting, flow cytometry analysis, MTT assay, and caspase3/7 assay. Gene expressions in BEL-7404 cells transfected with IDNK shRNA lentivirus plasmid and blank control plasmid were evaluated by microarray analysis. The differentially expressed genes induced by deregulation of IDNKwere identified, followed by pathway analysis.Results: The expression of IDNK at the mRNA and protein levels was considerably reduced in shRNA IDNK transfected cells. Knockdown of IDNK significantly inhibited HCC cell proliferation and increased cell apoptosis. A total of 1196 genes (585 upregulated and 611 downregulated) were differentially expressed in IDNK knockdown BEL-7404 cells. The pathway of tRNA charging with Z-score = 3 was significantly inhibited in BEL-7404 cells with IDNK knockdown.Conclusion: IDNK plays a key role in the proliferation and apoptosis of HCC cells. IDNK may be a candidate therapeutic target for HCC.

Keywords: hepatocellular carcinoma cells, shRNA IDNK, cell proliferation, cell apoptosis, microarray, differentially expressed gene

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License.By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

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Gluconokinase IDNK Promotes Cell Proliferation and Inhibits Apoptosis | OTT - Dove Medical Press

BOSTON--(BUSINESS WIRE)--Decibel Therapeutics, a development-stage biotechnology company developing novel therapeutics for hearing loss and balance disorders, today announced a new strategic research focus on regenerative medicine approaches for the inner ear. The company is also announcing a collaboration and option agreement that gives Decibel exclusive access to novel compounds targeting proteins in a critical regenerative pathway.

Decibels research focus on regeneration will be powered by the companys research and translation platform. The company has built one of the most sophisticated single cell genomics and bioinformatics platforms in the industry to identify and validate targets. Decibel has also developed unique insights into regulatory pathways and inner ear delivery mechanisms that together enable precise control over gene expression in the inner ear and differentiate its AAV-based gene therapy programs.

Our deep understanding of the biology of the inner ear and our advanced technological capabilities come together to create a powerful platform for regenerative medicine therapies for hearing and balance disorders, said Laurence Reid, Ph.D., acting CEO of Decibel. We see an exciting opportunity to leverage this platform to address a broad range of hearing and balance disorders that severely compromise quality of life for hundreds of millions of people around the world.

The first program in Decibels regeneration portfolio aims to restore balance function using an AAV-based gene therapy (DB-201), which utilizes a cell-specific promoter to selectively deliver a regeneration-promoting gene to target cells. In collaboration with Regeneron Pharmaceuticals, Decibel will initially evaluate DB-201 as a treatment for bilateral vestibulopathy, a debilitating condition that significantly impairs balance, mobility, and stability of vision. Ultimately, this program may have applicability in a broad range of age-related balance disorders. There are currently no approved medicines to restore balance. Decibel expects to initiate IND-enabling experiments for this program in the first half of 2020.

Decibel is also pursuing novel targets for the regeneration of critical cells in both the vestibule and cochlea of the inner ear; these targets may be addressable by gene therapy or other therapeutic modalities. As a key component of that program, Decibel today announced an exclusive worldwide option agreement with The Rockefeller University, which has discovered a novel series of small-molecule LATS inhibitors. LATS kinases are a core component of the Hippo signaling pathway, which plays a key role in regulating both tissue regeneration and the proliferation of cells in the inner ear that are crucial to hearing and balance. The agreement gives Decibel an exclusive option to license this series of compounds across all therapeutic areas.

The agreement also establishes a research collaboration between Decibel and A. James Hudspeth, M.D., Ph.D., the F.M. Kirby Professor at The Rockefeller University and the director of the F.M. Kirby Center for Sensory Neuroscience. Dr. Hudspeth is a world-renowned neuroscientist, a member of the National Academy of Sciences and the American Academy of Arts and Sciences, and a Howard Hughes Medical Institute investigator. Dr. Hudspeth has been the recipient of numerous prestigious awards, including the 2018 Kavli Prize in Neuroscience.

Rockefeller scientists are at the leading edge of discovery, and we are excited to see the work of Dr. Hudspeth move forward in partnership with Decibel, said Jeanne Farrell, Ph.D., associate vice president for technology advancement at The Rockefeller University. The ambitious pursuit of harnessing the power of regenerative medicine to create a new option for patients with hearing loss could transform how we address this unmet medical need in the future.

In parallel with its new research focus on regenerative strategies, Decibel will continue to advance key priority preclinical and clinical programs. DB-020, the companys clinical-stage candidate designed to prevent hearing damage in people receiving cisplatin chemotherapy, is in an ongoing Phase 1b trial. Decibel will also continue to progress DB-OTO, a gene therapy for the treatment of genetic congenital deafness, which is being developed in partnership with Regeneron Pharmaceuticals. The DB-OTO program aims to restore hearing to people born with profound hearing loss due to a mutation in the otoferlin gene and is expected to progress to clinical trials in 2021.

To support the new research focus, Decibel is restructuring its employee base and discontinuing some early-stage discovery programs.

About Decibel Therapeutics, Inc.Decibel Therapeutics, a development-stage biotechnology company, has established the worlds first comprehensive drug discovery, development, and translational research platform for hearing loss and balance disorders. Decibel is advancing a portfolio of discovery-stage programs aimed at restoring hearing and balance function to further our vision of a world in which the benefits and joys of hearing are available to all. Decibels lead therapeutic candidate, DB-020, is being investigated for the prevention of ototoxicity associated with cisplatin chemotherapy. For more information about Decibel Therapeutics, please visit decibeltx.com or follow @DecibelTx.

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Decibel Therapeutics Announces Strategic Research Focus on Regenerative Medicine for the Inner Ear - Business Wire