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Genetic scissors: a tool for rewriting the code of life
Emmanuelle Charpentier and Jennifer A. Doudna have discovered one of gene technology’s sharpest tools: the CRISPR/Cas9 genetic scissors. Using these, researchers can change the DNA of animals, plants and microorganisms with extremely high precision. This technology has had a revolutionary impact on the life sciences, is contributing to new cancer therapies and may make the dream of curing inherited diseases come true.
Researchers need to modify genes in cells if they are to find out about life’s inner workings. This used to be time-consuming, difficult and sometimes impossible work. Using the CRISPR/Cas9 genetic scissors, it is now possible to change the code of life over the course of a few weeks.
“There is enormous power in this genetic tool, which affects us all. It has not only revolutionised basic science, but also resulted in innovative crops and will lead to ground-breaking new medical treatments,” says Claes Gustafsson, chair of the Nobel Committee for Chemistry.
As so often in science, the discovery of these genetic scissors was unexpected. During Emmanuelle Charpentier’s studies of Streptococcus pyogenes, one of the bacteria that cause the most harm to humanity, she discovered a previously unknown molecule, tracrRNA. Her work showed that tracrRNA is part of bacteria’s ancient immune system, CRISPR/Cas, that disarms viruses by cleaving their DNA.
Charpentier published her discovery in 2011. The same year, she initiated a collaboration with Jennifer Doudna, an experienced biochemist with vast knowledge of RNA. Together, they succeeded in recreating the bacteria’s genetic scissors in a test tube and simplifying the scissors’ molecular components so they were easier to use.
In an epoch-making experiment, they then reprogrammed the genetic scissors. In their natural form, the scissors recognise DNA from viruses, but Charpentier and Doudna proved that they could be controlled so that they can cut any DNA molecule at a predetermined site. Where the DNA is cut it is then easy to rewrite the code of life.
Since Charpentier and Doudna discovered the CRISPR/Cas9 genetic scissors in 2012 their use has exploded. This tool has contributed to many important discoveries in basic research, and plant researchers have been able to develop crops that withstand mould, pests and drought. In medicine, clinical trials of new cancer therapies are underway, and the dream of being able to cure inherited diseases is about to come true. These genetic scissors have taken the life sciences into a new epoch and, in many ways, are bringing the greatest benefit to humankind.
Emmanuelle Charpentier, born 1968 in Juvisy-sur-Orge, France. Ph.D. 1995 from Institut Pasteur, Paris, France. Director of the Max Planck Unit for the Science of Pathogens, Berlin, Germany.
Jennifer A. Doudna, born 1964 in Washington, D.C, USA. Ph.D. 1989 from Harvard Medical School, Boston, USA. Professor at the University of California, Berkeley, USA and Investigator, Howard Hughes Medical Institute.
Other Articles on the Nobel Prize in this Open Access Journal Include:
there have been many instances of off-target effects where genes, other than the selected target, are edited out. This ‘off-target’ issue has hampered much of the utility of CRISPR in gene-therapy and CART therapy
However, an article in Science by Jon Cohen explains a Nature paper’s finding of a new tool in the CRISPR arsenal called prime editing, meant to increase CRISPR specificity and precision editing capabilities.
Primeediting promises to be a cut above CRISPR Jon Cohen CRISPR, an extraordinarily powerful genome-editing tool invented in 2012, can still be clumsy. … Primeediting steers around shortcomings of both techniques by heavily modifying the Cas9 protein and the guide RNA. … ” Primeediting “well may become the way that disease-causing mutations are repaired,” he says.
The effort, led by Drs. David Liu and Andrew Anzalone at the Broad Institute (Cambridge, MA), relies on the modification of the Cas9 protein and guide RNA, so that there is only a nick in a single strand of the double helix. The canonical Cas9 cuts both strands of DNA, and so relies on an efficient gap repair activity of the cell. The second part, a new type of guide RNA called a pegRNA, contains an RNA template for a new DNA sequence to be added at the target location. This pegRNA-directed synthesis of the new template requires the attachment of a reverse transcriptase enzymes to the Cas9. So far Liu and his colleagues have tested the technology on over 175 human and rodent cell lines with great success. In addition, they had also corrected mutations which cause Tay Sachs disease, which previous CRISPR systems could not do. Liu claims that this technology could correct over 89% of pathogenic variants in human diseases.
A company Prime Medicine has been formed out of this effort.
As was announced, prime editing for human therapeutics will be jointly developed by both Prime Medicine and Beam Therapeutics, each focusing on different types of edits and distinct disease targets, which will help avoid redundancy and allow us to cover more disease territory overall. The companies will also share knowledge in prime editing as well as in accompanying technologies, such as delivery and manufacturing.
Reader of StatNews.: Can you please compare the pros and cons of prime editing versus base editing?
The first difference between base editing and prime editing is that base editing has been widely used for the past 3 1/2 years in organisms ranging from bacteria to plants to mice to primates. Addgene tells me that the DNA blueprints for base editors from our laboratory have been distributed more than 7,500 times to more than 1,000 researchers around the world, and more than 100 research papers from many different laboratories have been published using base editors to achieve desired gene edits for a wide variety of applications. While we are very excited about prime editing, it’s brand-new and there has only been one paper published thus far. So there’s much to do before we can know if prime editing will prove to be as general and robust as base editing has proven to be.
We directly compared prime editors and base editors in our study, and found that current base editors can offer higher editing efficiency and fewer indel byproducts than prime editors, while prime editors offer more targeting flexibility and greater editing precision. So when the desired edit is a transition point mutation (C to T, T to C, A to G, or G to A), and the target base is well-positioned for base editing (that is, a PAM sequence exists approximately 15 bases from the target site), then base editing can result in higher editing efficiencies and fewer byproducts. When the target base is not well-positioned for base editing, or when other “bystander” C or A bases are nearby that must not be edited, then prime editing offers major advantages since it does not require a precisely positioned PAM sequence and is a true “search-and-replace” editing capability, with no possibility of unwanted bystander editing at neighboring bases.
Of course, for classes of mutations other than the four types of point mutations that base editors can make, such as insertions, deletions, and the eight other kinds of point mutations, to our knowledge prime editing is currently the only approach that can make these mutations in human cells without requiring double-stranded DNA cuts or separate DNA templates.
Nucleases (such as the zinc-finger nucleases, TALE nucleases, and the original CRISPR-Cas9), base editors, and prime editors each have complementary strengths and weaknesses, just as scissors, pencils, and word processors each have unique and useful roles. All three classes of editing agents already have or will have roles in basic research and in applications such as human therapeutics and agriculture.
Most genetic variants that contribute to disease1 are challenging to correct efficiently and without excess byproducts2,3,4,5. Here we describe prime editing, a versatile and precise genome editing method that directly writes new genetic information into a specified DNA site using a catalytically impaired Cas9 endonuclease fused to an engineered reverse transcriptase, programmed with a prime editing guide RNA (pegRNA) that both specifies the target site and encodes the desired edit. We performed more than 175 edits in human cells, including targeted insertions, deletions, and all 12 types of point mutation, without requiring double-strand breaks or donor DNA templates. We used prime editing in human cells to correct, efficiently and with few byproducts, the primary genetic causes of sickle cell disease (requiring a transversion in HBB) and Tay–Sachs disease (requiring a deletion in HEXA); to install a protective transversion in PRNP; and to insert various tags and epitopes precisely into target loci. Four human cell lines and primary post-mitotic mouse cortical neurons support prime editing with varying efficiencies. Prime editing shows higher or similar efficiency and fewer byproducts than homology-directed repair, has complementary strengths and weaknesses compared to base editing, and induces much lower off-target editing than Cas9 nuclease at known Cas9 off-target sites. Prime editing substantially expands the scope and capabilities of genome editing, and in principle could correct up to 89% of known genetic variants associated with human diseases.
From Anzolone et al. Nature 2019 Figure 1.
Prime editing strategy
Cas9 targets DNA using a guide RNA containing a spacer sequence that hybridizes to the target DNA site. We envisioned the generation of guide RNAs that both specify the DNA target and contain new genetic information that replaces target DNA nucleotides. To transfer information from these engineered guide RNAs to target DNA, we proposed that genomic DNA, nicked at the target site to expose a 3′-hydroxyl group, could be used to prime the reverse transcription of an edit-encoding extension on the engineered guide RNA (the pegRNA) directly into the target site (Fig. 1b, c, Supplementary Discussion).
These initial steps result in a branched intermediate with two redundant single-stranded DNA flaps: a 5′ flap that contains the unedited DNA sequence and a 3′ flap that contains the edited sequence copied from the pegRNA (Fig. 1c). Although hybridization of the perfectly complementary 5′ flap to the unedited strand is likely to be thermodynamically favoured, 5′ flaps are the preferred substrate for structure-specific endonucleases such as FEN122, which excises 5′ flaps generated during lagging-strand DNA synthesis and long-patch base excision repair. The redundant unedited DNA may also be removed by 5′ exonucleases such as EXO123.
The authors reasoned that preferential 5′ flap excision and 3′ flap ligation could drive the incorporation of the edited DNA strand, creating heteroduplex DNA containing one edited strand and one unedited strand (Fig. 1c).
DNA repair to resolve the heteroduplex by copying the information in the edited strand to the complementary strand would permanently install the edit (Fig. 1c).
They had hypothesized that nicking the non-edited DNA strand might bias DNA repair to preferentially replace the non-edited strand.
Results
The authors evaluated the eukaryotic cell DNA repair outcomes of 3′ flaps produced by pegRNA-programmed reverse transcription in vitro, and performed in vitro prime editing on reporter plasmids, then transformed the reaction products into yeast cells (Extended Data Fig. 2).
Reporter plasmids encoding EGFP and mCherry separated by a linker containing an in-frame stop codon, +1 frameshift, or −1 frameshift were constructed and when plasmids were edited in vitro with Cas9 nickase, RT, and 3′-extended pegRNAs encoding a transversion that corrects the premature stop codon, 37% of yeast transformants expressed both GFP and mCherry (Fig. 1f, Extended Data Fig. 2).
They fused a variant of M—MLV-RT (reverse transcriptase) to Cas9 with an extended linker and this M-MLV RT fused to the C terminus of Cas9(H840A) nickase was designated as PE1. This strategy allowed the authors to generate a cell line containing all the required components of the primer editing system. They constructed 19 variants of PE1 containing a variety of RT mutations to evaluate their editing efficiency in human cells
Generated a pentamutant RT incorporated into PE1 (Cas9(H840A)–M-MLV RT(D200N/L603W/T330P/T306K/W313F)) is hereafter referred to as prime editor 2 (PE2). These were more thermostable versions of RT with higher efficiency.
Optimized the guide (pegRNA) using a series of permutations and recommend starting with about 10–16 nt and testing shorter and longer RT templates during pegRNA optimization.
In the previous attempts (PE1 and PE2 systems), mismatch repair resolves the heteroduplex to give either edited or non-edited products. So they next developed an optimal editing system (PE3) to produce optimal nickase activity and found nicks positioned 3′ of the edit about 40–90 bp from the pegRNA-induced nick generally increased editing efficiency (averaging 41%) without excess indel formation (6.8% average indels for the sgRNA with the highest editing efficiency) (Fig. 3b).
The cell line used to finalize and validate the system was predominantly HEK293T immortalized cell line
Together, their findings establish that PE3 systems improve editing efficiencies about threefold compared with PE2, albeit with a higher range of indels than PE2. When it is possible to nick the non-edited strand with an sgRNA that requires editing before nicking, the PE3b system offers PE3-like editing levels while greatly reducing indel formation.
Off Target Effects: Strikingly, PE3 or PE2 with the same 16 pegRNAs containing these four target spacers resulted in detectable off-target editing at only 3 out of 16 off-target sites, with only 1 of 16 showing an off-target editing efficiency of 1% or more (Extended Data Fig. 6h). Average off-target prime editing for pegRNAs targeting HEK3, HEK4, EMX1, and FANCFat the top four known Cas9 off-target sites for each protospacer was <0.1%, <2.2 ± 5.2%, <0.1%, and <0.13 ± 0.11%, respectively (Extended Data Fig. 6h).
The PE3 system was very efficient at editing the most common mutation that causes Tay-Sachs disease, a 4-bp insertion in HEXA(HEXA1278+TATC).
References
Landrum, M. J. et al. ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res. 44, D862–D868 (2016).
Jinek, M. et al. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science337, 816–821 (2012).
Kosicki, M., Tomberg, K. & Bradley, A. Repair of double-strand breaks induced by CRISPR–Cas9 leads to large deletions and complex rearrangements. Biotechnol. 36, 765–771 (2018).
Rice University researches develop new CRISPR-CAS9 strategy to reduce off-target gene editing effects
Reporter: Stephen J. Williams, PhD
Rice University researches develop new CRISPR-CAS9 strategy to reduce off-target gene editing effects, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 2: CRISPR for Gene Editing and DNA Repair
Series B, Volume 2:
Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS & BioInformatics, Simulations and the Genome Ontology
Bioengineer Gang Bao and team explore CRISPR-Cas9 alternatives
Date:
February 8, 2016
Source:
Rice University
Summary:
Bioengineers have studied alternative CRISPR-Cas9 systems for precision genome editing, with a focus on improving its accuracy and limiting ‘off-target’ errors.
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FULL STORY
A Cas9 protein (light blue) with guide RNA (purple) and DNA (red) shows a DNA bulge, marking a sequence that would be considered off-target for CRISPR-Cas9 editing. The Rice University lab of bioengineer Gang Bao has developed Web-based tools to search for such off-targets.
Credit: Bao Lab/Rice University
Rice University bioengineers have found new techniques for precision genome editing that are more accurate and have fewer off-target errors.
The new strategies are shared in three papers in an upcoming special issue of the Nature journal Molecular Therapy on improving the revolutionary genome-editing technique called CRISPR-Cas9.
Bioengineering Professor Gang Bao and his colleagues present ideas for maximizing on-target gene editing with biological catalysts capable of cutting DNA called “engineered nucleases.” Several such systems have been studied for years, but for the past three, the promise of cut-and-paste editing via CRISPR-Cas9 has captured the attention of scientists worldwide.
CRISPR-Cas9, a naturally occurring defense system in bacteria, allows researchers to design a short sequence of RNA called “guide RNA” that targets a specific section of genetic code (DNA) in a cell. An associated Cas9 protein then cuts the section, disrupts it or replaces it with the desired code.
That’s how bacteria use CRISPR-Cas9 to immunize themselves from disease. Exposure to an invader causes the bacteria to adapt by adding the invader’s genetic signature to a CRISPR database. The bacteria then recognize future enemies and destroy them with an appropriate Cas9 protein.
About three years ago researchers discovered that bacterial CRISPR-Cas9 could be modified to edit DNA in human cells by, for instance, replacing mutant sequences with normal, or “wild-type,” sequences in much the same way a bacterium banks an invader’s DNA signature. The technique is seen as having great potential for disease modeling and treatment, synthetic biology and molecular pathway dissection.
But CRISPR-Cas9 is still vulnerable to snipping the wrong sequences — called “off-targets” — in addition to the right ones. In therapeutic applications, Bao said, off-target cutting by CRISPR-Cas9 could cause many detrimental effects, including cancer.
Bao, who moved to Rice’s BioScience Research Collaborative (BRC) in 2015 with a grant from the Cancer Prevention and Research Institute of Texas, is studying ways to refine CRISPR-Cas9, which he described as “nanoscissors for editing genes.”
One of his goals is to treat the hereditary disease sickle cell anemia, which he hopes CRISPR-Cas9 will eventually cure. But first the therapy must become much better at avoiding off-targets that can cause unwanted side effects.
In two of the papers, the researchers study different orthologs: Cas9 proteins from species with the same ancestors as the Streptococcus pyogenes (Spy)bacterium commonly used in CRISPR/Cas9.
“Our approach in these papers is to explore the possibility of using different Cas9 orthologs,” Bao said. “There are many possibilities.”
In the first paper, Bao and his group used experiments on mammalian cells to characterize a CRISPR-Cas9 system from the Neisseria meningitides (Nme) bacterium. It differs from Spy in a way that bioengineers can use to reduce the risk of off-target edits, he said.
That difference lies primarily in a sequence of code that is not part of the target, but close by. Known as a protospacer-adjacent motif (PAM), it’s a marker for target DNA sequences and necessary for Cas9 protein binding. InSpyCas9 editing, the PAM sequence is generally three nucleotides long. For Nme, the required PAM sequence is significantly longer — eight nucleotides. While Nme may find fewer targets, those targets are more likely to be the correct ones, according to the researchers. That, they argue, may make it a safer alternative for gene editing.
The second paper, a collaboration with colleagues at the University of Freiburg, Germany, addresses highly specific human-gene editing using yet another bacteria’s immune system. For this study, Cas9 proteins from Spy were replaced with Streptococcus thermophiles (Sth) proteins that also recognize longer PAMs. Tests carried out in human cells found Sth proteins with more stringent PAM requirements were significantly better than SpyCas9 proteins at avoiding off-targets.
Bao and company also looked at the effect of bulges in DNA and RNA that can influence targeting. Bulges appear when a sequence is one nucleotide longer or one nucleotide shorter than the expected DNA sequence targeted by guide RNA.
“We found that even with DNA or RNA bulges, the Cas9 protein can still cut,” he said. “That’s a unique contribution. Nobody saw that would be the case, but we demonstrated it. Consequently, we’ve developed a Web-based tool to search for three cases of potential off-target sites that contain base mismatches, RNA bulges and DNA bulges.”
Bao noted the Nme and Sth Cas9 proteins, unlike Spy, are small enough to be packaged within an adeno-associated virus for delivery to and treatment of specific cells in an animal. “That’s another advantage, and why we want to go on to explore these two systems,” he said.
The third paper is a review of current CRISPR-Cas9 techniques that focuses on genome-editing tools available for target selection, experimental methods and validation. Bao and his team also lay out a list of challenges yet to be solved to eliminate off-target effects.
He said there is a path forward, represented in part by his investigation of two new bacterial systems as well as the fact that CRISPR-Cas9 is a much easier technique to implement in the lab than other genome-editing systems such as TALEN and zinc finger nuclease.
Bao said that unlike those older genome-editing techniques, CRISPR-Cas9 is straightforward enough for students to learn and use in a short time.
Bao hopes to establish his lab as a focal point for genome editing in the Texas Medical Center. To that end, he brought the TMC genome-editing community together for a well-attended workshop at the BRC last December.
“We had a lot of good discussions,” he said. “One thing I would like to stimulate is the formation of a consortium among the many labs in TMC using CRISPR. They have needs to design CRISPR systems for different applications, but there are a lot of common issues. If we work together, it will be easier to address them.”
Story Source:
The above post is reprinted from materials provided by Rice University.Note: Materials may be edited for content and length.
Journal References:
Ciaran M. Lee, Thomas J. Cradick, Gang Bao. The Neisseria meningitidis CRISPR-Cas9 System Enables Specific Genome Editing in Mammalian Cells. Molecular Therapy, 2016; DOI:10.1038/mt.2016.8
Maximilian Müller, Ciaran M Lee, Giedrius Gasiunas, Timothy H Davis, Thomas J Cradick, Virginijus Siksnys, Gang Bao, Toni Cathomen, Claudio Mussolino. Streptococcus thermophilus CRISPR-Cas9 Systems Enable Specific Editing of the Human Genome. Molecular Therapy, 2015; DOI: 10.1038/mt.2015.218
Ciaran M. Lee, Thomas J. Cradick, Eli J Fine, Gang Bao. Nuclease Target Site Selection for Maximizing On-target Activity and Minimizing Off-target Effects in Genome Editing. Molecular Therapy, 2016; DOI: 10.1038/mt.2016.1
Rice University. “New strategies, tools offered for genome editing: Bioengineer Gang Bao and team explore CRISPR-Cas9 alternatives.” ScienceDaily. ScienceDaily, 8 February 2016. <www.sciencedaily.com/releases/2016/02/160208135449.htm>.
Avvinity will have exclusive rights in oncology to use Alphamer therapeutic platform, invented by a Nobel Laureate and developed by Centauri: A Case of a Joint Venture Model, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 1: Next Generation Sequencing (NGS)
Avvinity will have exclusive rights in oncology to use Alphamer therapeutic platform, invented by a Nobel Laureate and developed by Centauri: A Case of a Joint Venture Model
Reporter: Aviva Lev-Ari, PhD, RN
Horizon Discovery Group plc Enters Immuno-Oncology Therapeutic Development and Forms Joint Venture with Centauri Therapeutics Limited
·Newly formed company Avvinity Therapeutics will be jointly managed by Horizon, via its Research Biotech business, and Centauri
·Joint venture creates a differentiated new player in the rapidly growing immuno-oncology market, currently valued at £25 billion
·Avvinity will have exclusive rights in oncology to use Alphamer therapeutic platform,invented by a Nobel Laureate and developed by Centauri
·Horizon to invest up to £5.3 million, with an initial outlay of £2.5 million, in a joint venture to identify novel immuno-oncology therapeutics
·Horizon will contribute its gene editing technology platform and oncology expertise and will also benefit from service revenues from the joint venture
·Formation of the joint venture represents a strategic move by Horizon to capture the upside potential of its IP, platform technologies and capabilities in immuno-oncology, synthetic lethality and cell therapy based therapeutics
Cambridge, UK, 2 March 2016: Horizon Discovery Group plc (LSE: HZD) (“Horizon” or “the Company”), the leading international gene editing company, announces today that it has formed an immuno-oncology joint venture, Avvinity Therapeutics (“Avvinity”), with Centauri Therapeutics Limited (“Centauri”), a UK-based biotechnology company focused on the discovery and development of novel molecules targeting life-threatening infectious diseases. This transaction represents part of Horizon’s previously outlined strategy to invest up to £10 million, further leveraged by its IP, technology platforms and know-how, to identify the next generation of molecular and cellular cancer therapeutics.
Avvinity will combine Horizon’s gene editing, immunology, oncology and drug discovery capabilities with Centauri’s Alphamer technology to provide a powerful and proprietary platform to discover and develop novel immuno-oncology therapeutics, for both solid tumours and leukaemias. Avvinity will be targeting an immuno-oncology market currently worth £25 billion per year and expected to grow to approximately £50 billion per year by 2020.(1)
Under the terms of this agreement, Horizon will out-license certain background intellectual property relating to its translational genomics and drug discovery platforms, and will invest up to £5.3 million over two tranches with the first tranche of £2.5m committed, and the second to be committed at Horizon’s discretion pending the progress of three development programs. Centauri will license background IP and expertise on its Alphamer technology to Avvinity, which will have exclusivity for the field of oncology for an initial three year period and can be extended via the issue of further equity concurrently with the raise of new investment.
Avvinity will be managed jointly by Horizon and Centauri, and based on the investment of IP, technology and the first tranche of funding; Horizon will own 33% of Avvinity’s equity, representing 50% of the most-preferred class of voting shares. Upon completion of the 2nd tranche of funding Horizon will own 49.99% of Avvinity’s equity, representing 50% of the most-preferred class of voting shares. The joint venture will be managed within Horizon as part of the Company’s Research Biotech business (formerly Horizon’s Leveraged business unit).
Neither Horizon nor Centauri will be obliged to provide further funding to Avvinity, though both retain pre-emption rights and may elect to participate in future funding rounds. Subject to achieving key development milestones, Avvinity plans to raise significant new external investment to take its innovative drugs into clinical trials, at which time the value of Horizon’s stake in the business would be highly-material.
Dr. Darrin M. Disley, Chief Executive Officer, President Research Biotech of Horizon Discovery Group plc, said: “By combining Horizon’s deep understanding of the genetic basis of cancer alongside its gene editing, drug discovery and emerging immuno-oncology toolbox, with Centauri’s unique Alphamer technology and knowledge of its use, we have created an exciting new company to spearhead Horizon’s move into targeted therapeutic development. We are confident this joint venture will break new ground in the development of immunotherapies, and bring significant value creation to Horizon shareholders.
“The establishment of Avvinity is in line with our hybrid Research Biotech strategy to not only work with partners but also take advantage of the therapeutic upside potential of the most exciting new areas of personalised and genomic medicine in a risk-managed way.”
Dr. Mike Westby, Chief Executive Officer of Centauri Therapeutics Limited, commented: “Alphamers are an entirely novel way to target disease and represent an exciting new approach for recruitment of host immunity. At Centauri we have invested to build the Alphamer platform and assembled the drug discovery expertise necessary to exploit the platform in infectious diseases. Through this joint venture with Horizon, we look forward to applying our combined know-how and capabilities to develop Alphamers as important new immuno-oncology medicines, particularly for cancer indications that have proven intractable to date.”
Alphamer technology is based on chemically synthesized molecules that redirect naturally occurring antibodies in the human immune system to selected pathogens or cancer cells. One end of a molecule binds a cell-surface target on a pathogen or cancer cell using an aptamer, while the other end presents specific epitopes that attach to the circulating antibodies. The result of this redirection is cell death and subsequent recruitment of the T-Cell mediated pathways to clear the body of the pathogen or cancer cell.
Alphamers promise key advantages over conventional antibody and antibody-drug conjugate molecules in immuno-oncology applications, including the ability to target cancers driven by both wild type (“normal”) gene overexpression as well as mutant (”abnormal”) gene overexpression, and by exhibiting a short half-life in the body yielding reduced toxicity and systemic side-effects. Considerable investment has been made in the Alphamer technology over the past four years and its ability to engage the immune system to destroy bacteria has been confirmed.(2)
Platform technologies based around alternative immuno-oncology approaches have secured high valuations once early positive results in clinical trials have been achieved: Amgen’s 2012 acquisition of Micromet valued Micromet at $1.16b, and in 2013, Spirogen was acquired by AstraZeneca for up to $440m.
A conference call for analysts, investors and media will take place at 09:30 GMT today hosted by Darrin Disley, Chief Executive Officer and President, Research Biotech, and Richard Vellacott, Chief Financial Officer, who will run through a presentation followed by a Q&A session. The presentation will be made available shortly before the call at: https://www.horizondiscovery.com/about-us/investor-relations/corporate-videos-and-presentations.
The dial-in numbers for the conference call are:
UK: 08006940257
Standard International: +44 (0) 1452 555566
Conference call ID: 62637628
A replay of the call is available approximately four hours after the call concludes. For those unable to attend it live, or who would like to listen to it again, call +44 (0)1452550000 and quote the conference call ID: 62637628.
Horizon is a leading international gene-editing company that supplies products, services and research programmes that enable genomics research and the development of personalised and genomic medicines. Horizon has a diverse and global customer base of over 1,400 unique organisations across more than 50 countries, including major pharmaceutical, biotechnology and diagnostic companies as well as leading academic research centres. The Group supplies its products and services into multiple markets, estimated to total in excess of £29 billion in 2015.
Horizon’s core capabilities are built around its proprietary translational genomics platform, a highly precise and flexible suite of gene editing tools (rAAV, ZFN and CRISPR) able to alter almost any gene sequence in human or mammalian cell-lines.
Horizon offers over 23,000 catalogue products, almost all of which are based on the application of gene editing to generate in vitro and in-vivo models that accurately model the disease-causing genetic anomalies found in diseases like cancer. These ‘patients-in-a-test-tube’ are being used by customers to: understand the genetic drivers of disease; identify targets of therapeutic intervention that can moderate or correct these genetic drivers; develop novel medicines and companion diagnostic tests that result in the right patient getting the right medicine.
Horizon also provides custom in vitro and in vivo disease model generation services, biopharmaceutical manufacturing cell lines and generation services, quantitative molecular reference standards and contract research and custom screening services.
In addition, Horizon through its Research Biotech business deploys the Company’s intellectual property, gene-editing platform, products, services and know-how in cancer research, drug discovery and immunology to develop its immuno-oncology, synthetic lethality and cell therapy platforms which aim to deliver novel drug treatments into the pharmaceutical pipeline.
Horizon is headquartered in Cambridge, UK, and is listed on the London Stock Exchange’s AIM market under the ticker “HZD”. For further information please visit: www.horizondiscovery.com.
Centauri Therapeutics is a UK-based biotechnology company focused on the discovery and development of novel molecules targeting life threatening diseases.
Centauri Therapeutics has established a core R&D facility at Discovery Park in Sandwich, Kent, with an experienced team of industry scientists focused on discovery, optimisation and development of novel Alphamers targeting acute hospital acquired infections. The company is currently focussed on the development of Alphamers against anti-microbial resistant (AMR) pathogens, which pose an increasing threat to human health.
Centauri Therapeutics’ Executive team is led by Mike Westby, Chief Executive Officer (previously Pfizer, Roche) and Stuart Lawson, Chief Financial Officer (CEO of the private investment group Animatrix Capital LLP, and previously KPMG). Clive Dix is Non-Executive Director and Chairman of the Board (previously Convergence Pharmaceuticals, PowderMed, PowderJect, Glaxo Wellcome).
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