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New strategies, tools offered for genome editing

 Reported from Science Daily at  https://www.sciencedaily.com/

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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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:

  1. 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
  2. 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
  3. 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

Cite This Page:

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>.
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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

 

Horizon will host a conference call today at 09:30 GMT to discuss this news. To access the live conference call please use the dial-in details below. The presentation will be made available shortly before the call at:https://www.horizondiscovery.com/about-us/investor-relations/corporate-videos-and-presentations.

 

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.”

 

More information on Avvinity can be found at www.avvinity.com.

 

 ENDS

 

Notes for Editors:

 

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.

 

References:

1. http://www.prnewswire.com/news-releases/global–usa-cancer-immunotherapy-market-analysis-2015—forecasts-to-2020-300157219.html

 

2. Retargeting pre-existing human antibodies to a bacterial pathogen with an alpha-Gal conjugated aptamer. Kristian SA, Hwang JH, Hall B, Leire E, Iacomini J, Old R, Galili U, Roberts C, Mullis KB, Westby M, Nizet V. J Mol Med (Berl). 2015 Jun;93(6):619-31

 

Conference call:

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.

 

For further information, please contact:

 

Horizon Discovery Group plc

Dr. Darrin Disley CEO / Richard Vellacott CFO

Tel: +44 (0) 1223 655580

 

Centauri Therapeutics Limited

Dr. Mike Westby CEO

Tel +44 (0) 1304 728611

 

Zyme Communications (Trade and Regional Media)

Katie Odgaard

Tel: +44 (0)7787 502 947

Email: katie.odgaard@zymecommunications.com

 

Consilium Strategic Communications (Financial Media and Investor Relations)

Amber Fennell / Jessica Hodgson / Matthew Neal / Laura Thornton

Tel: +44 (0) 20 3709 5701

Email: horizon@consilium-comms.com

 

Panmure Gordon & Co. (NOMAD)

Corporate Finance: Freddy Crossley / Duncan Monteith / Fabien Holler

Broking: Tom Salvesen

Tel: +44 20 7886 2500

 

 

About Horizon Discovery Group plc www.horizondiscovery.com/

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.

 

 

About Centauri Therapeutics Ltd www.centauritherapeutics.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).

 

SOURCE

From: “Katie Odgaard” <katie.odgaard@zymecommunications.com>

Date: March 2, 2016 at 2:12:41 AM EST

To:avivalev-ari@alum.berkeley.edu” <avivalev-ari@alum.berkeley.edu>

Subject: Horizon Discovery Group plc Enters Immuno-Oncology Therapeutic Development and Forms Joint Venture with Centauri Therapeutics Limited

Reply-To: katie.odgaard@zymecommunications.com

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