Sangamo Files for CT Order 12/8/16

SECURITIES AND EXCHANGE COMMISSION
8 December 2016
ORDER GRANTING CONFIDENTIAL TREATMENT
UNDER THE SECURITIES EXCHANGE ACT OF 1934
Sangamo BioSciences, Inc.
File No. 0-30171 -- CF# 34340
_____________________
Sangamo BioSciences, Inc. submitted an application under Rule 24b-2 requesting
confidential treatment for information it excluded from the Exhibits to a Form 10-Q filed
on October 27, 2016.
Based on representations by Sangamo BioSciences, Inc. that this information
qualifies as confidential commercial or financial information under the Freedom of
Information Act, 5 U.S.C. 552(b)(4), the Division of Corporation Finance has determined
not to publicly disclose it. Accordingly, excluded information from the following
exhibit(s) will not be released to the public for the time period(s) specified:
Exhibit 10.1 through January 8, 2019
Exhibit 10.2 through July 10, 2022
Exhibit 10.3 through September 20, 2026
For the Commission, by the Division of Corporation Finance, pursuant to
delegated authority:
Brent J. Fields
Secretary

2012 Dow Agro Inks Reseach License with Agriculture Victoria, 2016 Commercial License

From 2012:

Aug 31, 2012

NEW YORK (GenomeWeb News) – Dow AgroSciences has struck a collaboration with Australia's Victoria Department of Primary Industries (DPI)to develop new genetics technologies to boost crop performance, the Dow Chemical subsidiary said this week.
Under the agreement, the partners plan to develop elite crop varieties with improved productivity and product quality traits.
The collaboration expands an earlier research and development program, launched in 2009, between DPI and Dow AgroSciences, a subsidiary of Dow Chemical.

Today:

Dec. 7, 2016

Source: Dow AgroSciences news release

New and innovative forage products are on the horizon driven by continued collaboration between Dow AgroSciences, a wholly owned subsidiary of The Dow Chemical Company (NYSE: DOW), and Agriculture Victoria, Australia.

Dow AgroSciences works on a variety of projects with Agriculture Victoria through its commercial arm, Agriculture Victoria Services Pty Ltd. (AVS), and today announces that AVS is taking a commercial license to the EXZACT™ Precision Technology Platform to continue the development and commercialization of new forage grass varieties to benefit farmers in Australia and around the world.

The commercial license agreement focuses on the development of forage grass varieties and associated fungal endophytes developed using precision genome editing technologies. It builds on the major Research License Agreement AVS has with Dow AgroSciences to conduct research using the company's proprietary EXZACT™ Technology.

The announcement of a milestone commercial license between Dow AgroSciences and AVS recognizes the advances Agriculture Victoria has made researching and developing innovative forage products using this gene editing platform that Dow AgroSciences has developed under an exclusive license and collaboration agreement in plants with Sangamo BioSciences, Inc.

"Our focus is on the farmer, and this commercial license validates the broad application of the EXZACT™ technology that can translate into new products for farmers around the world, and also illustrates the power of collaboration to advance technology," said Daniel R. Kittle, Ph.D., vice president, Research and Development, Dow AgroSciences.

"Our most productive collaboration with Dow AgroSciences has enabled the development of a suite of innovations for crop improvement. It has also provided us with access to the EXZACT™ technology for its application in forage grasses with global reach, to deliver benefits on-farm to dairy, beef and sheep industries," said Professor German Spangenberg, Agriculture Victoria's Executive Director Biosciences Research. 

UPENN-SANGAMO Genetically engineered T cells render HIV's harpoon powerless

PHILADELPHIA-- When HIV attacks a T cell, it attaches itself to the cell's surface and launches a "harpoon" to create an opening to enter and infect the cells. To stop the invasion, researchers from the Penn Center for AIDS Research at the University of Pennsylvania and scientists from Sangamo BioSciences, Inc. have developed genetically engineered T cells armed with a so-called "fusion inhibitor" to disrupt this critical step and prevent a wide range of HIV viruses from entering and infecting the T cells. The findings were reported today online in a preclinical study in PLOS Pathogens.
HIV medicine experienced a breakthrough in the early 2000s with a unique class of drugs known as "fusion inhibitors." Unlike most drugs that block virus replication inside of T cells, these drugs prevent HIV from entering cells in the first place. The drug, enfuvirtide, modeled after a peptide from the viral envelope and used today in combination with other antiretroviral therapies, has been shown to keep the virus at bay. However, patients need to inject enfuvirtide daily under their skin, limiting its utility and acceptability to patients, especially when compared to many other orally available drugs. HIV can also become resistant to enfuvirtide.
Building on this approach with a powerful genetic technique, researchers developed a novel way to deliver the fusion inhibitor peptide precisely to the spot on the cell surface where the virus attaches and launches its envelope, like a harpoon. The team genetically altered T cells by introducing a so-called C34 peptide, modeled after enfuvirtide, directly onto receptors, CXCR4 and CCR5, which are crucial for HIV entry. By using these molecules to deliver the C34 peptide to the site where the virus enters, these investigators showed that HIV was potently inhibited and that this inhibition extended to genetically diverse HIVs, including those that were resistant to the drug, enfuvirtide.
The most impressive results were seen when the C34 peptide was attached to CXCR4, where the Penn investigators showed that T cells expressing this molecule were protected in a mouse model of HIV infection.
"We believe that our approach to precisely target an inhibitory drug to the site of viral entry creates a new way to engineer human T cells to become resistant to HIV infection," said senior author James Hoxie, MD, a professor of Medicine in the division of Hematology/Oncology in the Perelman School of Medicine at the University of Pennsylvania. "It's potent and very broad. Every strain of HIV we tried was sensitive to it, regardless of whether the virus used CCR5 or CXCR4, which is a big advantage, since HIV typically uses CCR5 to establish infection, but can over time, evolve to use a CXCR4 instead. With this approach, it doesn't matter where the virus came from or what cellular molecule it needs to infect cells."
The findings set the stage for an upcoming phase I clinical trial in HIV-positive patients to determine the safety and appropriate dosage of a patient's own T cells engineered to express the C34-CXCR4 molecule, as well as to demonstrate their ability to resist infection when antiretroviral therapy is interrupted.
The research team also includes James L Riley, PhD, an associate professor of Microbiology, Pablo Tebas, MD, a professor of Medicine and director of the AIDS Clinical Trials Unit at the Penn CFAR, along with co-first authors, George Leslie, PhD, a senior research investigator in Hoxie's lab, Jianbin Wang, PhD and Michael C. Holmes, PhD, of Sangamo Biosciences, Inc. and Max W. Richardson, PhD, a senior research investigator in Riley's Lab.
Peptides derived from the HIV-envelope protein inhibit HIV entry by interfering with the formation of what is termed the 6-helix bundle during fusion of the viral and cellular membranes that occurs during viral entry. This is how enfuvirtide works, although when injected as a drug, enfuvirtide is distributed throughout the entire body. In the work described by the Penn and Sangamo researchers, performed in the laboratory and in a humanized mouse model, the C34 peptide attached to the CXCR4 molecule delivered the peptide to where fusion was actually occurring.
In the lab, the researchers found that T cells expressing either C34-CCR5 or C34-CXCR4 were enriched in the presence of HIV infection, going from 25 percent of the T cell population to greater than 60 percent after 7-10 days of additional culture. This enrichment was observed against a wide array of HIV strains, suggesting that this approach will be highly effective in a vast majority of individuals. Similar data was obtained using a humanized mouse model of HIV infection. In the experiments, only CD4 T cells expressing C34-CXCR4 were able to resist HIV infection and survive within the mouse. For this reason, C34-CXCR4 was chosen to be used in a phase I clinical trial.
This work builds off past experimental, genetic HIV techniques. In 2014, Penn researchers successfully genetically engineered the immune cells of HIV positive patients to resist infection, and decreased the viral loads of some patients taken off therapy entirely. The group used the zinc finger nuclease (ZFN) technology developed by Sangamo BioSciences to modify the T cells in the patients--a "molecular scissors," of sorts, to eliminate the CCR5 surface proteins. Without it, the virus couldn't enter. However, there are some limitations with this approach: it only addresses viruses that use CCR5 and both CCR5 alleles need to be knocked out for the T cells to be protected from infection.
The clinical trial investigating the work with C34 is slated to start in December 2016. The researchers will infuse C34-CXCR4 expressing T cells into well-controlled HIV infected individuals. It will be a dose-escalation study in which 1, 3, or 10 billion engineered T cells will be infused. After infusion, an "analytical treatment interruption" will occur for about 16 weeks and time to viral rebound and enrichment for the C34-CXCR4 expressing cells will be monitored. At present, patients infected with HIV must continue to take anti-HIV drugs to prevent the virus from replicating and causing disease. Efforts are underway at Penn and throughout the world to develop strategies that will enable drug therapy for HIV to be discontinued safely.
"This may provide a successful novel strategy to supplement anti-viral immune responses that complement approaches to target or control HIV reservoirs in patients infected with the virus," the authors said.

###

Co-authors on the study include Beth Haggarty, Kevin L. Hua, Jennifer Duong, Anthony J. Secreto, Andrea P.O. Jordon, Josephine Romano, Kritika Kumar, Joshua J. DeClercq, Philip D. Gregory, Carl H. June, and Michael J. Root.
The study was supported with grants from the National Institutes of Health (U19 AI117950, U19 AI082628, and P30 AI045008) and the Penn Center for AIDS Research

UniQure to cut up to 25% of Staff

http://www.uniqure.com/investors-newsroom/press-releases.php

uniQure expects to realize €5 to €6 million of annualized cost savings

 in personnel and other related operating expenses as a 

result of the elimination

 of approximately 50 to 60 positions, or 20% to 25% of global headcount,

 by the end of 2017. Additionally, the Company expects to

 further reduce planned 

operating expenses by €11 to €15 million over the next two years through

 the focusing of its pipeline. Based on its strong cash position

 and the above actions,

 uniQure believes its existing cash resources will be

 sufficient to fund operations into 2019

Jefferies 2016 London Healthcare Conference 9 AM EST Thursday

Sangamo BioSciences Announces Participation At Upcoming Investor Conferences

RICHMOND, Calif., Nov. 10, 2016 /PRNewswire/ -- Sangamo BioSciences, Inc. (NASDAQ: SGMO), the leader in therapeutic genome editing, announced today that Sandy Macrae, M.B., Ch.B., Ph.D., Sangamo's president and chief executive officer, will participate in the following conferences in November.

• Jefferies 2016 London Healthcare Conference, London, UK, November 16-17, 2016Dr. Macrae will present an update on the Company's therapeutic development programs on Thursday, November 17^th at 2:00 pm GMT. The presentation will be webcast live and may be accessed via a link on the Sangamo BioSciences website in the Investor Relations section under Events and Presentation for two weeks after the event.
• 28^th Annual Piper Jaffray Healthcare Conference, New York, NY, November 29-30, 2016Dr. Macrae will participate in a panel discussion on Tuesday, November 29^th at 3:00 pm ET. Webcasting services are not provided for this session.

About SangamoSangamo BioSciences, Inc. is focused on Pioneering Genetic Cures^™ for monogenic and infectious diseases by deploying its AAV-based gene therapy platform, and therapeutic genome editing and gene regulation platforms based on its novel zinc finger DNA-binding protein technology. The Company's proprietary zinc finger nuclease (ZFN)-mediated in vivo genome editing approach is focused on monogenic diseases, including hemophilia and lysosomal storage disorders MPS I and MPS II. Sangamo has initiated a Phase 1/2 clinical trial for hemophilia B, the first in vivo genome editing application cleared by the FDA. In addition, Sangamo has Phase 1/2 and Phase 2 clinical programs in HIV/AIDS (SB-728). The Company has also formed a strategic collaboration with Biogen Inc. for hemoglobinopathies, including sickle cell disease and beta-thalassemia, and with Shire International GmbH to develop therapeutics for Huntington's disease. It has established strategic partnerships with companies in non-therapeutic applications of its technology, including Dow AgroSciences and Sigma-Aldrich Corporation. For more information about Sangamo, visit the Company's website at www.sangamo.com.

Sangamo gets HIV mention

https://www.statnews.com/2016/10/25/crispr-identifies-hiv-genes/

CRISPR identifies genes that might be targeted to hobble HIV infection

.....

The hope is that using genome editing to change one or more such genes in T cells will prevent or vanquish AIDS. Current therapies keep infections at bay but do not eliminate the virus from a patient’s immune system. Patients must therefore take antiretroviral drugs for the rest of their lives. In its clinical trials of editing the CCR5 gene, Sangamo Biosciences has found ⁷that patients’ viral load fell and, in some cases, stayed low even without HIV/AIDS drugs; updated results are expected in 2017, said company spokesperson Elizabeth Wolffe.

Whether editing genes other than CCR5 might help patients is unknown, said Michael Holmes, Sangamo’s vice president of research. The UCSF study did “a good job” of using CRISPR to identify additional potential HIV targets, he said, but “CCR5 and CXCR [another gene] still seem to be the best targets, which is not to say that additional ones might not be useful.”

.....

'Gene therapy in a box' effective, reports Nature Communications - Stem Cells

A table-top device that enables medical staff to genetically manipulate a patient's blood to deliver potential new therapies for cancer, HIV and other diseases would eliminate the need for multi-million-dollar "clean rooms," making gene therapy more possible for even the poorest of countries.
The so-called "gene therapy in a box," developed by scientists at Fred Hutchinson Cancer Research Center, delivered modified blood stem cells that were as good as -- or better -- than those manufactured in highly regulated clean rooms -- and required less than half the staff, according to a study that will be published on Oct. 20 in Nature Communications. The adapted cells also successfully repopulated the blood system when tested in two different animal models, the study noted. It hasn't been tested in humans.
The portable device suggests a solution to one of the most vexing challenges of gene therapy: How to make these emerging, high-tech treatments accessible and affordable beyond a handful of specialized research centers to clinics worldwide.
"We either had to think about how to build million-dollar-infrastructure and clean-room facilities in clinics all around the world, which is not feasible, or we had to think about simplifying this process into what I originally envisioned as a black box," said Fred Hutch researcher Dr. Jennifer Adair, the study's lead author. "This was the first proof that 'gene therapy in a box' could work."
Gene therapies or cell therapies that involve genetically modified cells today are available at only a limited number of research centers that can afford the necessary technology and the highly trained staff. Adair said there are a dozen or so worldwide.
No gene therapies are approved yet for use in the United States. But thousands of patients with at least 15 or 20 inherited or infectious diseases and cancers are being treated with experimental therapies, and many are showing promise.
The semi-automated "point of care" delivery system developed by Adair's team using instrumentation available from Miltenyi Biotec reduces the space required to produce the modified cells from 500 square feet to less than 5 square feet and the staffing from five or 10 people to one or two, according to oncologist Dr. Hans-Peter Kiem, a Fred Hutch and University of Washington cell and gene therapy researcher and the paper's senior author.
"This is truly transformative," Kiem said. "It will change the way we manufacture and deliver cell and gene therapy products and will have a major impact on making stem cell gene therapy and transplantation and likely also immunotherapy available to patients with genetic diseases, HIV and cancer worldwide."
The "box" itself costs about $150,000 to purchase -- a one-time investment that would be used for thousands of patients. An individual kit specific to the disease being treated would cost about $26,000, Adair said. Though not inexpensive, the box could drive down costs of gene therapy because it requires less infrastructure and staffing. Even putting aside the clean-room and other infrastructure costs, it could be less than what cell-based gene therapy treatment costs research institutions now -- between $38,000 and $55,000, according to Adair.
What's more, the cost of what could be a one-time treatment compares favorably to lifetime care for many diseases. Take HIV, for example: lifetime treatment with antiretroviral drugs to suppress the virus is estimated to cost about $600,000.
An idea takes root
The innovation can be traced to 2008, when Kiem hired Adair to run a clinical trial for a gene therapy to treat glioblastoma, the deadliest form of brain cancer. The study called for extracting a patient's blood stem cells and inserting a special "resistance" gene designed in the laboratory to protect blood cells from damage by chemotherapy drugs. Infused back into the patient, the resistant cells would multiply and allow glioblastoma patients to receive higher doses of the cancer-killing chemo than they otherwise could withstand.
Stem cell-based gene therapy involves removing blood or bone marrow from patients, separating out the stem cells -- which give rise to all blood and immune cells in the body -- and using a deactivated virus to transfer genetic instructions for treating or preventing a disease into the cells. (Scientists also are investigating the use of targeted nucleases such as CRISPR to edit genes, but most gene therapies now being tested in humans rely on viral vectors.) After being infused back into the patient, the stem cells propagate new cells that carry the modification.
For Adair, the idea for gene therapy in a box was planted in 2009. She was on her way home in a taxi at 1 a.m. after having delivered genetically modified cells to the first patient in the newly launched brain cancer trial. Snatching only a few hours for sleep, Adair spent most of four days in a strictly regulated clean room where every bathroom break meant having to wash and suit up again in sterile clothing. The 96-hour marathon of time-sensitive, near-constant work left her physically and mentally exhausted.
"How are we ever going to be able to do this for more than one cancer patient a week?" she remembered thinking. "It just seemed harrowing."
Fast-forward five years, and blood stem cell-based gene therapy, though still experimental, was exploding. Patients in that early-phase brain cancer trial were living months or even years longer than most people with glioblastoma survive. Adair was running additional clinical trials, including one for a rare blood disorder called Fanconi anemia, and Kiem got a grant to investigate cell and gene therapy for curing HIV, the virus that causes AIDS -- once considered unimaginable.
It was at a 2014 conference on that HIV cure research that Adair had her second epiphany, this time about costs.
More than 25 million of the estimated 36.7 million people worldwide living with HIV are in sub-Saharan Africa, according to the World Health Organization. No country there could support multi-million-dollar clean rooms or afford the sky-high costs of whatever therapies might come out of them.
Adair remembers sitting at the conference and thinking, "If we cure HIV in a patient in the U.S., how are we ever going to get this to the countries that need it?'"
'Why not now?'
Adair had heard other gene therapy researchers dismissing questions about accessibility by saying, "First we have to show gene therapy works, and then we'll worry about that."
She wasn't buying it.
"Why not now?" she remembered thinking. "Is there a way we could do this, in a simplified fashion?"
With Kiem's encouragement, when Adair became head of her own lab in 2014, she used her Fred Hutch start-up funding to work on finding a way to make these still experimental therapies available and affordable wherever they are needed.
In the brain cancer clinical trial, Adair used a first-generation device made by Miltenyi Biotec to separate the stem cells from other blood cells. It involved adding specialized metal beads to bone marrow removed from patients, then used a magnet to pull out the stem cells.
But when she started working on a clinical trial for Fanconi anemia, a rare genetic disorder that leads to bone marrow failure, she needed something faster. Such patients have a tiny number of stem cells to begin with, and those are very susceptible to damage from exposure to ambient oxygen. To limit their exposure time, Adair had to find a way to speed up the process of separating and modifying the cells.
Serendipitously, Miltenyi had just sent over a demonstration model of a second-generation machine that automated and sped up the bead and magnet process and also happened to be capable of processing the exact volumes of bone marrow Adair needed for the trial. Working with Miltenyi's Tim Waters, Adair directed reprogramming of the device to see if it could meet her timetable. When initial tests worked, the Hutch bought the new machine and got federal approval to use it in the Fanconi anemia trial, treating the first patient in 2014.
The whole time she was thinking, "I want to make this device do everything."
The Miltenyi machine, called the CliniMACS Prodigy™, was small enough. It was a closed system, meaning no exposure to ambient air. It could be automated. Its interface was similar to an apheresis machine, another clinical device that separates blood into its components and which hospital staffs in many developing countries already are trained to use.
Adair shared her grand vision with Waters, who is a co-author on the Nature Communications paper. It called for reconfiguring and reprogramming the device to do all of the steps, including the clean-room jobs of adding the viral vector and removing residual reagents, then developing components specific to each disease that would be available in "kits" and kept in pharmacy freezers. Included in each kit would be disposable tubing to carry the patient's blood cells from a sterile bag into the machine. A nurse would attach the bag to the machine, add chemical reagents from the kit to pull out the stem cells, nutrients to support the growth of those cells and the viral vector engineered to do the gene transfer for that disease. Additional disposable tubing would carry the modified cells to a second sterile bag that would go right into the patient's IV.
Reconfiguring the device meant tedious calculations, mechanical tests and relearning physics principles she'd forgotten from college -- things she hadn't imagined ever doing, said Adair.
Adair and her team, which includes other Fred Hutch researchers and scientists at Washington State University, spent the last 18 months developing the device, comparing the products produced to those manufactured in clean rooms and testing the modified cells in animal models, key prerequisites to obtaining U.S. Food and Drug Administration consent to test the products in humans. She is hoping to send a box to a clinic that is not in a high-tech research center to test its ease of use.
"There are probably 1,000 modifications that could improve how efficient it is," she said. "But by making a platform that doesn't require you to be at one of the expert academic institutions for gene therapy, we're facilitating more people being able to explore these processes and potentially incorporate their own changes."

Sangamo BioSciences Announces Participation In Upcoming Scientific Conferences

RICHMOND, Calif., Oct. 17, 2016 /PRNewswire/ -- Sangamo BioSciences, Inc. (NASDAQ: SGMO), the leader in therapeutic genome editing, announced today that members of the Company's research and development team will participate in the following scientific conferences in October.

• European Society of Gene and Cell Therapy, Florence, Italy, October 18-21, 2016On Friday, October 21, 2016, Michael Holmes, Ph.D., Sangamo's vice president of research, is an invited speaker and will present an overview of the Company's therapeutic zinc finger nuclease (ZFN)-mediated in vivo genome editing programs for Mucopolysaccharidosis Type I (MPS I, Hurler syndrome) and Mucopolysaccharidosis Type II (MPS II, Hunter syndrome).
• The National Hemophilia Foundation's 13^th Workshop on Novel Technologies and Gene Transfer for Hemophilia, Washington, D.C., October 21-22, 2016Brigit Riley, Ph.D., Sangamo's director of discovery and translational research, has been invited to present an overview of data from the Company's ZFN-mediated in vivo genome editing approach for the treatment of monogenic disease, as well as its adeno-associated virus (AAV) cDNA based gene therapy approach for the treatment of hemophilia A.  Dr. Riley's presentations will take place during the Gene Editing and Cell Therapy session on Friday, October 21^st.

Webcasting services are not provided at the conferences listed above.
About Sangamo
Sangamo BioSciences, Inc. is focused on Engineering Genetic Cures^® for monogenic and infectious diseases by deploying its novel zinc finger DNA-binding protein technology, in therapeutic genome editing and gene regulation, and AAV-based gene therapy platforms. The Company's proprietary ZFN-mediated in vivo genome editing approach is focused on monogenic diseases, including hemophilia and lysosomal storage disorders. Based on its in vivo genome editing approach, Sangamo is initiating a Phase 1/2 clinical trial for hemophilia B, the first in vivo genome editing application cleared by the FDA. In addition, Sangamo has a Phase 2 clinical program to evaluate the safety and efficacy of novel ZFP Therapeutics^® for the treatment of HIV/AIDS (SB-728). The Company has also formed a strategic collaboration with Biogen Inc. for hemoglobinopathies, such as sickle cell disease and beta-thalassemia, and with Shire International GmbH to develop therapeutics for Huntington's disease. It has established strategic partnerships with companies in non-therapeutic applications of its technology, including Dow AgroSciences and Sigma-Aldrich Corporation. For more information about Sangamo, visit the Company's website at www.sangamo

Sangamo Hemophilia B Trial Open - as of 10/12/16

Verify on  https://clinicaltrials.gov/

Ascending Dose Study of Genome Editing by the Zinc Finger Protein (ZFP) Therapeutic SB-FIX in Severe Hemophilia B

This study is currently recruiting participants. (see Contacts and Locations)

Verified October 2016 by Sangamo Biosciences

Sponsor:

Sangamo Biosciences

Information provided by (Responsible Party):

Sangamo Biosciences

ClinicalTrials.gov Identifier:

NCT02695160

First received: February 24, 2016

Last updated: October 12, 2016

Last verified: October 2016

History of Changes

Michael Holmes comments on CRISPER Sickle Cell research

http://www.nature.com/news/crispr-deployed-to-combat-sickle-cell-anaemia-1.20782

In a paper published 12 October in Science Translational Medicine¹, researchers reported some success in correcting the mutation in mice, though they concede that human applications are still years away. The efficiency of the process is also slightly too low for practical use, cautions author Jacob Corn, a biochemist at the University of California, Berkeley.

The refined technique will be a boon for researchers looking at other applications of gene editing, says Michael Holmes, vice-president of research at Sangamo Biosciences in Richmond, California. But it also highlights another problem: the attempts at gene editing leave plenty of genes with a deletion where the Cas9 enzyme cut. Some of those deletions could result in abnormal haemoglobin production — causing another serious condition called β-thalassaemia.
Sangamo also ran up against this problem, Holmes says, and decided to try a different approach. The company, and several others in the field, are using gene editing to disrupt expression of a gene that suppress the production of fetal-haemoglobin: a form of haemaglobin that is expressed in the developing fetus and resists sickling. Boosting the production of fetal-haemoglobin could thereby reduce the amount of sickle-shaped haemoglobin in adults.

Monsanto Licenses EXZACT PRECISION TECHNOLOGY !!!!!!!!!!!!

ST. LOUIS & INDIANAPOLIS--(BUSINESS WIRE)--Monsanto Company (NYSE: MON) and Dow AgroSciences LLC, a wholly-owned subsidiary of The Dow Chemical Company (NYSE: DOW), announced today that the companies have reached a non-exclusive global option and licensing agreement on Dow AgroSciences’ EXZACT™ Precision Technology^® Platform for research and commercial development of new crop solutions across Monsanto Company’s research portfolio.
EXZACT technology, which Dow AgroSciences has developed under an exclusive license and collaboration agreement in plants with Sangamo        BioSciences, Inc., facilitates the creation of crop varieties and lines having improved traits.
“Monsanto is pleased to pursue applications of this genome-editing technology for the development of new plant discoveries and solutions for farmers,” said Tom Adams, Ph.D., biotechnology lead for Monsanto. “Zinc finger nucleases are a well-established technology for gene editing and this license, together with our existing and other licensed technology, will allow us to pursue product development while further enabling our growing body of research in this emerging field.”
“EXZACT technology is helping to deliver next generation crop improvements into the hands of farmers,” said Daniel R. Kittle, Ph.D., vice president, research and development, Dow AgroSciences. “Broad adoption of EXZACT by industry partners, such as Monsanto, expands access to solutions that will improve grower productivity and profitability.”
Both companies noted that genome-editing technology and the broad array of emerging genome-editing techniques, including the zinc finger nuclease (ZFN) technology in EXZACT, represent key scientific applications that can deliver breakthroughs in agriculture. Monsanto believes that genome-editing technologies will enable plant breeders to deliver better hybrids and varieties more efficiently, as well as offer plant scientists additional resources to provide new improvements in plant biotechnology.
Additional terms of the agreement were not disclosed.

Management Changes at uniQure

Sep 22, 2016

uniQure Announces Management and Board Changes

Lexington, MA and Amsterdam, the Netherlands, September 22, 2016 — uniQure N.V. (NASDAQ: QURE), a leader in human gene therapy, today announced that its Board of Directors has accepted the resignation of Daniel Soland as chief executive officer (CEO) and an executive member of the Board, effective immediately.  The Board is pleased to announce that Matthew Kapusta, the Company’s chief financial officer (CFO) since January 2015 who also serves as an executive member of the Board, has been appointed interim CEO.  In addition, Philip Astley-Sparke, a member of the Board of Directors and former President of uniQure’s US operations, has been elected unanimously by the Board to serve as its Chairman.

“My decision to resign as Chief Executive Officer is due solely to personal family reasons,” stated Mr. Soland, “I regret the abrupt nature of this decision but believe that it is in the best interests of uniQure, its employees and shareholders to ensure that the business has the fully committed leadership it requires. I have continued confidence in the Company’s gene therapy platform, its research and clinical development programs and its leadership in manufacturing.  I wish everyone associated with the Company tremendous success.”

“We thank Dan for his service to uniQure and wish him well,” stated Philip Astley-Sparke, chairman of the board of uniQure.  “We are fortunate to be able to rely on the continued leadership of Matt Kapusta as interim CEO.  Since joining the Company nearly two years ago, Matt has been instrumental in completing our landmark collaboration with Bristol-Myers Squib, recapitalizing the Company and, more recently, guiding an ongoing, comprehensive strategic planning process.  The Board looks forward to working closely with Matt and the leadership team.”

“This is an exciting and important time for the Company as we advance our hemophilia B program into a potential pivotal trial and more clearly define our focus through the completion of our strategic planning process,” stated Mr. Kapusta.  “I am personally energized and fully committed to driving success at uniQure and ensuring the execution of our key objectives.”

Mr. Kapusta will continue to serve as CFO and rely on the support of the company’s Global Controller, Christian Klemt, to advance the daily responsibilities of the finance team.

“At this time, the Board has elected not to initiate a search process for a permanent CEO while the Company focuses on implementing the corporate strategy being finalized with Matt and the leadership team,” stated Mr. Astley-Sparke.

Following Mr. Soland’s resignation, the Company’s Board of Directors currently consists of seven members, of whom four are independent within the meaning of the applicable Nasdaq rules.  As a consequence, the Company is in compliance with Nasdaq Listing Rule 5605, which requires that at least a majority of the Board consist of independent directors.

About uniQure
uniQure is delivering on the promise of gene therapy – single treatments with potentially curative results. We are leveraging our modular and validated technology platform to rapidly advance a pipeline of proprietary and partnered gene therapies to treat patients with liver/metabolic, central nervous system and cardiovascular diseases. www.uniQure.com

Nature Mag - Gene therapy: A new chapter - Sangamo Mention

http://www.nature.com/nature/journal/v537/n7621_supp/full/537S158a.html
Lots of competition !
Great review of LSD programs, here is the Sangamo mention:

The AAVs' payload can be combined with nuclease enzymes for gene editing. This enables the gene to be spliced into the cell's DNA at a predetermined location, reducing the risk of an off-target insertion. Researchers at Sangamo BioSciences in Richmond, California, use AAVs to deliver zinc-finger nucleases and IDUA to liver cells in the patient's body.
“We only have to edit a small number of liver cells, predicted to be less than 1%,” says Michael Holmes, Sangamo's vice-president of research. “That will give a sufficient amount of enzyme to be therapeutic.” As the liver grows, it replicates the edit, generating enzymes throughout the person's life. Sangamo is planning a phase I/II trial involving up to 12 adults with Hurler syndrome this year, and hopes to begin a trial for Hunter syndrome (MPS II) next year.

Cell & Gene Meeting on the Mesa Oct 5-7 Sandy Macrae - Panelist

About the Event The Cell & Gene Meeting on the Mesa is a three-day conference bringing together senior executives and top decision-makers in the industry with the scientific community to advance cutting-edge research into cures. The meeting features a nationally recognized Scientific Symposium, attended by leading researchers and clinical experts from around the globe, in conjunction with the industry's premier annual Partnering Forum, the first event of its kind dedicated solely to facilitating connections in this sector. Combined, these meetings attract over 800 attendees, fostering key partnerships through more than 700 one-on-one meetings while highlighting the significant clinical and commercial progress in the field. Oct 5 GENE EDITING INTERVIEW {Ballroom 1}

10:30am – 11:15am

Gene editing, including CRISPR/Cas, TALENs, Zinc Finger Nucleases and other approaches, represents the ability to treat and potentially cure genetic disorders and other forms of disease by inserting, replacing or removing DNA using “molecular scissors,” or artificially engineered gene constructs. This interview will explore the current state of the science and both near-term and longer-term clinical and research applications.

Chair:

Blythe Thomson, M.D., Senior Director, Medical Affairs, Hematology and Oncology, Medpace

Speakers:

Alexandra Glucksmann, Ph.D., Chief Operating Officer, Editas Medicine

Sandy Macrae, Ph.D., President and CEO, Sangamo BioSciences

Prashant Mali, Ph.D., Assistant Professor, Department of Bioengineering, UC San Diego OCT 6 COMPANY PRESENTATIONS {Ballroom 1} 1:00pm – 1:15pm Sangamo BioSciences 1:15pm – 1:30pm bluebird bio 1:30pm – 1:45pm Editas Medicine 1:45pm – 2:00pm Intellia Therapeutics 2:00pm – 2:15pm Dimension Therapeutics 2:15pm – 2:30pm Voyager Therapeutics 2:30pm – 2:45pm Adverum Biotechnologies

Prospective Grant of Exclusive Patent License: The Development of an Anti-CD19 Chimeric Antigen Receptor (CAR) for the Treatment of Human Cancers

A Notice by the National Institutes of Health on 09/07/2016

AGENCY:

National Institutes of Health, HHS.

ACTION:

Notice.

SUMMARY:

This notice, in accordance with 35 U.S.C. 209 and 37 CFR part 404, that the National Institutes of Health, Department of Health and Human Services, is contemplating the grant of an exclusive patent license to practice the inventions embodied in the following Patents and Patent Applications and all continuing U.S. and foreign patents/patent applications to Sangamo BioSciences, Inc. located in Richmond, California, USA:

Intellectual Property

U.S. Provisional Patent Application 62/006,313, filed 2 June 2014 and entitled “Chimeric Antigen Receptors Targeting CD-19” [HHS Ref. E-042-2014/0-US-01]; and PCT Patent Application PCT/US2015/033473, filed 1 June 2015 and entitled “Chimeric Antigen Receptors Targeting CD-19” [HHS Ref. E-042-2014/0-PCT-02].

The patent rights in these inventions have been assigned and/or exclusively licensed to the Government of the United States of America.

The prospective exclusive license territory may be worldwide and the field of use may be limited to the use of Licensed Patent Rights for the following: “The integration of a monospecific anti-CD19 chimeric antigen receptor (CAR) into genome-edited, allogeneic T cells (where the donor and recipient are different), where the monospecific CAR has at least: (a) The complementary determining region (CDR) sequences of the anti-CD19 47G4 antibody; and (b) a T cell signaling domain, for the prophylaxis and treatment of CD19-positive malignancies.”

DATES:

Only written comments and/or applications for a license which are received by the NIH Office of Technology Transfer on or before September 22, 2016 will be considered.

ADDRESSES:

Requests for copies of the patent application, inquiries, comments, and other materials relating to the contemplated exclusive license should be directed to: David A. Lambertson, Ph.D., Senior Licensing and Patenting Manager, National Cancer Institute, 9609 Medical Center Drive, Rm. 1-E530 MSC9702, Rockville, MD 20850-9702, Email: david.lambertson@nih.gov.

End Preamble Start Supplemental Information

SUPPLEMENTARY INFORMATION:

This invention concerns an anti-CD19 chimeric antigen receptor (CAR) and methods of using the CAR for the treatment of CD19-expressing cancers, including B cell malignancies. With regard to the proposed license, the CAR covered by the invention will be integrated into a genome-edited allogeneic (where the donor and recipient of the T cell are different individuals) T cell, and the resulting anti-CD19 CAR-expressing genome-edited allogeneic T cell will be introduced into a cancer patient to exhibit a therapeutic effect. CD19 is a cell surface antigen that is preferentially expressed on certain types of cancer cells, particularly cancers of B cell origin such as Non-Hodgkin's Leukemia (NHL), acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL). The anti-CD19 CARs of this technology contain (1) antigen recognition sequences that bind specifically to CD19 and (2) signaling domains that can activate the cytotoxic functions of a T cell. The anti-CD19 CAR can be integrated into genome-edited allogeneic T cells; from there, genome-edited allogeneic T cells expressing the anti-CD19 CAR are selected, expanded and then introduced into a patient. Once the anti-CD19 CAR-expressing genome-edited allogeneic T cells are introduced into the patient, the T cells can selectively bind to CD19-expressing cancer cells through its antigen recognition sequences, thereby activating the T cell through its signaling domains to selectively kill the cancer cells. Through this mechanism of action, the selectivity of the a CAR allows the T cells to kill cancer cells while leaving healthy, essential cells unharmed. This can result in an effective therapeutic strategy with fewer side effects due to less non-specific killing of cells.

The prospective exclusive license will be royalty bearing and will comply with the terms and conditions of 35 U.S.C. 209 and 37 CFR part 404.7. The prospective exclusive license may be granted unless within fifteen (15) days from the date of this published notice, the NIH receives written evidence and argument that establishes that the grant of the license would not be consistent with the requirements of 35 U.S.C. 209 and 37 CFR part 404.7.

Complete applications for a license in the prospective field of use that are filed in response to this notice will be treated as objections to the grant of the contemplated Exclusive Patent License Agreement. Comments and objections submitted to this notice will not be made available for public inspection and, to the extent permitted by law, will not be released under the Freedom of Information Act, 5 U.S.C. 552.

Start Signature

Dated: August 31, 2016.

Richard U. Rodriguez,

Associate Director, Technology Transfer Center, National Cancer Institute.

End Signature End Supplemental Information

[FR Doc. 2016-21366 Filed 9-6-16; 8:45 am]

BILLING CODE 4140-01-P

Additional Source of Revenue - Merck

Merck Launches New Gene Editing Technology to Engineer Virus Resistant CHO Cell Lines

PR Newswire

DARMSTADT, Germany, Sept. 8, 2016

– Enhances viral safety while maintaining cell line productivity, protein quality
DARMSTADT, Germany, Sept. 8, 2016 /PRNewswire/ — Merck, a leading science and technology company, today launched a first-of-its-kind gene editing technology to modify CHO cell lines to be resistant to minute virus of mice (MVM), a common contamination threat that remains despite the shift to chemically defined, animal component-free manufacturing processes. CHO cells are commonly used in the manufacture of biologics.
Photo – http://photos.prnewswire.com/prnh/20160906/404353
Merck’s new Centinel^™ technology targets genes which play a role in MVM susceptibility. Viral contaminations like MVM can have major consequences for biopharmaceutical manufacturers, costing hundreds of millions of dollars, according to industry reports. The greatest impact of such contamination is on patients, as access to therapies can be put in jeopardy. Centinel^™ technology provides manufacturers with an additional path for mitigating the risk of MVM contamination, while maintaining an equivalent level of protein quality and cell line productivity.
“The Centinel^™ program is just one example of how we are combining years of expertise and credibility in process development, biologics manufacturing and gene editing tools to increase safety for our customers and their patients,” said Udit Batra, member of the Merck Executive Board and CEO, Life Science. “We are also leveraging this unique combination of experience and technologies to address some of the industry’s most complex challenges and exciting applications, including cell therapy.”
Under the Centinel^™ program, Merck can modify customers’ CHO cell lines to provide viral resistance to MVM. A patent application has been submitted for the technology used in the gene editing approach to viral resistance.
The company’s BioReliance^® testing services can validate MVM resistance and demonstrate the virus is not propagated in the cell line. Alternatively, customers can purchase the zinc finger nuclease pairs to engineer cell lines directly.
Merck’s new Centinel^™ technology builds on the company’s expertise in gene editing and biomanufacturing processes, as well as its in-depth understanding of the regulatory environment. In addition to enhancing the safety of biomanufacturing, Merck is also applying this expertise and approach to develop other technologies and services, including those supporting the cell therapy industry.
All Merck news releases are distributed by email at the same time they become available on the Merck website. Please go to www.merckgroup.com/subscribe to register online, change your selection or discontinue this service. 

Reactivating Fetal Hemoglobin Expression in Human Adult Erythroblasts Through BCL11A Knockdown Using Targeted Endonucleases

http://www.nature.com/mtna/journal/v5/n8/full/mtna201652a.html

Carmen F Bjurström¹, Michelle Mojadidi¹, John Phillips², Caroline Kuo³, Stephen Lai¹, Georgia R Lill¹, Aaron Cooper¹, Michael Kaufman¹, Fabrizia Urbinati¹, Xiaoyan Wang⁴, Roger P Hollis¹ and Donald B Kohn^1,3

1. ¹Department of Microbiology, Immunology, & Molecular Genetics, University of California, Los Angeles, Los Angeles, California, USA
2. ²Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, California, USA
3. ³Department of Pediatrics, University of California, Los Angeles, Los Angeles, California, USA
4. ⁴Department of General Internal Medicine and Health Services Research, University of California, Los Angeles, Los Angeles, California, USA

Correspondence: Donald B Kohn, Department of Microbiology, Immunology, & Molecular Genetics, University of California, Los Angeles, 3163 Terasaki Life Sciences Building (TLSB) 610 Charles E. Young Drive, East, Los Angeles, California 90095–7364, USA. E-mail: dkohn@mednet.ucla.edu

Received 17 April 2016; Accepted 18 April 2016

Abstract

We examined the efficiency, specificity, and mutational signatures of zinc finger nucleases (ZFNs), transcriptional activator-like effector nucleases (TALENs), and clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 systems designed to target the gene encoding the transcriptional repressor BCL11A, in human K562 cells and human CD34⁺ progenitor cells. ZFNs and TALENs were delivered as in vitro transcribed mRNA through electroporation; CRISPR/Cas9 was codelivered by Cas9 mRNA with plasmid-encoded guideRNA (gRNA) (pU6.g1) or in vitro transcribed gRNA (gR.1). Analyses of efficacy revealed that for these specific reagents and the delivery methods used, the ZFNs gave rise to more allelic disruption in the targeted locus compared to the TALENs and CRISPR/Cas9, which was associated with increased levels of fetal hemoglobin in erythroid cells produced in vitro from nuclease-treated CD34⁺ cells. Genome-wide analysis to evaluate the specificity of the nucleases revealed high specificity of this specific ZFN to the target site, while specific TALENs and CRISPRs evaluated showed off-target cleavage activity. ZFN gene-edited CD34⁺ cells had the capacity to engraft in NOD-Prkdc^SCID-IL2Rγ^null mice, while retaining multi-lineage potential, in contrast to TALEN gene-edited CD34⁺ cells. CRISPR engraftment levels mirrored the increased relative plasmid-mediated toxicity of pU6.g1/Cas9 in hematopoietic stem/progenitor cells (HSPCs), highlighting the value for the further improvements of CRISPR/Cas9 delivery in primary human HSPCs.

FierceBiotech Reports: Shire Abandons Baxalta Aquired Hemophilia Program

From the FierceBiotech website:
http://www.fiercebiotech.com/biotech/shire-cans-baxalta-hemophilia-b-gene-therapy-thinning-field-for-uniqure-spark

Shire ($SHPG) has scrapped plans to further develop BAX 335, a hemophilia B gene therapy it gained in its $32 billion takeover of Baxalta. The move will see Shire focus its attention on a preclinical gene therapy program it thinks has a better chance of success, clearing the path for uniQure ($QURE) and Spark Therapeutics ($ONCE) to beat their bigger rival to market.
Baxalta had advanced the gene therapy as far as a Phase I/II clinical trial, early data from which were released more than one year ago. Those results showed the gene therapy, which uses an AAV8 vector to deliver factor IX (FIX) Padua, elevated the FIX activity of one participant by 20% to 25% for a full year. Yet, while this represented a success for this one patient over that period of time, the overall, longer-term dataset has failed to convince Shire that BAX 335 is worth pursuing.
“The expression was good but it was a little inconsistent between different patients. And, with time for some patients, the level of expression decreased,” Philip Vickers, head of R&D at Shire, said on a conference call with investors to discuss the company’s second-quarter results.
Shire plans to use the experience gained in the clinic to shape a preclinical program. Vickers said the team has an idea of some of the technical factors that could account for the inconsistency and slide in activity over time. And, with the Phase I/II trial showing that when the AAV8 vector works, it works well, Shire thinks it has the makings of an effective asset. Baxalta, through its then parent company Baxter ($BAX), acquired the AAV8 vector in the $70 million takeover of Chatham Therapeutics.
The decision to scrap BAX 335 removes one of the more advanced riders from the congested race to bring a hemophilia B gene therapy to market. As recently as last month, Baxalta was revising the list of clinical trial sites in the Phase I/II study and BAX 335 was still penciled in to start Phase III this year. Now, Shire has pulled the plug on the trial, shortening the odds that one of the biotechs leading the pack will bring a hemophilia B gene therapy to market before their bigger rival.
UniQure and Spark have both delivered some clinical data on their gene therapies, while Dimension Therapeutics ($DMTX) and Sangamo Biosciences ($SGMO) are closing in on that point, too. Of the group, uniQure is seen by investors as having the most to gain from the scrapping of BAX 335. The share price of the Dutch biotech, which has taken repeated hits over the past year, rose 8.5% on the day Shire revealed its decision. Dimension, Sangamo and Spark all closed down.

Interesting Data presented at International Aids Conference 2016

https://www.buzzfeed.com/azeenghorayshi/repeating-the-berlin-patient?utm_term=.aodGGEgvq#.fiObbNGnj

(snip)
Some of the patients received transplants with the mutation, and others did not. By comparing these two groups, the researchers wanted to see whether Brown’s cure was the result of the CCR5 mutation, or of simply getting infused with foreign cells. (Bone marrow transplants often come with “graft-versus-host disease,” which kills off the body’s native cells and, some speculate, could be involved in wiping out HIV.)
The trial’s initial results are encouraging, Wensing said, though it’s still unclear whether the results are due to the CCR5-altered cells, the bone marrow transplant itself, or the standard antiretroviral medications.
Of the three individuals who have made it three years since their transplants, two received normal bone marrow cells and one received the HIV-resistant type. One of the individuals who received the normal type cells luckily avoided graft-versus-host disease. The other two — one of whom had HIV-resistant cells, and one of whom didn’t — did experience graft-versus-host. Both of these individuals now have undetectable levels of their own immune cells in their blood, but also have undetectable levels of HIV. The other patient has low levels of their own immune cells and HIV still detectable in their blood.
It will take some work to determine how the various factors are at play, but Wensing says the worst is over since the three patients are healthy and cancer-free. The next step will be deciding whether the patients will go off their antiretroviral medications, to see whether the bone marrow transplants were solely responsible for eradicating their HIV.
The researchers did not present any results from the other three patients in the trial, who got their transplants less than three years ago.

Do CRISPR enthusiasts have their head in the sand about the safety of gene editing?

https://www.statnews.com/2016/07/18/crispr-off-target-effects/

At scientific meetings on genome-editing, you’d expect researchers to show pretty slides of the ribbony 3-D structure of the CRISPR-Cas9 molecules neatly snipping out disease-causing genes in order to, everyone hopes, cure illnesses from cancer to muscular dystrophy. Less expected: slides of someone kneeling on a beach with his head in the sand.

Yet that is what Dr. J. Keith Joung of Massachusetts General Hospital showed at the American Society of Hematology’s workshop on genome-editing last week in Washington. While the 150 experts from industry, academia, the National Institutes of Health, and the Food and Drug Administration were upbeat about the possibility of using genome-editing to treat and even cure sickle cell disease, leukemia, HIV/AIDS, and other blood disorders, there was a skunk at the picnic: an emerging concern that some enthusiastic CRISPR-ers are ignoring growing evidence that CRISPR might inadvertently alter regions of the genome other than the intended ones.

“In the early days of this field, algorithms were generated to predict off-target effects and [made] available on the web,” Joung said. Further research has shown, however, that such algorithms, including one from MIT and one called E-CRISP, “miss a fair number” of off-target effects. “These tools are used in a lot of papers, but they really aren’t very good at predicting where there will be off-target effects,” he said. “We think we can get off-target effects to less than 1 percent, but we need to do better,” especially if genome-editing is to be safely used to treat patients.

That, of course, is the hope of companies including Editas Medicine, which Joung cofounded, CRISPR Therapeutics, Caribou Biosciences, and Sangamo BioSciences, which all presented at the ASH workshop.

Read More

They’re going to CRISPR people. What could possibly go wrong?

Off-target effects occur because of how CRISPR works. It has two parts. RNA makes a beeline for the site in a genome specified by the RNA’s string of nucleotides, and an enzyme cuts the genome there. Trouble is, more than one site in a genome can have the same string of nucleotides. Scientists might address CRISPR to the genome version of 123 Main Street, aiming for 123 Main on chromosome 9, only to find CRISPR has instead gone to 123 Main on chromosome 14.
In one example Joung showed, CRISPR is supposed to edit a gene called VEGFA (which stimulates production of blood vessels, including those used by cancerous tumors) on chromosome 6. But, studies show, this CRISPR can also hit genes on virtually every one of the other 22 human chromosomes. The same is true for CRISPRs aimed at other genes. Although each CRISPR has zero to a dozen or so “known” off-target sites (where “known” means predicted by those web-based algorithms), Joung said, there can be as many as 150 “novel” off-target sites, meaning scientists had no idea those errors were possible.
One reason for concern about off-target effects is that genome-editing might disable a tumor-suppressor gene or activate a cancer-causing one. It might also allow pieces of two different chromosomes to get together, a phenomenon called translocation, which is the cause of chronic myeloid leukemia, among other problems.
Many researchers, including those planning clinical trials, are using web-based algorithms to predict which regions of the genome might get accidentally CRISPR’d. They include the scientists whose proposal to use CRISPR in patients was the first to be approved by an NIH committee. When scientists assure regulators that they looked for off-target effects in CRISPR’d cells growing in lab dishes, what they usually mean is that they looked for CRISPR’ing of genes that the algorithms flagged.
As a result, off-target effects might be occurring but, because scientists are doing the equivalent of the drunk searching for their lost keys only under the lamppost, they’re not being found.

Read More

Federal panel approves first use of CRISPR in humans

One little-appreciated feature of CRISPR’s DNA-cutting enzyme is that it doesn’t stop at one. Even if the enzyme cuts its intended target, the risk of off-target cutting remains. The enzyme “still has energy to bind with off-target sites,” Joung said, so “it can still cleave those sites.”
Scientists from some of the leading genome-editing companies said they are confident they will be able to minimize off-target CRISPR’ing, by picking “high-quality” guide RNAs, among other methods. While “bad” RNAs hit as many as 152 wrong targets, studies show, good ones hit only one, and the algorithms “capture most of” the potential off-target effects, said Dr. Bill Lundberg, chief scientific officer of CRISPR Therapeutics. Still, he conceded, “At the end of the day we’re taking a cell where we can’t predict a priori where the edit has happened.”
Scientists have recently recognized another reason to worry about off-target effects: No two people’s genomes are identical. Off-target-identifying methods, which are based on a composite or “reference” human genome, might indicate that there are no stretches of DNA that CRISPR can mistakenly snip. But because of random mutations and genetic variations, some patients might have additional “123 Main Street”s, attracting CRISPR and its DNA-cutting enzyme where they’re not supposed to go.
“There are a significant percent of sites, more than I would have thought,” where that might happen, said Joung, “and it varies by ethnic group.”
Said Andrew May, chief scientific officer of Caribou: “There is going to have to be some consideration of that” as genome-editors try to bring CRISPR to patients.

Sharon Begley can be reached at sharon.begley@statnews.com
Follow Sharon on Twitter @sxbegle

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Fred Hutch HIV cure program extended, expanded

The National Institutes of Health today awarded a second five-year round of funding to defeatHIV, a public-private research group based at Fred Hutchinson Cancer Research Center that has spent the last five years investigating the use of genetically modified, HIV-resistant blood stem cells as a potential cure for the virus that causes AIDS.
“We’re excited and honored to be able to continue defeatHIV’s work and keep Fred Hutch at the center of HIV cure research, particularly in the area of cell and gene therapy,” said defeatHIV co-director Dr. Keith Jerome, a Fred Hutch virologist.
The new $23.5 million award will allow the group to tackle three new approaches that build on its earlier work. They include:

• Exploring CAR T-cell therapy, a type of immunotherapy that already is being hailed as a potent anti-cancer weapon, against HIV, in partnership with Seattle-based biopharmaceutical company Juno Therapeutics
• Using gene therapy to induce production of a synthetic “super antibody” to target HIV
• Adding a therapeutic vaccine to boost the proliferation and function of genetically modified HIV-resistant cells

All three new tactics have in common a focus on using the immune system to eradicate or at least control HIV.
“We’ve learned that the immune response — the patient’s immune system — plays a critical role in controlling HIV, just like in cancer,” said defeatHIV co-director Dr. Hans-Peter Kiem, a Fred Hutch stem cell transplant and gene therapy researcher. “It’s set the stage for the next generation of studies to further mobilize and harness the immune system to fight HIV.”
An ambitious agenda
DefeatHIV was one of six groups nationwide to receive a total of $150 million over the next five years from the NIH’s Martin Delaney Collaboratory: Towards an HIV-1 Cure program. That is double the number of research collaborations funded in the program’s first iteration in 2011.
The three original groups ­— based at Fred Hutch, the University of California San Francisco and the University of North Carolina at Chapel Hill — received funding again for new projects. Three new groups were added, based at George Washington University in Washington, D.C., the Wistar Institute in Philadelphia and Beth Israel Deaconess Medical Center in Boston.
Named in honor of a late HIV/AIDS activist who served on the advisory committee for the National Institute of Allergy and Infectious Diseases, or NIAID, the Martin Delaney program strongly encourages collaboration within and among research groups and between scientists and private industry. The goal is to translate research into the clinic as rapidly as possible.
“The two greatest challenges remaining in HIV/AIDS research are finding a cure and developing a safe and effective preventive vaccine,” said NIAID Director Dr. Anthony S. Fauci in a statement announcing the awards. “A simple, safe and scalable cure for HIV would accelerate progress toward ending the HIV/AIDS pandemic.”
Moving therapies to clinical trials is an ambitious aim considering that until about eight years ago, curing HIV was considered all but impossible.
The biggest success story for HIV came in 1996, when combination antiretroviral treatment turned the virus from a certain death sentence to a chronic manageable disease, at least for those who have access to the drugs and can tolerate them. But hopes that this treatment would eventually cure infection were dashed when scientists learned that the virus, which integrates itself into a person’s own DNA, can hide out in cells, dormant and out of reach of the drugs. Some likened HIV to the proverbial cockroach that can survive a nuclear blast: Stop treatment, and the virus comes back.
But in at least one case — that of Timothy Ray Brown — the virus did not roar back after the blast. In 2008, the world learned about the Seattle-born Brown, who while living in Berlin had undergone two grueling bone marrow transplants to treat acute myeloid leukemia. In what proved to be a successful attempt to also cure Brown’s HIV infection, his Berlin doctor found a stem cell donor who carried two copies of a rare gene mutation that confers natural resistance to the virus. Brown stopped taking antiretroviral drugs after the first transplant in 2007 and shows no sign of HIV.
In its first five years, defeatHIV used Brown’s cure as a blueprint for developing a less toxic therapy than the one he endured by seeking to genetically engineer resistance in an infected person’s own immune cells. In preclinical experiments, Kiem’s lab has successfully modified blood stem cells using a gene editing technique that employs molecules called zinc-finger nucleases and returned the resistant stem cells to repopulate the immune system.  Research into this approach will continue under a separate five-year grant to Kiem’s lab from the National Heart, Lung and Blood Institute, a division of the NIH. The biopharmaceutical company Sangamo Biosciences, which developed zinc-finger nucleases, will continue as a defeatHIV partner.
New approaches, new partners
The first new approach — engineering HIV-resistant and anti-HIV T cells — will be led by Fred Hutch virologist Dr. Larry Corey and immunology and infectious disease experts Drs. David Rawlings and Thor Wagner of the University of Washington and Seattle Children’s, along with Juno Therapeutics.
Researchers at Fred Hutch and elsewhere have been working on still-experimental therapies that genetically reprogram patients’ own T cells — a type of white blood cell that searches out and destroys pathogens — with synthetic receptors called chimeric antigen receptors, or CARs, to kill cancer cells bearing a particular marker. There are now dozens of clinical trials underway of CAR T cells for cancer, with promising early results.
DefeatHIV proposes to transfer this approach from cancer to HIV by producing CAR T cells that target markers expressed by cells that harbor HIV.
Corey, whose early work in treating herpes laid the groundwork for antiretroviral treatment for HIV and who now leads the world’s largest network for testing preventive HIV vaccines, will discuss the CAR T-cell approach as the keynote speaker at the upcoming 2016 Conference on Cell and Gene Therapy for HIV Cure on Aug. 4-5 at Fred Hutch.
The second new approach — genetically engineering the production of a synthetic broadly neutralizing antibody — will be led by Dr. Michael Farzan, professor of immunology and microbial science at the Scripps Research Institute in Jupiter, Florida. Farzan made headlines last year for developing a lab-made molecule that is more powerful than any antibody humans produce against HIV. In preclinical models, Farzan’s lab used a virus to insert a gene into muscle cells to direct production of this “super antibody” and showed that it protected against HIV infection. Farzan described his research at the 2015 Conference on Cell and Gene Therapy for HIV Cure, hosted by defeatHIV at Fred Hutch, which cemented the scientists’ decision to work together, according to Jerome.
The defeatHIV proposal calls for pairing each of these two new strategies with a latency-reversing agent developed by the biotechnology company Gilead  Biosciences to “wake up” the reservoir of dormant HIV so infected cells can be targeted by CAR T cells or Farzan’s broadly neutralizing antibodies. Reducing the viral reservoir is seen as key to an HIV cure.
Preclinical and limited human trials in Kiem’s and others’ labs have already shown that genetically modifying stem and T cells not only makes them resistant to HIV infection but improves immune function overall. So for the third new tactic, defeatHIV will seek to boost that immune response by adding a therapeutic vaccine. (A vaccine given before infection is called a preventive vaccine; it helps healthy people set up defenses against infection. Therapeutic vaccines are designed to treat people after they are infected by strengthening the body’s natural immune response. So far, neither type of vaccine has been successfully developed for HIV.)
“Even a small percentage of gene-edited cells help orchestrate an immune response against the virus,” said Jerome. “So we thought we could build on that going forward by adding a therapeutic vaccine.”
Leading the vaccine effort will be University of Washington microbiologists Dr. Jim Mullins, who already has a vaccine in clinical trials, and Dr. Deb Fuller.
In addition to its new partners, Jerome and Kiem stressed the continued partnership with the volunteer community members who make up its Community Advisory Board, or CAB.
“Our CAB is the model for community involvement around cure. It’s the greatest partner we could hope for,” said Jerome. “Representatives from the CAB are at pretty much all of our planning meetings to listen, to advise as we talk about clinical trials, for information flow in both directions. They wrote an incredibly strong section of the proposal for the grant.”
Hope and caution
The plan is that at least one and maybe more of these three strategies will be ready for clinical trials in the next four to five years, Jerome and Kiem said. And unlike clinical trials that tried to replicate Timothy Ray Brown’s transplant cure, the new strategies will not require testing in people with both HIV and cancer.
“Before, we talked about that we would have to test in patients with malignancies because we needed high-dose irradiation and chemotherapy for the transplant procedure,” harsh treatments that would only be appropriate if needed to also treat cancer, said Kiem.
In fact, efforts elsewhere to replicate Brown’s cure in patients who needed stem cell transplants as a last-resort cancer treatment have so far failed to show the same results. In part, these are often very ill patients to begin with; in most cases, they died from the cancer or the transplant before it could be determined whether their HIV was gone. Brown remains the only known person in the world to be cured of HIV.
As excited as the Hutch researchers are about the new, less toxic approaches and as optimistic as they are about getting to clinical trials, they remain cautious when it comes to using the word “cure,” whether for cancer or HIV.
“We’ve become a bit more careful in terms of the words ‘HIV cure,’” said Kiem, who works with both cancer and HIV patients. “It is difficult to determine whether every single cancer cell has been eliminated in the body after a bone marrow transplant. Yet we know we can cure the cancer because in many patients it does not return even after five or 10 years, and we know the immune system plays a critical role.”
HIV and the HIV reservoir pose a similar challenge. So far, there are no good tests or markers to tell for sure whether HIV might be still hiding in a few cells.
“It will take time to determine whether HIV has the potential to return, and we think just like in cancer, therapies establishing a solid immune system and response that can recognize HIV will be an important and critical part in our HIV cure effort,” Kiem said. “If HIV can be made undetectable, it is first like a remission and then after several years we will know whether it is a cure, just like in cancer. Many investigators have also come to the conclusion that this is a very reasonable first step and expectation.”

UPENN Receives HIV Grant

PHILADELPHIA—(July 13, 2016)—The Wistar Institute is pleased to announce that the National Institutes of Health (NIH) has awarded a nearly $23 million Martin Delaney Collaboratories for HIV Cure Research grant to the BEAT-HIV: Delaney Collaboratory to Cure HIV-1 Infection by Combination Immunotherapy (BEAT-HIV Delaney), a consortium of top HIV researchers led by co-principal investigators Luis J. Montaner, D.V.M., D.Phil., director of the HIV-1 Immunopathogenesis Laboratory at The Wistar Institute Vaccine Center, and James L. Riley, Ph.D., research associate professor at the Perelman School of Medicine at the University of Pennsylvania.
The Philadelphia-based BEAT-HIV Delaney project is one of six grants awarded by the Delaney initiative, joining a highly-selective group of U.S.-led teams charged with advancing the global efforts to develop a cure for HIV. The five-year award promotes a preeminent partnership of more than 30 leading HIV investigators from The Wistar Institute, the University of Pennsylvania, Philadelphia FIGHT, Rockefeller University, VA San Diego Healthcare System, Johns Hopkins University, the University of Nebraska-Lincoln, and the University of Utah working with government, non-profit, and industry partners to test combinations of several novel immunotherapies under new preclinical research and clinical trials.
With 37 million people now living with HIV worldwide and 17 million receiving antiretroviral therapy, the Martin Delaney Collaboratories for HIV Cure Research initiative reflects the interest in HIV cure research that has grown into a global priority over the last five years and follows President Obama’s call for increased HIV cure research.
“The lifelong stigma, economic burden on society, strain on healthcare resources, and sheer toll on human life across the globe makes finding a cure a top priority,” said Montaner. “Together we’re building on our teams’ extensive established efforts to move forward and make those next transformative steps that will bring us closer to an HIV cure.”
Three Research Pillars
Incorporating three distinct areas of study, the goals of the BEAT-HIV Delaney project are to investigate where HIV hides after therapy and test novel clinical strategies aimed at an HIV cure that eliminates the hidden virus. The first area of study or “pillar” will identify where and how HIV hides so researchers can better assess if proposed clinical strategies can eradicate the virus. This pillar links three research teams who will measure HIV in the body, determine how HIV persists after therapy, access new areas in the body that have not been studied before where HIV may hide, and distinguish HIV by “fingerprinting” or “barcoding” to determine the fate of each infected cell. The BEAT-HIV Delaney research team plans to develop clear criteria to evaluate reductions in the virus beyond what is measured in the clinic.
The second pillar focuses on stimulating the immune system with which we are all born (innate immunity) through a combination immunotherapy approach using highly-potent antibodies against HIV together with pegylated interferon alpha 2b. The researchers plan to conduct the first human clinical trial combining these two therapeutic strategies (which have been tested separately and have shown activity in reducing HIV in humans) with the expectation that a boosted innate immune system empowered with unique antibodies to target HIV-infected cells will achieve greater reductions in HIV than observed previously. In addition, the researchers will look to develop novel DNA-based delivery systems that may make administering anti-HIV treatments more simple and effective than by transfusions.
The third pillar will bring together two promising gene therapy strategies, independently tested in humans, with the goal of engineering, growing and administering killer cells that are uniquely empowered to find and kill HIV-infected cells. The proposed gene therapy strategy is based on the success of small human trials of killer T-cells (Chimeric Antigen Receptor [CAR] T-cell therapy). Earlier studies showed that killer T-cells can be generated and administered safely. The research team will repeat these studies and for the first time safeguard the new killer cells from being attacked by HIV when “activated” by removing the CCR5 protein. HIV needs this protein to infect and kill the killer cells, so removing it can “protect” killer cells so they can continue to proliferate and kill HIV-infected cells. The ability of cells to remain unaffected by HIV in the absence of CCR5 has already been shown clinically, but this strategy has not yet been joined with gene therapy in making killer cells.
“The results of this trial are expected to show for the first time what the long-term effects of these killer cells can be in finding and eradicating HIV,” said Riley.
The BEAT-HIV Delaney project benefits from decades-long partnerships in the Philadelphia HIV community. Philadelphia FIGHT, a comprehensive AIDS care and service organization, and Penn Center for AIDS Research (CFAR) will ensure community input and outreach as research develops. The three main research pillars will be supported by separate smaller teams that include longstanding industry partners Merck & Co., Inc., Sangamo BioSciences, Inc. and Inovio Pharmaceuticals, Inc.