CROI: Furthest along is Sangamo Biosciences Inc., which is in phase II with its gene edited SB-728-T in T cells for the treatment of HIV, and in phase I with SB-728-T in stem cells

Immunizing the well and flushing the reservoir may be ways to HIV cure

http://www.bioworld.com/content/immunizing-well-and-flushing-reservoir-may-be-ways-hiv-cure

 By Anette Breindl 

Senior Science EditorSomewhat like a vaccine for HIV, a cure has been on the horizon yet out of reach for a frustratingly long time.
"I think it's fair to say that the score card is not very impressive," Mario Stevenson, chief of the division of infectious disease at the University of Miami Medical School, told the audience at a the plenary session of the Conference on Retroviruses and Opportunistic Infections (CROI), which is going on in Boston this week. He cited "40 million or so infected individuals worldwide and one documented cure" in form of "Berlin patient" Timothy Ray Brown.
In a CROI plenary talk on "Progress in Gene Therapy for HIV Cure," Paula Cannon, professor of molecular microbiology and immunology at the University of Southern California, traced the origin of the idea of an HIV cure using gene therapy back to 1988, when molecular biologist and Nobel Prize winner David Baltimore wrote about the possibility of "intracellular immunization" against HIV.
That, Cannon said, set off a golden age of HIV gene therapy, when "anyone could be an armchair gene therapist."
Tangible success with the concept, however, awaited progress on multiple fronts, including integrating gene transfer vectors, adoptive T-cell therapy, autologous hematopoietic stem cell transplants – first for cancer patients, and then gentler regimens that were appropriate for wider use – and targeted nucleases that have enabled more precise gene editing.
One advantage of gene therapy, Cannon said, is that "in many ways, it's the opposite of a daily pill – if we can get it to work well enough, it could be kind of a single pill approach."
That remains an important goal because although the development of single-tablet regimens has greatly simplified what used to be much more complex dosing regimens, toxicity remains a concern with the simpler regimens.
And sometimes adherence remains a concern, too. The case of the Mississippi baby, for example, a child who experienced an extraordinary 27 months of remission after early aggressive treatment followed by a treatment interruption, came to light not because the child went off of antiretroviral treatment (ART) in a planned way, but because her parents stopped seeking medical care for her for several months. (See BioWorld Today, Aug. 8, 2014.)
And even for those who do diligently take their daily pill or pills, it is fair to say that many wish they did not have to.
Successful gene therapy offers one avenue to long-lasting or even permanent treatment, and in her talk, Cannon gave an overview of academic institutions and biopharmas involved in the space.
Furthest along is Sangamo Biosciences Inc., which is in phase II with its gene edited SB-728-T in T cells for the treatment of HIV, and in phase I with SB-728-T in stem cells. (See BioWorld Today, March 6, 2014.)
Also in the clinic is Calimmune Inc., which published preclinical primate data this week on its gene therapy Cal-1, which is in phase I/II trials in patients who are not taking ART.
Cal-1-treated cells are engineered to resist HIV in two ways. Treatment inhibits the expression of CCR5, a co-receptor that HIV uses to enter cells and that is also the target of SB-728-T. Engineered cells also express a fusion inhibitor on their surface.
The treatment is used to engineer not only T cells, but also hematopoietic stem cells isolated from patients. That approach has two advantages. First, engineering stem cells can potentially provide patients with a lifetime of resistant cells.
Second, though T cells make up the bulk of infected cells, HIV can also infect other cell types, and resistance of those cells decreases HIV's hiding spots. Latently infected cells – the so-called reservoir – are a major obstacle to an HIV cure.
In their paper, which was co-authored with researchers from the Fred Hutchison Cancer Research Center and published online in Molecular Therapy – Methods & Clinical Development on Feb. 24, 2016, the team described treating pigtail macaques and then infecting them with SHIV, a version of HIV that can infect primates besides humans.
The study, Calimmune's senior vice president of research and development, Jeffrey Bartlett, told BioWorld Today, was not directly analogous to the situation in patients, where gene therapy follows infection rather than preceding it; however, the work gave new insights into the interplay between T-cell counts and viral load.
After being infected with SHIV, treated animals showed an acute rise in viral levels and drop in CD4 T cells that was similar to the course of infection that would be expected from historical control data.
During chronic infection, he said, though the viral loads were lower than those of historical controls even at the beginning of the chronic phase, a precipitous drop in viral load came only after T-cell levels had recovered into the normal range, which took several months. "It shows the importance of immune function before we could have an impact on the virus," he said.

Many Sangamo Authors Listed on Scientific Reports with MD Anderson and Ziopharm

• Hiroki Torikai¹
• , Tiejuan Mi¹
• , Loren Gragert²
• , Martin Maiers²
• , Amer Najjar¹
• , Sonny Ang¹
• , Sourindra Maiti¹
• , Jianliang Dai³
• , Kirsten C. Switzer¹
• , Helen Huls¹
• , Gladys P. Dulay⁴
• , Andreas Reik⁴
• , Edward J. Rebar⁴
• , Michael C. Holmes⁴
• , Philip D. Gregory⁴
• , Richard E. Champlin⁵
• , Elizabeth J. Shpall⁵
• […]
•  & Laurence J. N. Cooper^{1, 6}
• - Show fewer authors

• Scientific Reports 6, Article number: 21757 (2016)
• doi:10.1038/srep21757
• Download Citation
• • Stem-cell biotechnology |
  • Transplant immunology

Received:

30 October 2015

Accepted:

27 January 2016

Published online:

23 February 2016

http://www.nature.com/articles/srep21757

Genetic editing of HLA expression in hematopoietic stem cells to broaden their human application

AbstractAbstract

Mismatch of human leukocyte antigens (HLA) adversely impacts the outcome of patients after allogeneic hematopoietic stem-cell transplantation (alloHSCT). This translates into the clinical requirement to timely identify suitable HLA-matched donors which in turn curtails the chances of recipients, especially those from a racial minority, to successfully undergo alloHSCT. We thus sought to broaden the existing pool of registered unrelated donors based on analysis that eliminating the expression of the HLA-A increases the chance for finding a donor matched at HLA-B, -C, and -DRB1 regardless of a patient’s race. Elimination of HLA-A expression in HSC was achieved using artificial zinc finger nucleases designed to target HLA-A alleles. Significantly, these engineered HSCs maintain their ability to engraft and reconstitute hematopoiesis in immunocompromised mice. This introduced loss of HLA-A expression decreases the need to recruit large number of donors to match with potential recipients and has particular importance for patients whose HLA repertoire is under-represented in the current donor pool. Furthermore, the genetic engineering of stem cells provides a translational approach to HLA-match a limited number of third-party donors with a wide number of recipients.

This latest study marks the first time researchers have successfully swapped alleles in an animal’s genetic code using gene editing

Pig’s genetic code altered in bid to tackle deadly virus

Published on 22 February 2016
Researchers have made an advance in the fight against a deadly virus that affects pigs.
The team used advanced genetic techniques to produce pigs that are potentially resilient to African Swine Fever – a highly contagious disease that kills up to two-thirds of infected animals.
The new pigs carry a version of a gene that is usually found in warthogs and bush pigs, which researchers believe may stop them from becoming ill from the infection.
African Swine Fever is spread by ticks. When standard farmed pigs are infected, they quickly become ill and die, but warthogs and bush pigs show no disease symptoms when infected.
The research is focused on one of the pig genes associated with African Swine Fever Virus infection called RELA. The gene causes the immune system to overreact with devastating effects.
Warthogs and bush pigs carry a different version of the RELA gene from that found in farmed pigs. Scientists believe that this variant – known as an allele – may dampen their immune response and explain why they are more resilient to African Swine Fever.
Researchers at the Roslin Institute used a gene-editing technique to modify individual letters of the pigs’ genetic code. By changing just five letters in their RELA gene, they converted it to the allele that is found in the warthog.
The work builds on previous research from the team, which used similar techniques to produce pigs with a single letter of their genetic code altered.  These animals produce a shorter version of RELA.
This latest study marks the first time researchers have successfully swapped alleles in an animal’s genetic code using gene editing.
All of these changes to the pig’s genetic code could have occurred spontaneously in nature.
Scientists will now conduct controlled trials to test whether the genetic changes have improved the pigs’ resilience to the disease.
African Swine Fever is endemic in Sub-Saharan Africa and some areas of Russia. The disease has never been found in the UK, although recent outbreaks in Eastern Europe have raised concerns amongst farming groups that it could spread.
The study – published in the journal Scientific Reports – involved collaboration between scientists at The Roslin Institute and Sangamo Biosciences Inc. It was funded by Genus plc and the Biotechnology and Biological Sciences Research Council (BBSRC). The Roslin Institute receives strategic support from the BBSRC.
Professor Bruce Whitelaw, Head of Developmental Biology at the University of Edinburgh’s Roslin Institute, said: “Our goal is to improve the welfare of farmed pigs around the world, making them healthier and more productive for farmers.”
For further information, please contact: Hazel Lambert, Press and PR Office; tel 0131 650 6357; email Hazel.Lambert@ed.ac.uk
http://www.roslin.ed.ac.uk/news/2016/02/22/pigs-genetic-code-altered-in-bid-to-tackle-deadly-virus/

Sangamo BioSciences Reports Fourth Quarter And Full Year 2015 Financial Results

Company Begins 2016 in Strong Financial Position with $210 Million in Cash
Poised to Initiate First in vivo Genome Editing Clinical Trials for Hemophilia B and MPS I

RICHMOND, Calif., Feb. 9, 2016 /PRNewswire/ -- Sangamo BioSciences, Inc. (NASDAQ: SGMO), the leader in therapeutic genome editing, today reported its fourth quarter and full year 2015 financial results and accomplishments.

"2015 was an important and very productive year for Sangamo, and we enter 2016 poised to initiate the first human clinical trials of in vivo therapeutic genome editing," said Edward Lanphier, Sangamo's president and chief executive officer. "Our zinc finger nuclease (ZFN) technology leads the therapeutic genome editing field and we have established the core competencies necessary to move our ground-breaking genome editing programs through IND enabling studies and into clinical trials. We believe our IVPRP clinical studies will provide fundamental proof-of-concept data and significantly differentiate the technical advantages of our ZFN platform from other genome editing technologies of bacterial origin as well as conventional gene therapy approaches. In addition to our two new open IVPRP INDs we plan to file six more IND applications in 2016 for our other IVPRP-based programs, and our hemoglobinopathies programs which we are developing in collaboration with Biogen. We began the year with approximately $210 million in cash, which puts Sangamo in a strong financial position and will allow us to accomplish all of our goals in 2016."
Recent Highlights

• Announcement of FDA clearance of IND application for Phase 1/2 clinical trial of MPS I (Hurler syndrome) program. In February 2016, Sangamo announced that its Investigational New Drug (IND) application for the Company's SB-318 program was cleared by the U.S. Food and Drug Administration (FDA) and is now active. SB-318 is an application of the Company's proprietary In Vivo Protein Replacement Platform™ (IVPRP™) genome editing approach, for the treatment of MPS I. In December 2015, the NIH Recombinant DNA Advisory Committee (RAC) unanimously approved the clinical protocol for SB-318.
• Announcement of FDA clearance of IND application for Phase 1/2 clinical trial of hemophilia B program. In December 2015, Sangamo announced that an IND application for SB-FIX, the Company's IVPRP genome editing approach for the potential cure of hemophilia B, has been cleared by the FDA and is now active.
• Presentation of Phase 2 clinical data from SB-728-T HIV studies demonstrating superiority of adenoviral delivery of zinc finger nucleases to T-cells for viral load control and reservoir reduction. In December 2015, Sangamo presented Phase 2 clinical data from ongoing clinical trials of the Company's SB-728-T HIV program, SB-728-1101 Cohort 3* and SB-728mR-1401. The preliminary comparative data suggest that adenoviral delivery of ZFNs to T-cells may be uniquely immune-stimulatory for both acute viral load control and HIV reservoir reduction. The trial is currently ongoing with the accrual of five additional subjects in '1101 Cohort 3*.
• Presentation of data at the 2015 American Society of Hematology meeting (ASH) highlighting ZFP Therapeutic programs for hemophilia and hemoglobinopathies. In December 2015, Sangamo presented data at ASH demonstrating the production of therapeutic levels of Factor IX (FIX) clotting protein in non-human primates (NHPs) from its hemophilia B program, and clinical scale manufacturing and engraftment of ZFN-modified hematopoietic stem and progenitor cells (HSPCs) for the treatment of beta-thalassemia.
• Publication of improved method for efficient targeted integration in HSPCs and T-cells. In November 2015, Sangamo announced the publication in Nature Biotechnology of data demonstrating efficient ZFN-mediated, targeted gene insertion in HSPCs, as well as a study in Nucleic Acids Research, demonstrating a similarly efficient process in primary human T-cells.
• Internal Organization. Sangamo promoted Stewart Craig, Ph.D., from Vice President to Senior Vice President of Technical Operations. Dr. Craig joined Sangamo in May 2014 and has led the development of the Company's successful and growing manufacturing capabilities. Fyodor Urnov, Ph.D., Senior Scientist, was promoted to Vice President of Discovery & Translational Research. Dr. Urnov is a key contributor to the development of Sangamo's ZFP Therapeutic technology platform and leads Sangamo's hemoglobinopathies research collaboration with Biogen Inc. (Biogen). Nathalie Dubois-Stringfellow, Ph.D. was promoted from Senior Director to Vice President of Product Development & Management. Dr. Dubois-Stringfellow, with extensive experience in pre-clinical drug development and project management, established an effective cross-functional team-based culture at Sangamo, enabling the Company's successful and timely IND submissions.

Upcoming Events in the First Half of 2016

• Initiation of Phase 1/2 clinical trials for IVPRP-based SB-FIX-1501 (hemophilia B) and SB-318-1502 (MPS I / Hurler syndrome) programs. The trials will be the first two in vivo clinical studies of genome editing in humans and the first clinical programs based on Sangamo's IVPRP approach. Sangamo expects to initiate the Phase 1/2 trial for hemophilia B in the first half of 2016, and the Phase 1/2 trial for MPS I in mid-2016.
• Presentation of clinical data from Sangamo's HIV program at the 2016 Annual Conference on Retroviruses and Opportunistic Infections (CROI). Sangamo's collaborator, Rafick Pierre Sekaly, Ph.D., will present further immunologic and viral reservoir analyses of clinical data from the Company's SB-728-1101 study, suggesting potential mechanisms of viral control post-treatment with SB-728-T.
• Preclinical data presentation from Sangamo's MPS I and MPS II programs at the 2016 Annual WORLDSymposium Meeting. Sangamo expects to present data from its animal model studies for the Company's IVPRP-based MPS I and MPS II (Hunter syndrome) programs for lysosomal storage disorders (LSDs). The meeting is being held in San Diego, CA from February 29 to March 4, 2016.
• Submission of IND applications for Sangamo's SB-913 (MPS II) program and beta-thalassemia program. Sangamo expects to file both IND applications in the first half of 2016. SB-913, for the treatment of MPS II, is the second LSD application of the Company's proprietary IVPRP approach. The beta-thalassemia program, which is being developed in collaboration with Biogen, employs Sangamo's ZFN-mediated ex vivo genome editing approach to knockout the BCL11A Enhancer.

Fourth Quarter 2015 Results
For the fourth quarter ended December 31, 2015, Sangamo reported a consolidated net loss of $14.0 million, or $0.20 per share, compared to a net loss of $4.3 million, or $0.06 per share, for the same period in 2014. As of December 31, 2015, the Company had cash, cash equivalents, marketable securities and interest receivable of $209.3 million.
Revenues for the fourth quarter of 2015 were $9.1 million, compared to $15.0 million for the same period in 2014. Fourth quarter 2015 revenues were generated from the Company's collaboration agreements with Biogen, Shire International GmbH (Shire), and Dow AgroSciences, enabling technology agreements and research grants. The revenues recognized for the fourth quarter of 2015 consisted of $9.0 million in collaboration agreements and approximately $0.2 million in research grants, compared to $14.5 million and approximately $0.4 million, respectively, for the same period in 2014.
The decrease in collaboration agreement revenues was primarily a result of an amendment to the Company's collaboration and license agreement with Shire in the third quarter of 2015, returning the rights to the hemophilia programs to Sangamo. In the fourth quarter of 2015, Sangamo recognized $1.9 million of revenues related to research services performed under the collaboration agreement with Shire, and $1.9 million of revenues related to research services performed under the collaboration agreement with Biogen. In addition, pursuant to the agreements entered into with Shire in January 2012 and Biogen in January 2014, Sangamo received upfront payments of $13.0 million and $20.0 million, respectively. These payments are being recognized as revenue on a straight-line basis over the initial six-year research term for Shire and approximately 40 months for Biogen. The Company recognized $0.5 million of the Shire upfront payment and $1.6 million of the Biogen upfront payment as revenue for the fourth quarter of 2015.
Research and development expenses were $19.9 million for the fourth quarter of 2015, compared to $15.1 million for the same period in 2014. The increase was primarily due to increases in manufacturing expenses, external research expenses associated with our preclinical programs, and personnel-related expenses, including stock-based compensation. General and administrative expenses were $4.9 million for the fourth quarter of 2015, compared to $4.3 million for the same period in 2014.
Total operating expenses for the fourth quarter of 2015 were $24.8 million, compared to $19.4 million for the same period in 2014.
Full Year 2015 Results
For the year ended December 31, 2015, the consolidated net loss was $40.7 million, or $0.58 per share, compared to a consolidated net loss of $26.4 million, or $0.39 per share, for the year ended December 31, 2014. Revenues were $39.5 million for the year ended December 31, 2015, compared to $45.9 million for the same period in 2014. Total operating expenses were $86.4 million for the year ended December 31, 2015, compared to $72.7 million for the same period in 2014.
Financial Guidance for 2016

• Cash and Investments: Sangamo expects that its cash, cash equivalents and marketable securities will be at least $150 million at the end of 2016, inclusive of research funding from existing collaborators but exclusive of funds arising from any additional new collaborations or partnerships, equity financings or other new sources.
• Revenues: In light of the amendment to our collaboration and licensing agreement with Shire, that returned the rights of the hemophilia programs to Sangamo, the Company expects that revenues will be in the range of $20 million to $25 million in 2016, inclusive of research funding from existing collaborations.
• Operating Expenses: Sangamo expects that operating expenses will be in the range of $85 million to $95 million for 2016.

Conference Call
Sangamo will host a conference call today, February 9, 2016, at 5:00 p.m. ET, which will be open to the public. The call will also be webcast live and can be accessed via a link on the Sangamo BioSciences website in the Investor Relations section under "Events and Presentations" http://investor.sangamo.com/events.cfm.  A replay of the webcast will also be available for two weeks after the call. During the conference call, the Company will review these results, discuss other business matters and provide guidance with respect to 2016.
The conference call dial-in numbers are (877) 377-7553 for domestic callers and (678) 894-3968 for international callers. The conference ID number for the call is 39287479.  For those unable to listen in at the designated time, a conference call replay will be available for one week following the conference call, from approximately 8:00 p.m. ET on February 9, 2016 to 11:59 p.m. ET on February 16, 2016. The conference call replay numbers for domestic and international callers are (855) 859-2056 and (404) 537-3406, respectively. The conference ID number for the replay is 39287479.
About Sangamo
Sangamo BioSciences, Inc. is focused on Engineering Genetic Cures^TM for monogenic and infectious diseases by deploying its novel DNA-binding protein technology platform in therapeutic genome editing and gene regulation. The Company's proprietary In Vivo Protein Replacement Platform™ (IVPRP™) approach is focused on monogenic diseases, including hemophilia and lysosomal storage disorders. 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.com. 

Excellent Review of Current Sickle Cell Research

100 Years But Only One Drug: Sickle Cell Patients Wait For Help

http://www.healthmojo.org/2016/02/08/100-years-but-only-one-drug-sickle-cell-patients-wait-for-help/

Last week, 100,000 Americans with sickle cell disease and millions more around the world got encouraging news. Investors gave a vote of confidence, in the form of a $120 million IPO, to Global Blood Therapeutics (NASDAQ: GBT), a four-year-old biotech working on a pill that could become the biggest medical advance ever for the disease.
That pill, which just began its first human trial in January, is a once-a-day medicine that a patient would have to take for life. If approved, the drug would be only the sickle cell treatment to potentially halt the effects of the disease. The lone drug currently on the market for the disease only addresses some of its symptoms.
Patients with sickle cell disease carry a mutated form of hemoglobin that causes normally disk-like red blood cells to change into rigid crescent-shaped cells. Those misshapen cells get hung up in the blood vessels, wreaking all sorts of havoc. In the face of the disease’s worst complications—strokes, deadly lung complications, bouts of excruciating pain, anemia, and more—one pill a day doesn’t seem like much burden. (Global Blood CEO Ted Love declined to answer questions, citing quiet period regulations.)
But even more tantalizing hope lies on the horizon. Gene therapy, ideally a one-shot cure, could arrive in the next decade.
“The first documented sickle cell patient was in 1910, and we only have one medication,” says Sonja Banks, president of the Sickle Cell Disease Association of America in Baltimore, MD. “Anything cutting edge is great; we’re so far behind in the game.”
Banks is fully aware that, as with any new area of medicine, there are still hurdles to overcome in the field of gene therapy, which has seen a renaissance in the past few years. Just recently two gene therapy companies, Celladon (NASDAQ: CLDN) and Avalanche Biotechnologies(NASDAQ: AAVL), cratered after terrible late clinical results, while others, namely Spark Therapeutics (NASDAQ: ONCE) and Bluebird Bio (NASDAQ: BLUE), have watched investors flee the stock despite no public setbacks.
And gene therapies for sickle cell, specifically, have a long, long way to go. Bluebird has one in development, called LentiGlobin, and it’s the most advanced. Positive data from a single patient was enough to cause a stir earlier this year, as my colleague Ben Fidler reported.
The therapy requires extracting a sample of the patient’s hematopoietic, or blood-producing, stem cells from the bone marrow, modifying them outside the body, and giving them back to the patient. The technique uses a virus to deliver a healthy copy of the hemoglobin-beta gene into the stem cells. It’s supposed to be a gentler version of bone marrow transplant, which is the only cure so far for the disease.
A bit farther behind Bluebird is a different form of gene therapy, called gene editing, and it should soon provide early milestones in two very different programs. One is based on CRISPR/Cas9, the gene editing system that has spread around the world’s research labs because it’s so easy to use. Three startups—Crispr Therapeutics, Editas Medicine, and Intellia Therapeutics—have raised hundreds of millions of dollars, collectively, to move the system forward into human therapeutics. They have in recent months revealed plans to work oncancer immunotherapy, blood diseases known as hemoglobinopathies (sickle cell is a hemoglobinopathy), and, most recently with Editas, a genetic form of blindness.
But the first data on a CRISPR/Cas9 therapy for sickle cell disease—or any disease, for that matter—to be unveiled could come from a nonprofit effort.
At the Innovative Genomics Initiative, a University of California-funded group on the Berkeley campus, researchers collaborating with Children’s Hospital in nearby Oakland, CA, have been trying to cure sickle cell disease in mice. (IGI was cofounded by Jennifer Doudna, the Berkeley professor who helped turn CRISPR/Cas9, a bacterial defense system, into a gene editing tool. How much she invented is in dispute, as I detailed most recently here.)
IGI scientific director Jacob Corn and colleagues should know in less than two months if their experiments have worked. They’ve removed the hematopoietic stem cells from mice with an approximate version of sickle cell disease, replaced the mutated gene with the healthy version using CRISPR/Cas9, and put the cells back into the mice. Will their blood contain sickled red blood cells? Will the stem cells that repopulate their bone marrow have the sickle mutation? If so, in what numbers?
Corn declines to project what kind of data would move the program closer to a human trial, or to speculate on the timing of a trial , which would take place at Children’s Hospital. But he feels the urgency, not just from doctors and patients but from other academics who are “hot on this trail,” he says.
Taking hematopoietic stem cells out of the body, editing them, and putting them back into the bone marrow to spawn healthy versions of red blood cells is an obvious use of gene editing. “People have wanted to cure sickle cell disease for a long time this way,” says Corn. “It’s a very worthwhile problem, and it’ll be huge when someone cracks the nut. We hope to be the first.” (IGI researchers have used a technical advance that they hope will persuade the edited cells to function properly when reintroduced; Corn declined to reveal the technique until the data are published.)
Gene editing might be a quantum technological leap, but, like Bluebird’s LentiGlobin gene therapy, it would still require a form of bone marrow transplant. When the cells are taken out for editing, the patient’s remaining bone marrow cells would be killed, a precarious procedure that leaves the patient with a compromised immune system for a period of time.
The hope, however, is that both the gene therapy and gene editing approach will lessen the severity and
danger of the procedure for several reasons—in part because the patient’s own cells, not a donor’s, are being transferred back, which theoretically could make for better immune compatibility and less need for harsh drugs.
Another advantage to gene editing or therapy is availability: a patient is his or her own bone marrow donor. In the U.S., sickle cell disproportionately affects African Americans—one in 500 children are born with the disease. The next highest prevalence is in Hispanic Americans, with 1 in 36,000 children born with the disease.
One in 12 black Americans has sickle cell trait, which is an inherited gene from one parent but not the other. Having the ‘trait’ instead of disease doesn’t entirely preclude someone from developing symptoms, however.
For traditional transplants, though, African Americans have a much harder time finding matched donors than any other group.

All in all, it’s estimated that only a few hundred sickle cell patients have had a transplant, and it’s not clear how many of them have succeeded. (A U.S.-funded database shows 353 transplants from 2008 to 2012; survival data is incomplete but shows that patients receiving marrow from unrelated donors have a lower rate of survival.)
Meanwhile, the only approved pharmaceutical for sickle cell is hydroxyurea, a repurposed chemotherapy. It’s useful for relieving the pain episodes, known as crises, and acute chest syndrome, a lung-related complication that can turn deadly.
There are maintenance therapies and ever more sophisticated plans for giving sickle cell patients better lives. For example, one doctor who runs a sickle cell center at a big-city U.S. hospital told me that kids born with either of two genetic variants of the disease get an ultrasound at the age of two. There are four main variants of sickle cell; the two in question are correlated with more strokes. The ultrasound helps predict near-term stroke risk—within the next year—and if the results come back in the danger zone, the child is put on blood transfusions every three to five weeks. (The conversation was on background because the doctor was not cleared by the center to speak to the press.)
Another gene editing program for sickle cell is in the works from Sangamo Biosciences (NASDAQ: SGMO) of Richmond, CA. Sometime in the second half of 2016, Sangamo and its development partner Biogen (NASDAQ: BIIB) will ask FDA permission to start human trials with its program.
To do its gene editing, Sangamo uses a system called zinc finger proteins, which it owns. No one else can use zinc fingers without a license, and Sangamo, with 20 years of development under its belt, is the only company to advance a gene-editing product into human trials, for HIV.
CRISPR/Cas9 hasn’t been around as long as zinc finger proteins, and the technology has a major hurdle to overcome: making sure the molecular “scissors” it uses are making DNA cuts in the right places. Right now, the methods used to detect off-target cuts simply aren’t sophisticated enough. And all it takes is one cut in the wrong place to trigger a tragic unintended consequence. The fear dates back to gene therapy experiments fifteen years ago, in which genes meant to heal kids with severe combined immunodeficiency—the so-called “bubble boy disease”—inserted themselves in the wrong place and triggered cancer. Being more precise with gene editing tools, like CRISPR/Cas9, is still a goal, not a reality.
“Our ability to find off targets isn’t great right now,” says Corn. “No matter how bullish you are, the field [of gene therapy] has been bitten by kids getting leukemia. That should keep everyone in the hematopoietic field up at night.”
(For more on the rollercoaster history of gene therapy, read Ben Fidler’s feature on hemophilia published in March.)
The rapid spread of CRISPR/Cas9—it might not be long before high school students are doing experiments with it—is also keeping people worried for another reason: the potential engineering of human eggs, sperm, and embryos to modify people for aesthetic or social reasons, not medical reasons, and allow those traits to passed on to future generations. There’s also concern that traits engineered into plants and animals meant to spread to entire populations—to create less harmful mosquitoes, for example—could spread out of control.
(My colleagues and I have written about these developments here and here, and Antonio Regalado at Technology Review has done important reporting on the topic. Spurred by papers penned by Doudna, Sangamo CEO Edward Lanphier, and several others, the U.S. National Academy of Sciences and National Academy of Medicine will hold a summit this fallto discuss guidelines on germline editing.)
Curing sickle cell disease should hold no such controversy, of course.
But it holds other cautions. Patient advocate Banks worries that the eventual cost of a product will be out of reach for many U.S. sickle cell patients, 70 percent of whom are low income, she says. If and when that time comes, insurers like
the state Medicaid programs will no doubt weigh the savings of a cure against what the drug companies decide to charge.
What will those savings be? It’s not entirely clear. But a 2009 study tabbed the costs sickle cell treatments–culled from 2001-2005 Florida Medicaid data—at $892 a month for young children up to $2,562 per month for people from 50 to 64 years old. The average was $1,389 per month. Three years earlier, this study estimated that in 2004, 113,000 hospitalizations for sickle cell disease in the U.S. cost nearly half a billion dollars.
The health economics disparities within the U.S. pale next to those between the U.S. and regions like Africa and India, where sickle cell disease takes a huge toll.
For example, there are roughly 100,000 people with the disease in the U.S.; more than 100,000 babies are born with the disease every year in Nigeria alone, the highest burden in the world, according to the U.S. Centers for Disease Control.  (Having sickle cell trait helps protect against malaria, which explains why so many people in areas with endemic malaria survive to pass on the gene.)
A biopharma veteran says another hurdle could be difficulty getting people to join trials. For good reason, African Americans have historically been suspicious of the medical community. Checkmate Pharmaceuticals CEO Art Krieg, who has had tours of duty with several companies, remembers looking at sickle cell while at Rana Therapeutics and at Pfizer (NASDAQ: PFE). “From a scientific point of view we liked it,” he says, but clinical and commercial questions blunted the companies’ enthusiasm. “We didn’t get too far.”
(Krieg has worked for years on the problem of delivering RNA-based drugs into cells, which CRISPR/Cas9 companies will need to solve. He is a scientific advisor to CRISPR/Cas9 developer Intellia.)
Krieg also notes that hydroxyurea, while it doesn’t work for everyone, has gone generic. Insurers will have to be convinced that new, pricey therapies will not just be marginally better than existing treatments, including bone marrow transplant.
Banks stresses that sickle cell disease (sometimes still called “sickle cell anemia”) is complicated. A patient’s genetic variant doesn’t always line up with the severity of his or her disease. There’s no easy way to say, in advance, who might be eligible for a future gene therapy. Jacob Corn says if the IGI program, using CRISPR/Cas9 to edit blood stem cells, gets to humans, the plan is to start with those who’ve already had a stroke or who’ve had a lot of pain crises or acute chest syndrome. “We’d like to start with people who are already ill and reverse their disease,” he says.

If he’s still saying that in two months, it’ll be a good step forward.

Biogen Features Sangamo Program in Recruiting ad for Intern

https://jobs.biogen.com/job/Cambridge-Intern-Clinical-Development%2C-Hemophilia-Hematology-Development-MA-02138/325627600/

Date: Feb 8, 2016

Location: Cambridge, MA, US

Company: Biogen

External Posting Title	Intern: Clinical Development, Hemophilia Hematology Development
Job Description	This is a full-time Internship role from June-August 2016. Biogen rare disease early development is a newly created function within the Biogen R&D organization. We currently are focusing on non-malignant hematology, ophthalmology and neurology utilizing therapeutic modalities from small molecules, proteins, oligonucleotides, to cell and gene therapies to address significant unmet needs for many adult and pediatric patients afflicted by numerous rare/orphan diseases. Examples of some of our currently ongoing programs include: - The Biogen/Sangamo clinical development program utilizes the zinc finger folk nuclease technology to ex-vivo edit the autologous CD34 hematopoietic stem cell BCL11a enhancer in an attempt to up-regulate the HbF expression and to cure beta thalassemia and sickle cell disease. - The Biogen/AGTC clinical development program utilizes the AAV2 viral vector to deliver genes to correct inherited monogenic blindness including X-Linked Retinoschisis and X-Linked Retinitis Pigmentosa. - The Biogen/TIGET clinical development program utilizes lentiviral vectors to deliver clotting factors VIII and IX genes to treat hemophilia A and B A qualified intern will benefit from exposures to the latest advancement and challenges in gene therapies, the dynamic early development environment, strategic discussions of internal pipeline and external assets, and will craft his/her own goals and job descriptions.
Location	Cambridge, MA, US
Job Category	Internship
Requisition Number	27443BR

Sangamo BioSciences Announces Presentation At The Leerink Partners 5th Annual Global Healthcare Conference

Sangamo BioSciences, Inc. (NASDAQ: SGMO), the leader in therapeutic genome editing, announced today that Edward Lanphier, Sangamo's president and chief executive officer, will provide an update on the progress of Sangamo's ZFP Therapeutic^® development programs and an overview of the company's business strategy at 2:40 pm ET on Thursday, February 11, 2016, at the Leerink Partners 5^th Annual Global Healthcare Conference. The conference is being held in New York.
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. The presentation will be archived on the Sangamo website for two weeks after the event.
About SangamoSangamo BioSciences, Inc. is focused on Engineering Genetic Cures^® for monogenic and infectious diseases by deploying its novel DNA-binding protein technology platform in therapeutic genome editing and gene regulation. The Company's proprietary In Vivo Protein Replacement Platform™ (IVPRP™) approach is focused on monogenic diseases, including hemophilia and lysosomal storage disorders. 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.com.

Charles River Blogs about Sangamo's IVPRP

http://www.criver.com/about-us/eureka/blog/february-2016/a-potential-cure-for-hemophilia

A Potential Cure for Hemophilia

Feb 03, 2016
     The first in vivo genome editing compound is cleared for human trials, a major milestone in the rejuvenated field of gene therapy.
On Dec 1, 2015, Sangamo BioSciences, Inc. received FDA clearance for the first clinical application of an in vivo genome editing therapeutic, SB-FIX, a potentially curative, single treatment therapy for hemophilia B. This is history in the making. While conventional gene therapy approaches have the potential to wash-out over time, necessitating repeated administration, the proprietary In Vivo Protein Replacement Platform™ (IVPRP™) from Sangamo is expected to result in therapeutic levels of human Factor IX (hFIX) for the lifetime of patients with hemophilia B, with only a single treatment with SB-FIX.
Truly efficacious therapies for genetic disease will treat the disease at the source, the genome. Sangamo's IVPRP™ technology takes advantage of zinc finger proteins (ZFPs), the most abundant DNA binding proteins in the body. An individual ZFP recognizes and binds to 3 base pairs of DNA. Several ZFPs can be strung together to recognize and bind to longer target DNA sequences. ZFPs are designed with "exquisite specificity" toward a unique site in the genome and strongly bind only that targeted site. These DNA binding domains are then coupled to a nuclease domain to create a zinc-finger nuclease (ZFN) that binds to and cleaves DNA at a specific spot to allow for the insertion of a gene. Sangamo's modular design of SB-FIX incorporates two ZFNs that are targeted to bind 6 base pairs of DNA in a specific location in the albumin gene of human liver cells. In this case, a correct copy of hFIX is inserted where the DNA is cleaved by the ZFN so that it can produce functional Factor IX protein.
In SB-FIX, adeno-associated virus (AAV) vectors encoding the engineered ZFNs and hFIX, were created to deliver both the nuclease and the correct copy of the FactorIX gene in liver cells. AAV was selected because it is preferentially taken up by the liver when given intravenously and has a history of safe and efficacious use in humans. The manufacturing of AAVs are also well understood. Only a small percentage of the liver cells actually will incorporate and express the hFIX gene after injection of SB-FIX. However, these liver cells, and more importantly their progeny, should express Factor IX for the lifetime of the patient. Because the promoter for the albumin gene is so powerful, the incorporation of the hFIX gene should produce stable, therapeutic levels of Factor IX from this small percentage of liver cells and permanently treat hemophiliaB in patients.

Charles River's role

At Charles River, we feel privileged to have participated in these advancements by completing toxicology studies that supported the safety and efficacy of SB-FIX to win IND clearance for commencing clinical trials. These studies demonstrated that Sangamo's SB-FIX could precisely insert a copy of the hFIX gene into a specific location within the albumin gene of liver cells leading to the stable production of therapeutic levels of Factor IX. We look forward to watching the development of SB-FIX and other therapies incorporating ZFP Therapeutics^® strategies. Beyond systemic application for liver-related diseases such as hemophilia and lysosomal storage diseases, there are potential direct tissue applications for treating several other diseases caused by protein deficiencies that could revolutionize treatment for patients.
For more on this groundbreaking scientific advancement and additional therapeutic interventions underway at Sangamo, click here.

How to cite:

Walker Comba, Rebecca. A Potential Cure for Hemophilia. Eureka blog. Feb 3, 2016. Available: http://www.criver.com/about-us/eureka/blog/february-2016/a-potential-cure-for-hemophilia