Dale Ando Presents at ISBIOTECH March 7-9 2016

Dale Ando, MD

Chief Medical Officer and Vice President of Development, Sangamo BioSciences, Inc.

First-in-Man Gene Editing Using Zinc Finger Nucleases to Modify CCR5 in HIV Subject T Cells http://www.isbiotech.org/cellulartherapies

ZFN's Cross the Blood Brain Barrier - Angelman Syndrome

The FIRE team of FAST turns on Ube3a in mice with Angelman Syndrome….the future gets even MORE promising with Zinc Finger technology.

http://cureangelman.net/the-fire-team-of-fast-turns-on-ube3a-in-mice-with-angelman-syndrome-the-future-gets-even-more-promising-with-zinc-finger-technology/

FAST is very excited to provide a summary of the newly published and incredibly promising manuscript titled, Protein Delivery of an Artificial Transcription Factor Restores Widespread Ube3a Expression in an Angelman Syndrome Mouse Brain[1] . This is work performed by Dr. David Segal and his laboratory at the Genome Center, MIND Institute, and Department of Biochemistry and Molecular Medicine at the University of California, Davis.  This work was funded in part by The Foundation for Angelman Syndrome Therapeutics (FAST).  Dr. Segal is a member of the FAST FIRE Team. 
Summary:
This is an interpretation by Dr. Allyson Berent, Scientific Director of FAST, of the manuscript. This summary is not written by any of the authors of this scientific manuscript. Please review the prior summary on Angelman Syndrome in the FAST blog to re-introduce the genetic basics of Angelman Syndrome (AS). This will make it easier to follow each future discussion. 
Angelman Syndrome (AS) is a neurological genetic disorder caused by the loss of expression of the maternal copy of the gene UBE3A. Since the paternal copy, which is present and normal in individuals with AS, is imprinted in the neurons of the brain, it is essentially “turned off” or “silenced.” When the maternal copy is not present, as in the case of AS, there is an essential deficit of this gene’s functional end-products within the brain, and this results in the syndrome known as AS.
The paternal copy of this gene is “turned off” by something known as the “antisense transcript” or AT (UBE3A-AT), which is only present in the neurons of the central nervous system (CNS). Inhibiting the function of this antisense transcript may lead to unsilencing, or “turning on” of the paternal UBE3A gene, providing a therapeutic approach to restoring functional UBE3A in the CNS of those with Angelman Syndrome. This has been tried in laboratory animals with various different types of molecules and drugs (e.g. topoisomerase inhibitor drugs, antisense oligonucleotides [ASO], etc…), and partial unsilencing and some phenotypic rescue has been seen. The challenge with most therapeutics of this type trialed in animal models of AS has been attaining widespread delivery of the therapeutic throughout the brain so that a maximal effect can be achieved where it is needed, while concurrently avoiding undesirable side effects. In addition, this approach requires developing a delivery method that is safe and minimally invasive (e.g. spinal fluid injection, direct brain injection, etc…). In this report, a newly engineered artificial transcription factor (ATF), called a Zinc-finger based ATF, was used to silence the UBE3A-AT in a mouse model. The Zinc-finger based ATF, and other technology such as CRISPR (clustered regularly interspaced short palindromic repeat) and TALEs (transcription activator-like effectors), are all purified genetically engineered DNA binding proteins that can be designed as specifically as necessary. These factors can be programmed to affect gene expression by attaching to various areas on DNA. In AS, the UBE3A-AT on the paternal allele is the area of focus.
This study showed that Zinc-finger based ATF technology, when injected peripherally, meaning not directly into the brain or spinal fluid but rather into the subcutaneous tissue (under the skin) or peritoneal cavity (into the abdominal space surrounding the organs), was able to effectively cross the blood brain barrier (BBB). and provide Ube3a protein expression in a widespread distribution throughout the brain of genetically engineered mice with Angelman Syndrome. This means that the only way these mice would be able to get production of the Ube3a protein would be if the paternal UBE3A gene was activated to produce this protein. This activation supports that unsilencing the paternal UBE3A was successful using Zinc-finger based ATF technology. This technology not only “turned off the off switch,” but also provided widespread distribution throughout the brain with a simple peripheral injection!
This is the first report of using a peripherally injectable Zinc-finger protein that caused widespread activation of a gene within the brain, and the first report of this being done with any technology by peripheral administration, thus avoiding the need for direct brain or spinal fluid puncture. These findings will have very important implications in further explorations of treatment options for AS.
The blood brain barrier is made by a tight connection of cells within the blood vessels surrounding the CNS. This limits the method of delivery for most biologics, protecting the brain from exposure to systemic drugs or molecules. When it is desired for these therapeutics to get into the CNS, then, direct brain or spinal fluid injections may be needed. Previous approaches, like adeno-associated virus gene therapy, which required direct injection into various regions of the brain tissue, was able to show restoration of Ube3a in the brain of mice, but there was only a partial improvement seen in learning and memory, and no major change in motor coordination. This may be explained by the fact that there was limited distribution of the viral vectors throughout the brain tissue due to this direct injection. Widespread distribution, and crossing of the BBB through a peripheral injection, as seen with the Zinc finger based-ATF in this study, is an incredibly important accomplishment for future therapeutics.
An alternative delivery approach utilizing a penetrating peptide (HIV TAT), was explored in this study in order to accomplish delivery and distribution. This peptide is capable of delivering large proteins to the entire brain after a single peripheral injection. This was the case with both subcutaneous and intraperitoneal injections.
In this study, the ATF’s only provided transient gene regulation, suggesting they would need to be re-administered on a regular basis for long-term efficacy; therefore, peripheral subcutaneous injections would be a more reasonable therapeutic approach in the future.
Throughout the course of this 4-week study, no overt signs of toxicity were observed in the mice. There was a normal appearance and behaviors observed in the mice, no visual organ pathology on post-mortem examination was reported, and all regions of the brain showed widespread distribution of the ATFs.  Ube3a protein was found to be significantly increased in the AS mice treated with the TAT-Zn finger based-ATF (TAT-S1). The level of Ube3a protein increased to an intermediate level, between the AS-untreated and wild type control mice (mice unaffected by AS and not receiving treatment).  The cause for only an intermediate level of rescue may have been due to an insufficient concentration of the TAT-S1 protein at the target site. Future experiments with an increased dose or frequency of administration are needed.
In principle, the use of ATF biologics with short-term effects, similar to drugs with a short half-life, may have some advantages over more permanent therapeutic consideration where distribution, dosage and reversibility are currently problematic. One limitation of the current study was its short-term nature, as long-term immunity to these therapeutic proteins was not able to be studied; however, it is exciting that the development of the ATF approach could have a significant impact on Angelman Syndrome, and beyond. Other neurological disorders would only require small adjustments to the DNA-binding domain of the ATF used in this study in order to target other disease-related loci (e.g. Rett Syndrome or Prader-Willi, Huntington’s Disease, Pitt-Hopkins, and numerous autism spectrum disease genes).
Further research by Dr. Segal’s lab is currently underway to assess phenotypic rescue in the AS mouse model using this technology. This will more accurately give us an idea of the clinical impact this could have on individuals with AS. Other animal models will be considered if behavioral characteristics can be quantified allowing for changes to be observed.
[1] Bailus B, Pyles B, McAlister M, O’Green H, Lockwood S, Adams A, Tran Nguyen J, Yu A, Berman R, and Segal D., “Protein Delivery of an Artificial Transcription Factor Restores Widespread Ube3a Expression in an Angelman Syndrome Mouse Brain.” Mol Ther. 2016 Epub.

ARM's Rare Disease Roundtable January 27, 2016

This event will be the first in a series of patient roundtables in which ARM will partner with leading patient advocacy organizations to provide opportunities for patient advocates to meet with leaders in academia, government and industry. The goals of the event are to educate multi-sector stakeholders about the latest scientific progress and delivery challenges associated with rare diseases, specifically focusing on areas relating to regenerative medicine, and to help bridge the gap between industry and patient groups who are working toward the common goal of durable, and potentially curative, therapies.

Program Agenda
Wednesday, January 27, 2016
2:00-2:15pm | Welcome & Introductory Remarks            
Ron Bartek, President & Co-Founder, Friedreich’s Ataxia Research Alliance
Morrie Ruffin, Managing Director, Alliance for Regenerative Medicine
2:15-2:45pm | Featured Talk
Barry Byrne, M.D., Ph.D., Director, Powell Center for Rare Disease Research and Therapy, University of Florida 
2:45-3:45pm | Research for Rare Disease: Unique Opportunities & Challenges      
A multi-stakeholder panel discussion emphasizing the unique opportunities & challenges facing research and development in rare and orphan diseases while exploring the regenerative medicine landscape for rare diseases, basic research in the field and the company decision-making process.
Moderator: 
Karen Kozarsky, Ph.D., CEO, Vector Partners
Speakers:
Deborah Ascheim, M.D., Chief Medical Officer, Capricor Therapeutics
Julie Venners Christensen, Head of Global Patient Advocacy - Gene Therapy, R&D, Rare Disease Unit, GlaxoSmithKline 
Sharon Hesterlee, Ph.D., Chief Science Officer, Myotonic Dystrophy Foundation 
3:45-4:00pm | Break
4:00-5:00pm | Collaborating on Cures for Rare Disease        
Case studies on successful partnerships between advocacy organizations and ARM companies
Moderator: 
Ron Bartek, President & Co-Founder, Friedreich’s Ataxia Research Alliance
Speakers:
Jennifer Cutie, M.D., Associate Director, Patient Advocacy, Voyager Therapeutics
Tim Miller, Ph.D., President & CEO, Abeona Therapeutics
Barbara Wuebbels, Vice President of Patient Advocacy, Audentes Therapeutics
5:00-5:30pm | Featured Talk: The Patient Perspective
Michele Rhee, Head of Global Patient Affairs, bluebird bio
Jean Walsh, Patient Advocate; Ambassador, Friedreich's Ataxia Research Alliance
5:30-5:45pm | Closing Remarks: Next Steps
Michael Werner, Executive Director, Alliance for Regenerative Medicine

Short Interest Declines 25%

Sangamo Biosciences (SGMO) Short Interest Update

DATE                                   SHORT INTEREST

12/31/15                                8,382,214 (6.16 days to cover)

12/15/15                              11,153,021 

11/30/15                              11,483,202

11/13/15                              11,088,163                    
10/30/15                              11,668,561 

10/15/15                              12,821,197    

9/30/15                                12,619,596

9/15/15                                10,882,795

8/31/15                                10,150,146

8/14/15                                  9,488,474

7/31/15                                  9,207,150

7/15/15                                  9,205,202

6/30/15                                  9,387,951
6/15/15                                  9,393,825
5/29/15                                  8,938,987
5/15/15                                  8,668,559
4/30/15                                  8,198,983
4/15/15                                  8,050,307
3/31/15                                  8,285,803
3/13/15                                  8,441,291
2/27/15                                  8,939,000
2/13/15                                  9,268,065
1/30/15                                  9,082,814
1/15/15                                  9,387,913

UAB’s Undiagnosed Diseases Program gives answers where there were none

January 07, 2016
Written by  Bob Shepard

https://www.uab.edu/medicine/news/latest/item/929-uab-s-undiagnosed-diseases-program-gives-answers-where-there-were-none
Stephanie and Christopher Smith have been on a long, difficult and often frustrating journey to find answers for the mysterious health issues of their children. It started 24 years ago when their third child, Gage, was born. Gage, his younger brother Aiden and then sister Mandalynn, now 13, all developed mysterious symptoms that mystified doctors. All had severe inflammation of their joints, and delayed intellectual development. But no one knew why.
“We went to numerous physicians in Florida, South Carolina, Washington, D.C., and never got answers,” said Stephanie Smith. “They wrote “unknown bone disease” in the charts. We knew there was something dreadfully wrong with three of our five children, and no one could tell us what it was.”
Through luck, or fate, or divine providence, the family ended up in Boaz, Alabama. The children became patients of Children’s of Alabama and pediatric rheumatologist Robb Lowe, M.D., Ph.D., an assistant professor in the University of Alabama at Birmingham  Department of Pediatrics. Their timing was fortunate, because UAB had just created the Undiagnosed Diseases Program, a multidisciplinary effort aimed at unraveling the most perplexing medical cases that have defied diagnosis.
“We created the UDP to tackle cases where a diagnosis has not been made despite extensive efforts by physicians,” said Bruce Korf, M.D., Ph.D., director of the UDP and chair of the UAB Department of Genetics. “Some of these conditions may be so rare that only a handful of people in the world have them. Others may be more common, but have symptoms that present in an unusual way, making diagnosis difficult.”
Lowe referred the family to the UDP, which partnered with HudsonAlpha Institute for Biotechnology to employ a cutting-edge technique known as whole exome sequencing. The results of the sequencing revealed that all three siblings had two variants in a gene associated with mucolipidosis III, an inherited metabolic disorder known as a lysosomal storage disease.
Lysosomes are cellular structures that contain enzymes that break down large molecules in cells and recycle the remnants into products the cell can utilize. The three Smith children are missing the ability to package enzymes into the lysosome, so molecular material is not broken down and instead accumulates within the cells.

“Every new diagnosis broadens our understanding of rare diseases. Every therapy we try, whether it works or not, tells us something of the mechanisms by which these diseases operate. That’s the reason for the Undiagnosed Diseases Program and our collaboration with Children’s of Alabama and HudsonAlpha. The more we learn about rare genetic conditions, the closer we are to unlocking treatments that will have a meaningful impact on people’s lives.”

Lysosomal storage diseases are rare — mucolipidosis III especially so. The Smith’s are only aware of about 650 cases worldwide. Lowe found one scientific paper in the research literature, published in 2002. He had to self-educate.
“That one research paper discussed a drug in the bisphosphonate family called pamidronate, which has been used to treat bone diseases,” said Lowe. “The results were mixed in the previous study, but it was a starting place.”
Mandalynn began getting monthly infusions of pamidronate in the fall of 2015. Gage and Aiden may soon follow. The infusion takes about three hours. So far, Stephanie has seen benefits.
“It seems to lessen the pain in her legs and joints,” she said. “It should also reduce the risk of fracture. Mandalynn had a bad fall in a parking lot the other day and wasn’t injured.”
After the first infusion, Stephanie noted improvement in Mandalynn’s memory and ability to concentrate.
“Her teacher noticed it, too,” she said. “We’re not sure it will continue, but it’s encouraging.”
“We fortunately sometimes see unexpected beneficial effects for medications that have unexplained anti-inflammatory effects,” Lowe said. “In the case of pamidronate, pediatric rheumatologists have been using it “off-label” for over a decade to effectively a different rare bone disease called CRMO. Hopefully, knowledge of the underlying genetics will spur new research focusing on these poorly understood rare diseases.”
For Stephanie, finally knowing the name of this disease that has struck her children is important.
“It’s certainly somewhat overwhelming, but I’m grateful for the diagnosis,” she said. “After 24 years, we finally know what this is. We now know what to expect, what to look for and what to prepare for.”
Identifying a rare disease also opens up tantalizing research opportunities.
“Every new diagnosis broadens our understanding of rare diseases,” said Korf. “Every therapy we try, whether it works or not, tells us something of the mechanisms by which these diseases operate. That’s the reason for the Undiagnosed Diseases Program and our collaboration with Children’s of Alabama and HudsonAlpha. The more we learn about rare genetic conditions, the closer we are to unlocking treatments that will have a meaningful impact on people’s lives.”
“This is not an ending point, this is a beginning,” said Lowe. “With a better understanding of the genetics involved, new medications such as biologics or even some of the older tried and true chemotherapy agents may prove to be very useful in treating rare and little understood conditions. The genetic data that we can now access will unlock that potential.”

European Drug Trial Goes Awry

(This is not related in any way to Sangamo Biosciences)

'Serious accident' at clinical trial in France leaves one 'brain-dead' and several hospitalized

French clinical trial goes wrong and hospitalizes test subjects

 One man has been left brain dead and three others face permanent brain damage after taking part in clinical trials for a new drug, the worst such accident in France’s medical history.

Ninety people from the Brittany area in western France took part in the trial, taking some dosage of the drug aimed at reducing pain and anxiety.
 Six men aged between 28 and 49 started taking repeated doses at higher levels than other participants on January 7. By Sunday, one member of the group was rushed to hospital, with a brain condition that was so bad doctors thought he was suffering from a stroke. Four others have since been hospitalised.

"What has happened is unprecedented in France," said Marisol Touraine, the health minister, on Friday. The Paris prosecutor's office said an investigation had been opened.

One of the six men appeared to be unaffected, but “among the remaining four, there are three whose condition is sufficiently severe to fear a handicap that could be irreversible in the best of worlds,” said Pierre-Gilles Edan, head of neurosciences at Rennes hospital.
He said that he feared their condition would deteriorate and that there was “no known antidote” to their “brain lesions”.
The remaining participants in the trial have been contacted to undergo brain scans.
Based on a compound similar to the active ingredient in marijuana, the drug was developed by Portuguese pharmaceutical company Bial.
 The oral trial, which has now been suspended, was conducted by Biotrial, a private French-based company with a solid track record and offices in London and America.
In a message on its website, the company said that "serious adverse events related to the test drug" had occurred. The company insisted that "international regulations and Biotrial's procedures were followed at every stage".
A spokesman for the London branch of Biotrial said that it did not conduct trials in the UK.
Britain saw an equally horrific accident in 2006 when six men were hospitalised in Northwick Park Hospital in London after a clinical trial where they were given a drug intended to fight autoimmune disease and leukaemia. One was described as looking like "the elephant man" after his head ballooned.

Up to 300,000 clinical tests for medical drugs take place every year and serious mishaps are extremely rare, according to doctors.
“The shock is all the greater as these people undergoing the clinical trials are healthy, they are not ill and don’t expect such an accident,” said Ms Touraine.
Dr Ben Whalley, a neuropharmacology professor at the University of Reading, said that while such incidents were incredibly rare, "there is an inherent risk in exposing people to any new compound".
New EU regulations to speed up clinical drug trials and streamline testing procedures across the 28-nation bloc are due to take effect in May.

Cellectis CEO Andre Choulika on gene editing, TALENs

Gene editing grabbed headlines recently after the discovery of CRISPR, a tool that allows scientists to cut out a particular, potentially faulty gene and paste another one in its place.

Dozens of other gene-editing technologies existed before CRISPR. French biotechnology company Cellectis was experimenting with one such technique, called TALENs.

Using the tool, Cellectis is developing treatments for cancers, and last year as part of a rare exception to a limited clinical trial, they treated an 11-month-old girl named Layla who had otherwise untreatable leukemia.
Business Insider sat down with Cellectis CEO Andre Choulika to learn more about TALENs and his plans toward getting more treatments like the one that helped Layla approved.

TALENs, the trademarked acronym that stands for "transcription activator-like effector nucleases" refers to proteins that can be used to make cuts in DNA. By programming the TALENs, researchers can use it to remove faulty DNA. Once the targeted DNA has been removed, it sends our natural DNA repair system into panic mode, hopefully repairing the gene.
This is the method Cellectis used to treat an infant identified only as Layla who was born in London with leukemia.
After Layla was born, her doctors tried to treat her using chemotherapy and a bone marrow transplant. When nothing worked, they reached out to Cellectis, who they knew had been working with TALENs, and asked if they'd try their experimental treatment on Layla using something called "compassionate use," which would allow them to try it outside of a clinical trial setting.
The company said yes.
After extracting some of Layla's blood and targeting some of her T-cells, special cells that play a critical role in our immune system, with the TALENs treatment, they were able to stimulate her immune system to attack her cancerous cells.
When she was tested a month later, all of Layla's blood was tumor-free. At that point, "you could consider the patient in complete remission," said Choulika.
Since June, Layla has reportedly stayed in remission.

Right now, three main gene-editing technologies are being explored for therapeutic use: CRISPR, TALENs, and zinc fingers. Of the three, zinc fingers was the first method to hit clinical trials. CRISPR, on the other hand, is new, advanced, and gaining traction fast.
With CRISPR, scientists choose which gene they want to modify, use a pair of "molecular scissors" to snip out the faulty one, and swap in a more desirable version. Both methods require using a bit of molecular material to guide the scissors to the correct gene so that the cell can repair the DNA. But while CRISPR uses a strand of easy-to-build RNA, or ribonucleic acid, to guide the scissors to the right location, TALENs uses an amino acid — a protein.
From a business point of view, one of the main differences between CRISPR and TALENs is that CRISPR is being used by a handful of companies and institutions (which are now facing some patent disputes). TALENs is the proprietary technology of Cellectis, so there are even fewer people using it through licenses.

"We comprehensively have an interesting IP and license in this field," Choulika said. "That's what make people shy off TALEN, we have a pretty dominant position."
Cellectis plans to start human trials in patients with acute myeloid leukemia sometime this year.

http://canmua.net/world/cellectis-ceo-andre-choulika-on-gene-editing-talens-289258.html

Spark Therapeutics Ambitious Plans

Spark Unveils Vision of Having 10 Clinical-Stage Gene Therapy Programs by 2018, Including One Commercial and Two in Pivotal Trials

Data from five clinical programs and numerous regulatory milestones expected over the next 18 months ------------------ Strategic vision driven by Spark's fully integrated and validated gene therapy platform with financial resources exceeding $300 million PHILADELPHIA, Jan. 11, 2016 (GLOBE NEWSWIRE) -- Spark Therapeutics Inc. (NASDAQ:ONCE) today outlined a comprehensive three-year vision for expanding the company’s portfolio through 2018 and launching its first commercial product in 2017, during a presentation this afternoon at the J.P. Morgan 34th Annual Healthcare Conference in San Francisco. Spark Co-founder and Chief Executive Officer, Jeffrey D. Marrazzo, outlined plans for advancing 10 total programs across three therapeutic franchises by 2018, including one commercially approved therapy, two product candidates in pivotal-stage trials and at least seven additional programs in clinical proof-of-concept trials. The company’s 2018 vision for its portfolio is fully funded with existing financial resources, Marrazzo said. “The overwhelmingly positive data from our pivotal Phase 3 program for RPE65-mediated blindness, together with the multi-year durability data presented from the same program, provide strong validation of the Spark platform for AAV-based gene therapy that we are deploying across a large and growing pipeline of product candidates,” Marrazzo said. “Our results reflect the power of a true platform that combines proven capabilities across vector selection, design and manufacture, a history of collaborating with regulators to optimize clinical development and develop novel clinical endpoints, and our position at the forefront of shaping a patient-centric, commercial model for gene therapies. We are now leveraging this platform through internal innovation and commercialization, partnering and external collaboration to transform the treatment of a wide range of severe genetic diseases in three target tissues – the eye, the liver and the central nervous system (CNS).” Among the programs unveiled for the first time were two new indications, including Leber hereditary optic neuropathy (LHON), an additional inherited retinal dystrophy (IRD) program, which affects over 7,500 patients, with an even greater number of patients at risk for losing their sight in the United States and the five major European markets (EU5). Within the Company’s growing CNS portfolio, Spark unveiled its program targeting Huntington’s disease (HD), a hereditary genetic disorder that affects over 60,000 patients in the United States and the EU5. The Company also outlined multiple data readouts and regulatory milestones that it expects over the next 18 months across five separate product candidates, including: SPK-RPE65: A Biologics License Application (BLA) filing in the second half of 2016 and a Marketing Authorization Application (MAA) filing in early 2017, along with the readout of one-year efficacy data for the Phase 3 crossover subjects (n = 9), two- and four-year durability data from the Phase 3 intervention group (n = 20) and a comparable cohort of subjects (n = 8) from an earlier Phase 1 trial, respectively; SPK-CHM: Initial safety and efficacy data in the second half of 2016 from the Phase 1/2 trial for choroideremia; SPK-FIX: Initial efficacy data in mid-2016 for the Phase 1/2 trial for hemophilia B; SPK-FVIII: An Investigational New Drug (IND) filing in the second half of 2016 and initial efficacy data in hemophilia A in the first half of 2017; and SPK-TPP1: An IND filing in the second half of 2016 and initial efficacy data for TPP1 deficiency, a form of Batten disease, in the first half of 2017. Additionally, Spark announced four recent developments relating to its lead program, SPK-RPE65: Further analyses of the visual acuity data from the Phase 3 trial yielded statistically significant results: (i) using the Lange scale, intervention group subjects improved an average of 9 letters versus 1.6 for the control subjects (p = 0.047); and (ii) in a sub-group analysis that removes subjects that developed cataracts (n = 3), as recommended by the Company’s Data Safety Monitoring Board, intervention group subjects improved an average of 10.6 letters versus 1.6 for controls (p = 0.007);   The company received positive scientific advice from the European Medicines Agency (EMA) regarding the requirements for its MAA filing including the feasibility of pursuing an approach to the ultimate label that is similar to the approach being pursued with the Food and Drug Administration (FDA), combining a core clinical manifestation of the disease with a genetic mutation, RPE65;   The company converted the license from the University of Pennsylvania, the University of Florida and Cornell University with claims covering the method of treating RPE65-mediated diseases from co-exclusive to exclusive; and   SPK-RPE65 received its non-proprietary product name, voretigene neparvovec.              Spark closed 2015 with more than $290 million in cash and equivalents, following the completion of a follow-on offering in December 2015. This figure does not reflect a $15 million milestone payment from Pfizer that was earned in December 2015. About Spark Therapeutics Spark is a gene therapy leader seeking to transform the lives of patients with debilitating genetic diseases by developing one-time, life-altering treatments. Spark’s initial focus is on treating rare diseases where no, or only palliative, therapies exist. Spark’s most advanced product candidate, SPK-RPE65, which has received both breakthrough therapy and orphan product designation, recently reported positive top-line results from a pivotal Phase 3 clinical trial for the treatment of rare blinding conditions. Spark’s validated gene therapy platform is being applied to a range of clinical and preclinical programs addressing serious genetic diseases, including inherited retinal dystrophies, hematologic disorders and neurodegenerative diseases. Spark builds on two decades of research, development and manufacturing at The Children’s Hospital of Philadelphia, including human trials conducted across diverse therapeutic areas and routes of administration. To learn more, please visit www.sparktx.com.

ARM Presentation: Edward Lanphier, President & CEO, Sangamo BioSciences; Chairman, Alliance for Regenerative Medicine

Youtube 18 minutes, E.L starts at the four minute mark
https://www.youtube.com/watch?v=pD9ygwSJVd0

Milestones and Catalysts for 2015-2016

HIV - Plan to Partner for pivitol studies and COMMERCIALIZATION

Technology Platform - Competitive Analysis ex vivo Stem Cells

IVPRP What's Next

ZFN's vs AAV

ZFN vs CRISPR

The Sangamo Advantage

Reminder: Sangamo Presents at JP Morgan Today 12:30 pm EST

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 Company's clinical and preclinical ZFP Therapeutic^® programs and upcoming milestones, as well as an overview of Sangamo's business strategy at 9:30 am PT on Tuesday, January 12^th, at the 34^th Annual J.P. Morgan Healthcare Conference. The conference will be held from January 11-14 in San Francisco, CA

Edward Lanphier Speaking tomorrow at Regen Med & Advanced Therapies (live webcast) SGMO

Live Webcast.
Regen Med & Advanced Therapies State of the Industry Briefing
  ARM's Annual Regen Med & Advanced Therapies State of the Industry Briefing is a top-level gathering for key stakeholders in the sector - including business executives, investors, patient advocates and academic leaders - to learn more on the recent progress and outlook for the industry in the coming year. This event annualy attracts over 300 attendees and is the largest gathering specifically for regenerative medicine and advanced therapies taking place during JP Morgan week in San Francisco.

Program Agenda
8:00am - 8:20am | Program Introduction & Industry Update (pacific time, 11:00 am Eastern)
Morrie Ruffin, Managing Director, Alliance for Regenerative Medicine
Edward Lanphier, President & CEO, Sangamo BioSciences; Chairman, Alliance for Regenerative Medicine

8:20am - 9:05am | The 2016 Sector Forecast: Upcoming Clinical Data Events
This session features CEOs and senior executives from leading companies in the regenerative medicine and advanced therapies sector for a forward-looking discussion of expected clinical data events in 2016 and beyond. Panelists will address key issues related to continuing momentum in the sector as well as unique strategies and partnerships that will be required for success going forward.
Jason Kolbert, Head of Healthcare Research & Senior Managing Director, Maxim Group (co-moderator)
Jason McCarthy, Equity Research Analyst, Biotechnology, Maxim Group (co-moderator)
Silviu Itescu, Managing Director & CEO, Mesoblast
Sven Kili, VP & Head of Gene Therapy Development, GlaxoSmithKline
Gil Van Bokkelen, Chairman & CEO, Athersys
Jeffrey Walsh, COO, bluebird bio
Sue Washer, President & CEO, AGTC
9:05am - 9:50am | The Promise of Regenerative Medicine & Advanced Therapies in Oncology
This in-depth session will examine the progress of regenerative medicine and advanced therapies specifically as the field relates to the area of oncology. The panel's expert speakers will discuss a number of key hurdles on the path to commercialization including reimbursement and market access and what progress can be expected in the sector in the coming year.
Joshua Schimmer, Managing Director & Senior Research Analyst, Piper Jaffray (moderator)
Jeffrey Abbey, President & CEO, Argos Therapeutics
Usman Azam, Global Head, Cell & Gene Therapies Unit, Novartis
André Choulika, Chairman & CEO, Cellectis
Gregg Sando, Founder & CEO, Cell Medica
9:50am | Program End

Also actively publishing in the allogenic CAR-T race is Sangamo Biosciences of Richmond California

Article titled:

Off-the-shelf CAR-T therapy induces remission in child with ALL

Paid access only, http://www.nature.com/nbt/journal/v34/n1/full/nbt0116-12.html

The impressive response seen in the first leukemia patient treated using donor T cells genetically modified to target the CD19 antigen on tumor cells may signal the opening of a new chapter in the race to commercialize T cell–based chimeric antigen receptor (CAR-T) technologies. A formal clinical trial has yet to commence using the tr…

Zinc Fingers get More Specific

Multi-reporter selection for the design of active and more specific zinc-finger nucleases for genome editing

http://www.nature.com/ncomms/2016/160107/ncomms10194/full/ncomms10194.html

Abstract

Engineered nucleases have transformed biological research and offer great therapeutic potential by enabling the straightforward modification of desired genomic sequences. While many nuclease platforms have proven functional, all can produce unanticipated off-target lesions and have difficulty discriminating between homologous sequences, limiting their therapeutic application. Here we describe a multi-reporter selection system that allows the screening of large protein libraries to uncover variants able to discriminate between sequences with substantial homology. We have used this system to identify zinc-finger nucleases that exhibit high cleavage activity (up to 60% indels) at their targets within the CCR5 and HBB genes and strong discrimination against homologous sequences within CCR2 and HBD. An unbiased screen for off-target lesions using a novel set of CCR5-targeting nucleases confirms negligible CCR2 activity and demonstrates minimal off-target activity genome wide. This system offers a straightforward approach to generate nucleases that discriminate between similar targets and provide exceptional genome-wide specificity.

The Economist "Crushes" Editas, Mentions Sangamo

AS DIFFICULT sales pitches go, this one is hard to beat. This biotech company has burned through $75m in the past few years and has not yet started clinical work on a drug candidate. It says it will be many years, “if ever”, before it has something ready to commercialise. If this were not enough, not only is there a thorny patent thicket to manage but the firm must fight and win a case seeking to overturn its own intellectual-property claims on the ground that it was not the first to invent them.
Despite all this, shares in Editas Medicine, which filed on January 4th for an initial public offering, look set to draw great interest from investors. It will be an opportunity to buy into a revolutionary new technology called CRISPR-Cas9, which allows DNA to be cut and edited almost as easily as one might rewrite a document on a computer. Editas, spun out of the work of geneticists at the Broad Institute in Cambridge, Massachusetts, has already raised $163m from private investors and is seeking a further $100m from the markets. Its initial aim is to begin trials by 2017 on a possible treatment for a rare form of blindness

Editas is not alone in pursuing the CRISPR-Cas9 technology. Others include Caribou Biosciences, CRISPR Therapeutics and Intellia Therapeutics. There are also firms such as Bluebird Bio and Sangamo, which are further ahead with drug candidates developed using older, and clunkier, forms of gene-editing.
In the past two years about $1 billion of venture-capital financing has been invested in new gene-editing technologies, reckons the Boston Consulting Group. This reflects the promise the technology offers for producing treatments, and even cures, for a wide range of conditions—and not just those linked to mutated genes, such as haemophilia or sickle-cell anaemia. An early move to go public will help Editas stand out from the crowd, and perhaps help it recruit and retain good scientists.
CRISPR Therapeutics says it is also thinking about going public, given investors’ interest. Although enthusiasm for biotech IPOs as a whole may have cooled in the second half of 2015, Eva Haas of Hume Brophy, an investor-relations firm, says the Editas IPO is happening because it is “in a hot area and because it can.” Editas is also helped by having a stellar list of private investors, including Google, Bill Gates and Fidelity Investments, as well as three venture-capital backers, Polaris Partners, Third Rock and Flagship Ventures. (A number of other biotech companies filed to go public this week, including Corvus Pharmaceuticals, which is working on small-molecule drugs for cancer, and Audentes Therapeutics, a gene-therapy firm.)
Some startups in other areas of technology have chosen in recent years to delay going for IPOs and to raise money privately instead. However, Sam Zucker of Sidley Austin, a law firm that manages corporate transactions in biotech, says that early-stage firms in this area may be keen to go public because they want to be free from dependence on a small network of venture-capital firms. The pool of public capital they will then be able to dip into is often faster to materialise, as well as larger, than private capital, he says. Wherever the money comes from, however, Editas and other gene-editing firms will need to show results eventually.
http://www.economist.com/news/business/21685464-gene-editing-company-files-ipo-cutting-remarks?fsrc=rss%7Cbus

Uniqure Presents Hemophilia B Results

uniQure Announces Preliminary Topline Results from Low-Dose Cohort in Hemophilia B Phase I/II Gene Therapy Clinical Trial

--Meaningful Factor IX Expression Validates Successful Transduction of the Liver Using uniQure’s Proprietary AAV5 Vector--

--Four of Five Patients Have Fully Discontinued Prophylactic Recombinant Factor IX Therapy--

--Conference Call to Discuss Data Scheduled for 8:30 am EST Today, January 7--

Amsterdam, the Netherlands, January 7, 2016 —uniQure N.V. (Nasdaq: QURE), a leader in human gene therapy, today announced preliminary topline results from the low-dose cohort of an ongoing Phase I/II clinical trial being conducted in adult hemophilia B patients treated with uniQure’s novel AAV5/FIX gene therapy, AMT-060. All five patients in the low-dose cohort had Factor IX (FIX) phenotypic features of severe or moderately-severe hemophilia including documented Factor IX (FIX) levels less than 1-2% and required chronic treatment with prophylactic recombinant FIX (rFIX) therapy at the time of enrollment.
The first two patients out of five in the low dose cohort have completed at least 20 and 12 weeks of follow up and had central-lab-confirmed FIX expression levels of 5.5% and 4.5% of normal, respectively at the cutoff date of December 16^th, 2015.  The three additional patients have been dosed, but had not achieved the full 12 weeks of follow-up at the cutoff date. However, as of January 6, 2016, four of the five patients, including the first two patients enrolled in the study, have met a secondary objective in the trial by fully discontinuing prophylactic rFIX. The 12 week follow-up, post AMT-060 administration, marks the period in which investigators in the trial attempt discontinuation of prophylactic rFIX, based on FIX expression levels.  The first patient in the low-dose cohort experienced a mild, transient and asymptomatic elevation of transaminase levels at around 10 weeks post treatment.  This patient received a short, 8-week course of tapering prednisolone doses with rapid return of transaminase levels to baseline values. No elevated transaminase levels have been observed in the other four patients thus far, with all patients being on therapy for at least 10 weeks as of January 6, 2016.
AMT-060 consists of a codon-optimized wild type FIX gene and the LP1 liver promoter together with the AAV5 viral vector, manufactured using uniQure’s proprietary insect cell based manufacturing technology. AMT-060 is administered, without immunosuppressant therapy, through the peripheral vein in one treatment session for approximately 30 minutes. The study includes two cohorts, with the low-dose cohort using 5x10¹² gc/kg and the high-dose cohort using 2x10¹³ gc/kg. Thus far, there have been no patient screening failures due to pre-existing neutralizing antibodies against AAV5 and no patients have developed inhibitory FIX antibodies.
These early data from the low-dose cohort suggest that AMT-060 is generally well-tolerated and capable of successfully transducing the liver resulting in clinically meaningful FIX expression levels.  This current trial uses a starting dose of AAV5/FIX gene therapy that is similar to the highest dose of the same FIX gene cassette evaluated in a study conducted by Prof. Amit Nathwani and the St. Jude Children’s Hospital using an AAV8 serotype vector, and uniQure’s preliminary data are comparable with the endogenous FIX expression levels achieved in the St. Jude study. The results of the St. Jude study, which were published in the New England Journal of Medicine in 2011 and 2014, demonstrated that a durable mean FIX expression of 5.1% of normal (range 2.9% to 7.2%) can be achieved with this gene cassette and result in meaningful long-term clinical benefits for patients.  In the St. Jude study, four of six patients treated at the high dose had transient elevations of transaminase levels, managed with a tapering prednisolone regimen. The FIX gene cassette used in the St. Jude study is exclusively licensed by uniQure.
“Thus far, the overall tolerability and FIX expression profile in the low-dose cohort is encouraging for patients with hemophilia B and support the continuation of the study,” commented Professor Frank W.G. Leebeek, M.D. Ph.D. of the Erasmus Medical Center in Rotterdam, an investigator in the study. “Previous studies have demonstrated that maintaining durable FIX expression around 3% to 5% of normal may have a significant clinical benefit as measured by significant reduction in consumption of units of FIX concentrate and lower risk of spontaneous bleeding episodes.”
uniQure intends to present a more complete analysis of these data from this low-dose cohort at a scientific conference in the second quarter of 2016.  Subject to the Data Monitoring Committee’s approval, the Company also anticipates initiating enrollment of the high-dose cohort this quarter.
“These preliminary topline results support our hypothesis that AAV5/FIX can deliver clinically meaningful expression levels of FIX for patients with hemophilia B,” commented Dan Soland, Chief Executive Officer of uniQure. “So far, our AAV5-based gene therapies have been systemically administered to 13 adult patients across two clinical studies in two different disease states, and via direct central nervous system administration in four children in a third study, providing us with a strong safety dataset on the AAV5 vector and our proprietary insect cell based manufacturing technology.”
“Today, we are the only AAV gene therapy company in the world with both proprietary, commercial-scale manufacturing capabilities and encouraging clinical data across multiple diseases,” continued Mr. Soland.  “These preliminary results further support our modular platform approach and leadership in gene therapy.”

ARM's Regen Med & Advanced Therapies State of the Industry Briefing January 11

About the Briefing
ARM's Annual Regen Med & Advanced Therapies State of the Industry Briefing is a top-level gathering for key stakeholders in the sector - including business executives, investors, patient advocates and academic leaders - to learn more on the recent progress and outlook for the industry in the coming year. This event annualy attracts over 300 attendees and is the largest gathering specifically for regenerative medicine and advanced therapies taking place during JP Morgan week in San Francisco.
Attendance
This Briefing is free to attend and open to the public - RSVP is required below. Please note this Briefing is held in conjunction with EBD's Biotech Showcase. Therefore, anyone not registered for the full Biotech Showcase conference will be asked to leave the meeting area immediately following the close of this Briefing.
Program Agenda
8:00am - 8:20am | Program Introduction & Industry Update
Edward Lanphier, President & CEO, Sangamo BioSciences; Chairman, Alliance for Regenerative Medicine
Morrie Ruffin, Managing Director, Alliance for Regenerative Medicine
8:20am - 9:05am | The 2016 Sector Forecast: Upcoming Clinical Data Events
This session features CEOs and senior executives from leading companies in the regenerative medicine and advanced therapies sector for a forward-looking discussion of expected clinical data events in 2016 and beyond. Panelists will address key issues related to continuing momentum in the sector as well as unique strategies and partnerships that will be required for success going forward.
Jason Kolbert, Head of Healthcare Research & Senior Managing Director, Maxim Group (co-moderator)
Jason McCarthy, Equity Research Analyst, Biotechnology, Maxim Group (co-moderator)
Eduardo Bravo, CEO, TiGenix
Silviu Itescu, Managing Director & CEO, Mesoblast
Sven Kili, VP & Head of Gene Therapy Development, GlaxoSmithKline
Jeffrey Walsh, COO, bluebird bio
Sue Washer, President & CEO, AGTC
9:05am - 9:50am | The Promise of Regenerative Medicine & Advanced Therapies in Oncology
This in-depth session will examine the progress of regenerative medicine and advanced therapies specifically as the field relates to the area of oncology. The panel's expert speakers will discuss a number of key hurdles on the path to commercialization including reimbursement and market access and what progress can be expected in the sector in the coming year.
Joshua Schimmer, Managing Director & Senior Research Analyst, Piper Jaffray (moderator)
Usman Azam, Global Head, Cell & Gene Therapies Unit, Novartis
André Choulika, Chairman & CEO, Cellectis
Gregg Sando, Founder & CEO, Cell Medica
9:50am | Program End
Who Attends?
Over 300 of the advanced therapy and regenerative medicine field's top stakeholders including company founders, C-level business executives, investors, media, patient advocates and academic leaders interested in learning more on the sector's recent advances and outlook for the industry in the coming year.
Location
Parc 55 Hotel
55 Cyril Magnin St.
San Francisco, CA 94102

Sangamo BioSciences Announces Presentation At The 34th Annual J.P. Morgan Healthcare Conference

RICHMOND, Calif., Jan. 5, 2016 /PRNewswire/ -- 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 Company's clinical and preclinical ZFP Therapeutic^® programs and upcoming milestones, as well as an overview of Sangamo's business strategy at 9:30 am PT on Tuesday, January 12^th, at the 34^th Annual J.P. Morgan Healthcare Conference. The conference will be held from January 11-14 in San Francisco, CA.
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 Presentations.  The presentation will be archived on the Sangamo website for two weeks after the event.
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.

ZFP Therapeutic^® is a registered trademark of Sangamo BioSciences, Inc.

Urnov:"In one trial, "nine subjects have been able to stay off their meds for an extended period of time," he says. "The longest period of time has been more than a year and a half."

Medscape Article

Will Gene Editing Be in Your Medical Future?

Great Potential, but Not Ready for Prime Time

Leigh Page

Freelance healthcare writer, Chicago, Illinois

| Disclosures | January 05, 2016

Gene editing is a very compelling concept for physicians. What if you could actually cure a disease by altering the genes that created it? Then your patients wouldn't need drugs and other therapies, which often involve high costs and dangerous side effects. This revolutionary approach could either remove the disease or reduce it to a nonthreatening level.
Slowly but surely, researchers are trying to bring the concept of gene editing closer to clinical reality. Still, no one is saying that this therapy would be commercially available any time soon. Use of gene editing on humans is just beginning to enter clinical trials. At this point, research is focusing only on a small number of diseases that affect relatively small populations.
In gene editing, "the idea is not to treat the disease but to physically change the DNA in a way that cures the disease," says Fyodor Urnov, PhD, a genetic biologist and senior scientist at Sangamo BioSciences, a California company that owns the rights to a form of gene-editing technology called "zinc-finger nucleases."
More than 3000 diseases have been linked to mutations in individual genes, but researchers are starting with diseases that are most likely to yield positive results. These include HIV and diseases that involve a defect in only one gene, such as hemophilia, sickle cell disease, and beta thalassemia. Meanwhile, "there are many diseases that we are not looking at, such as heart disease, because they have contributions from multiple genes," Dr Urnov says.

How Gene Editing Works

Gene editing—more properly called "genome editing"—involves removing and adding specific bits of DNA in a patient's genome. The process is a lot like cutting and pasting words, which is why the process is called "editing." Sangamo's zinc-finger nucleases are engineered from natural enzymes and introduced into the blood, or into the brain or other organs. They can also be used outside the body on stem cells or T cells, which are then introduced into the body.
The zinc finger is able to locate a particular set of defective genes, make a break in the DNA strands there, and introduce new bits of DNA to take their place. "The beauty of this is that we can rely on a natural process to repair the break," Dr Urnov says. "We let Mother Nature do its work."
Dr Urnov says this process has become much more than just a concept. It has been shown to work on mice and other animals in research labs and is now beginning to be used in clinical trials. Sangamo is already in mid-stage clinical trials for HIV and is hoping to get approval for trials on beta thalassemia, sickle cell disease, and hemophilia.
"Gene editing is a reality," he says. "We can edit the genome of human cells so that they make a new therapeutic protein, or we can knock out a gene in order to have a therapeutic effect."
The next steps in developing gene editing are clear, Dr Urnov says. "We have done a lot of work on mice models, and now we have to translate that to the human setting." At this point, neither Dr Urnov nor anyone else can say when gene editing would be ready for normal clinical use on patients.

New Competition From CRISPR

The zinc-finger method was developed almost 20 years ago, but Dr Urnov says research on it only began to hit its stride in 2005, when it was first used to correct a mutant gene in human cells. In the next 3 years, zinc fingers were successfully used to add a whole gene to a specific place in the DNA and then to remove a specific gene, he says.
Sangamo has garnered millions of dollars from investors, industry partners, and grant funding agencies to research gene editing and translate the potential of the technology to the clinic. Company representatives say that Sangamo expects to end the year with at least $200 million in cash and investments, not to mention its partnerships with other biotech companies, such as Biogen and Shire.
Recently, however, interest in gene editing has begun to include a rival method to zinc fingers, called "clustered regularly interspaced short palindromic repeats" (CRISPR). Developed just 3 years ago, CRISPR has been hailed as a gene-editing wunderkind by the New York Times,^[1] the Wall Street Journal,^[2] and the New Yorker.^[3]
Despite an ongoing battle over the patent for CRISPR, the technique is beginning to attract substantial investments. In November 2014, Intellia Therapeutics announced^[4] a $15 million funding round led by Novartis and Atlas Venture to develop CRISPR.
Many genetic researchers, such as Gang Bao, PhD, at the Georgia Institute of Technology, have switched from zinc fingers to CRISPR, according to a 2014 article^[5] in MIT Technology Review. Using RNA molecules rather than zinc fingers, CRISPR "has quickly spread through biology laboratories" because "it is so precise and cheap to use," according to a November 2015 article^[6] in MIT Technology Review.
For all of its merits, however, CRISPR isn't as accurate as zinc fingers in locating specific DNA strands, Dr Urnov and many others contend. "For this reason, it will be difficult to develop as a therapeutic technology," Dr Urnov says.
Nonetheless, there's now a company called CRISPR Therapeutics, based in Cambridge, Massachusetts, whose stated mission^[7] is "to develop transformative gene-based medicines for patients with serious diseases."

Possible Use Against HIV

Sangamo's first substantial research into human applications for gene editing focused on HIV. The goal is to mimic the CCR5-delta 32 mutation, a very rare natural gene mutation that allows T cells to resist infection by HIV. CCR5-delta 32 came to light when doctors observed that some sexual partners and needle-sharers of AIDS patients didn't contract the virus. Then a patient in Berlin, Germany, was in effect cured of the HIV infection after receiving a bone marrow transplant from a donor who had the mutation.
"The goal is to modify HIV patients' immune system so that their own cells can destroy the virus," Dr Urnov says. This would mean that they would no longer have to be on individual "cocktails" of antiretroviral drugs for the rest of their lives.
Sangamo is currently active in three clinical trials involving gene therapy for HIV—two using T cells and one using stem cells. Dr Urnov says he's cautiously optimistic about the trial results so far. In one trial, "nine subjects have been able to stay off their meds for an extended period of time," he says. "The longest period of time has been more than a year and a half."
Dr Urnov says Sangamo would have to complete larger clinical trials before the HIV approach could gain approval by the US Food and Drug Administration (FDA), and the trials could be quite costly. If the results of the current trials are promising, the company would look for a partner to share the expenses for further development of this therapy, he says.
Researchers are also using CRISPR to mimic the CCR5-delta 32 mutation for HIV. In research^[8] published in the Proceedings of the National Academy of Sciences last year, a team of hematologists engineered a particular white blood cell to be HIV-resistant after altering the genome of induced pluripotent stem cells.

Targeting Some Simple Diseases

Meanwhile, Dr Urnov says Sangamo is focusing on other diseases that are thought to be the best fit for the gene-editing approach, such as sickle cell disease, beta thalassemia, and hemophilia. These diseases were chosen because they're monogenic—meaning they're caused by a genetic defect in a single gene. Developing the therapy would be relatively straightforward because "there's an unambiguous correlation between a mistake in the gene and the disease," Dr Urnov says.
Sangamo has partnered with Biogen to fund research and develop a gene-editing therapeutic to treat beta thalassemia and sickle cell disease. The two companies plan to file investigational new drug (IND) applications for clinical trials for beta thalassemia in the first half of 2016 and for sickle cell disease in the second half of 2016, Sangamo representatives say.
Both diseases are incurable and require ongoing therapy to keep the patient alive. Beta thalassemia is a blood disorder that reduces the production of hemoglobin, requiring lifetime blood transfusions. Sickle cell disease causes red blood cells to become misshapen and break down, decreasing the amount of oxygen in the blood. Patients with sickle cell disease need to have blood transfusions, iron chelation therapy, and other treatments and medications.
Gene editing for both diseases involves the clever idea of switching from the adult hemoglobin gene, which has been malfunctioning, to the fetal hemoglobin gene, which is in good shape. So it's a switch that would, in effect, cure the patient of the disease. Why are there two genes? The fetal hemoglobin gene is used in the womb when the fetus is taking oxygen from the mother's bloodstream. At birth, it's turned off and the adult gene is turned on. Already, in preclinical research in mice, it has been shown that gene editing with zinc fingers can turn the fetal gene back on, Dr Urnov says.
Meanwhile, CRISPR is also being used to edit sickle cell genes in research led by Dr Bao at Georgia Tech. In the 2014 article in MIT Technology Review, he said that even if gene editing could not remove all the sickle cells, it would still have the desired effect. "Even if we can replace 50%, a patient will feel much better," he said. "If we replace 70%, the patient will be cured."

Developing a Therapy for Hemophilia B

Dr Urnov is enthusiastic about using zinc fingers on hemophilia, another monogenic disease. The research is focusing on hemophilia B, which is caused by a defect in the gene for clotting factor IX (FIX).
In a study^[9] published in Nature in 2011, laboratory mice were virtually cured of hemophilia by using the zinc-finger technology. Scientists at Sangamo and at the Center for Cellular and Molecular Therapeutics at the Children's Hospital of Philadelphia spliced a new FIX gene into the gene sequence of a damaged FIX gene. This technique raised the level of the clotting protein only marginally, to about 5% of normal levels, but this was enough to have a dramatic impact on the mice's condition.
Subsequently, a Sangamo researcher led a similar study on 15 monkeys injected with zinc-finger nucleases and normal versions of FIX. Afterward, the monkeys' livers began producing much higher levels of FIX, and protein levels in the blood reached as much as 10% of normal levels. Dr Urnov adds that researchers have improved results using this technique by targeting the albumin gene in the liver.
Sangamo plans to file an IND application by the end of the year to begin the first clinical trial for its hemophilia B treatment. The company used to collaborate with Shire on research for hemophilia and Huntington disease, but in September, Sangamo announced^[10] that although the companies will keep their collaboration, Shire will focus its research on Huntington disease and Sangamo will focus on hemophilia.
Dr Urnov says Sangamo is also looking into the use of gene editing for lysosomal storage disorders, such as Hurler and Hunter syndromes. These diseases involve defects of the lysosomes, which act as recycling sites in cells, breaking down unwanted material into simple products for the cell to use to build new materials, and currently there are no cures. Company officials say Sangamo plans to file an IND application with the FDA for Hurler syndrome by the end of 2015 and for Hunter syndrome in the first half of 2016.

Ethical Considerations

Dr Urnov and most other researchers are exclusively using gene editing on somatic cells—cells that aren't involved in the reproductive process and thus will disappear with the death of their host. But there has been some talk about using gene editing for the germline—cells that will be passed on to succeeding generations. Many scientists aren't comfortable with this sort of research, because no one knows what sort of side effects gene editing might produce. If they entered the germline, they might be passed down to future generations.
In March, Dr Urnov and other Sangamo representatives wrote an opinion piece^[11] in Nature calling for a moratorium on editing the germline. Also that month, some scientists involved in the CRISPR technology made basically the same plea.^[12] These scientists will further discuss the issue in a meeting in December. Although the United States doesn't directly ban it, the National Institutes of Health won't fund human embryo research.
Dr Urnov is concerned that if the scientific community doesn't act against embryo research, authorities might move to ban all kinds of gene editing, including research on somatic cells that could be potentially life-changing for patients with some of these genetic diseases.
Researchers do agree on one thing, however: Gene editing shows great potential for clinicians, but it could take many years to develop.
"Although still in its infancy, genome editing presents tantalizing opportunities for tackling a number of diseases that are beyond the reach of previous therapies," according to a review of the approach in Nature Medicine^[13] earlier this year. "The technology will require a number of iterations to systematically optimize its efficacy, safety and specificity."
Nonetheless, Dr Urnov is optimistic that at least some breakthroughs will occur within the next decade. "There is no question—none whatsoever—that over the next decade the clinical landscape will change, and genome editing will play a major role in this," he said in a July lecture^[14] at the University of California, Berkeley. "We will think clinically on how to manage genetic and other diseases in a fundamentally new light."
http://www.medscape.com/viewarticle/856498