@RNAIanalyst picks new target for Sangamo's Liver Directed Therapy

1. Dirk Haussecker ‏@RNAiAnalyst 3h3 hours ago

   $SGMO Liver-directed gene therapy for Wilson's disease: http://www.ncbi.nlm.nih.gov/pubmed/26409215

BioMarin Enrolls First Patient in Phase 1/2 Trial of Gene Therapy Drug Candidate BMN 270 for the Treatment of Hemophilia A

BMN 270 is the First AAV-Factor VIII Gene Therapy to be Investigated in a Clinical Trial Setting for Patients With Hemophilia A

SAN RAFAEL, Calif., Sept. 28, 2015 (GLOBE NEWSWIRE) -- BioMarin Pharmaceutical Inc. (NASDAQ:BMRN) announced today that it has enrolled the first patient in a Phase 1/2 trial for BMN 270, an investigational gene therapy for the treatment of patients with hemophilia A. BMN 270 is an AAV-factor VIII vector, designed to restore factor VIII plasma concentrations, essential for blood clotting in patients with hemophilia A. The gene therapy program for Hemophilia A was originally licensed from University College London and St. Jude Children's Research Hospital in February 2013 and has since been developed at BioMarin's facilities.
"Hemophilia A results from mutations at the genetic level, making gene therapy a potentially powerful technique to treat patients with a single dose," stated Hank Fuchs, M.D., Executive Vice President, Chief Medical Officer of BioMarin. "For the first clinical trial of BMN 270, we are looking to demonstrate that treatment with BMN 270 increases the expression of the factor VIII protein, necessary for blood clotting."
"The global bleeding disorders community greatly benefits from a wide range of support to help advance our vision of Treatment for All," said Alain Weill, World Federation of Hemophilia (WFH) President. "We welcome BioMarin as a new WFH Corporate Partner and greatly appreciate their commitment to support people with hemophilia A through their innovative gene therapy research."
Study Design
The Phase 1/2 study will evaluate the safety and efficacy of BMN 270 gene therapy in up to 12 patients with severe Hemophilia A. The primary endpoints are to assess the safety of a single intravenous administration of a recombinant AAV, human-coagulation Factor VIII vector and to determine the change from baseline of Factor VIII expression level at 16 weeks after infusion. The kinetics, duration and magnitude of AAV-mediated Factor VIII activity in individuals with hemophilia A will be determined and correlated to an appropriate BMN 270 dose. This is a dose escalation study with the goal of observing an increase in Factor VIII levels. Secondary endpoints include assessing the impact of BMN 270 on the frequency of Factor VIII replacement therapy, the number of bleeding episodes requiring treatment and any potential immune responses. Patients will be monitored for safety for five years.

Dirk Hausseckar tweets Sangamo Related Info

1. Dirk Haussecker ‏@RNAiAnalyst 6h6 hours ago

   $SGMO key competitive technological advantage: obligate heterodimers for impressive targeting specificity.

   0 retweets 1 favorite
2. Dirk Haussecker ‏@RNAiAnalyst 10h10 hours ago

   PCSK9, CC5 etc..monoclonal antibody apologists say 100% inhibition by MAbs, 90-98% by RNAi. Well, MAb that's just for few days. $ARWR $ALNY

Sangamo short Interest

Sangamo Short Interest (SGMO)

Sangamo Short Interest (SGMO)

DATE                                   SHORT INTEREST

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

Days to cover as of 9/15/15 is 4.51

Aidsmeds.com Reports on Cohort 3

Gene Therapy Controls HIV Longer Than Four Months in Study

Sangamo Biosciences’ efforts to develop genetic therapies for HIV have had some early success, with two of three participants in one cohort maintaining control of the virus for an extended period during which they were not taking standard antiretroviral (ARV) treatment. The biotech company is conducting a Phase I/II study, known as SB-728-1101, of its genetic treatment, called SB-728-T. Updated results about what is known as Cohort 3 of the trial were presented at the 2015 Interscience Conference of Antimicrobial Agents and Chemotherapy (ICAAC) in San Diego, California.

Cohort 3 includes three HIV-positive participants who received a genetic treatment in which their own CD4 and CD8 immune cells were drawn out, genetically modified to resist HIV, and then infused back into their bodies. This treatment was different from what was given to other participants in the study because it included modified CD8 cells instead of just modified CD4s. All of the study participants received a treatment called Cytoxan preconditioning before they received the modified cells in order to prime the body to better accept the immune cell infusion.

After undergoing the genetic treatment, the members of Cohort 3 all stopped taking ARVs. Two of them have maintained control of HIV for longer than 16 weeks.

“The ability of subjects treated in Cohort 3 to suppress and sustain control of viral load, combined with durable increases in CD4 and CD8 cells, provide support for our hypothesis of an immunologic mechanism of action for SB-728,” Dale Ando, MD, Sangamo’s vice president of therapeutic development and chief medical officer, said in a press release. “The prolonged positive effects observed in these Cohort 3 subjects have not been seen before with other treatments and have encouraged us to enroll and treat an additional five subjects with this regimen.”

http://www.aidsmeds.com/articles/Sangamo_gene_treatment_1667_27834.shtml

To read a press release about the study, click here.

Search: Sangamo Biosciences, Interscience Conference of Antimicrobial Agents and Chemotherapy, ICAAC, SB-728-1101, SB-728-T, genetic treatment, CD4, CD8, Dale Ando.

ICAAC 2015 Slides

Sangamo's Press Release Today

RICHMOND, Calif., Sept. 21, 2015 /PRNewswire/ -- Sangamo BioSciences, Inc. (Nasdaq: SGMO) presented data demonstrating sustained functional control of viral load in the absence of antiretroviral drugs (ART) in two of three HIV-infected subjects treated in Cohort 3* of its Phase 1/2 study (SB-728-1101) of its ZFP Therapeutic (SB-728-T) for the treatment of HIV/AIDS.  The subjects remain on extended treatment interruption (TI), past the initial 16 week TI period. The data, which led to expanded enrollment of this Cohort, were presented at the 2015 Interscience Conference of Antimicrobial Agents and Chemotherapy (ICAAC) in San Diego September 17-21
\
The ability of subjects treated in Cohort 3* to suppress and sustain control of viral load, combined with durable increases in CD4 and CD8 cells, provide support for our hypothesis of an immunologic mechanism of action for SB-728," said Dale Ando, M.D., Sangamo's vice president of therapeutic development and chief medical officer. "The prolonged positive effects observed in these Cohort 3* subjects have not been seen before with other treatments and have encouraged us to enroll and treat additional five subjects with this regimen."

Urnov Presented Paper at ESGCT/FSGT 9/19/15

Efficient targeted gene addition to a safe harbor locus in long-term
repopulating hematopoietic stem cells for correction of X-linked
Chronic Granulomatous Disease via genome editing
Fyodor Urnov, Sangamo BioSciences Inc, Richmond CA

I do not have access to his presentation at ESGCT but this is the abstract from ASGCT May  2015:
54] Genome Editing of Primary Human CD34⁺ Hematopoietic Stem Cells Enables a Safe Harbor Targeted Gene Addition Therapeutic Strategy for Chronic Granulomatous Disease

Suk See De Ravin, Andreas Reik, Pei-Qi Liu, Linhong Li, Madhusudan V. Peshwa, Narda Theobald, Uimook Choi, Janet Lee, Sherry Koontz, Gary Lee, Philip D. Gregory, Fyodor D. Urnov, Harry L. Malech. Laboratory of Host Defenses, NIAID, NIH, Bethesda, MD; Sangamo BioSciences, Inc., Richmond, CA; MaxCyte, Inc, Gaithersburg, MD

Many monogenic recessive diseases of blood can, in principle, be cured by transfer of functional therapeutic transgene to the genome of the hematopoietic stem cell (HSC) – a strategy proven successful for multiple rare diseases using current integrating vector gene therapy. With a focus on X-linked chronic granulomatous disease (X-CGD), we report a directed approach orthogonal to randomly integrating retrovector gene therapy: the highly specific targeted placement of the curative transgene into a validated safe harbor locus in human HSCs via human genome editing with zinc finger nucleases (ZFNs) and donor insert delivery using an AAV6 vector.
We describe here an integrated targeted delivery platform customized for targeted addition to human HSCs using a cGMP-compliant electroporation system compatible with clinical scale production. Using next-generation, highly optimized ZFNs against the AAVS1/PPP1R12C gene locus, we optimized conditions for addition of the fluorescent Venus cDNA into human peripheral blood G-CSF mobilized CD34⁺ HSCs. Venus expression in manipulated human HSCs in vitro reached >50% efficiency, while earlier experiments demonstrated persistence of gene-modified cells in NSG mice with 12-15% Venus⁺ human CD45⁺ cells retrieved from transplanted mouse bone marrow and overall human HSC engraftment levels of >15%. Targeted integration (TI) rates achieved in human CD45+ cells from mouse bone marrow were 28-57%. Similar levels of Venus⁺ (~10%) are observed in spleen and peripheral blood CD45+ cells, indicating differentiation of gene-modified CD34 HSCs into circulating blood cells.
X-CGD patients suffer from severe bacterial and fungal infections with excessive inflammation due to a defect in the gp91phox subunit of phagocyte oxidase. To extend the results above to CGD, we therefore used the same approach to target addition of the relevant curative transgene, gp91phox, into the AAVS1 safe harbor locus of HSCs from patients with X-linked CGD. In vitro levels of gp91phox expression in gene-modified patient CD34+ HSCs population achieve 12-16% gp91phox expression by flow cytometric analysis, with an NSG xenograft study demonstrating 3-5% of the engrafted human CD45⁺ cells expressing gp91phox. Of note, the MND-driven gp91phox expression from the safe harbor locus in human neutrophils differentiating from CD34+ cells transplanted into the NSG mouse model parallels wildtype gp91phox levels produced at the native locus.
Our studies demonstrate the feasibility of targeted addition of different genes at the AAVS1 safe harbor site of the genome in human HSCs at an unprecedented efficiency and specificity; we demonstrate the efficient correction of the enzymatic defect in neutrophils arising from patient-derived HSCs in vivo. In sum with the advances in GMP-scale cell processing for genome editing, and the charted regulatory path for ZFNs to the clinic provided by ongoing trials in HIV, our studies represent the foundation for a rapid translation of ZFN-driven targeted addition as a clinical modality for X-linked CGD.
Keywords: Hematopoietic Stem Cells; Gene Correction/Modification/Targeting; Zinc-finger nucleases

Here is the Fetal Hemoglobin Paper EL mentioned in the Morgan Stanley Conference

Hemoglobin switching's surprise: the versatile transcription factor BCL11A is a master repressor of fetal hemoglobin.

Bauer DE¹, Orkin SH².

Abstract

The major disorders of β-globin, sickle cell disease and β-thalassemia, may be ameliorated by expression of the fetal gene paralog γ-globin. Uncertainty regarding the mechanisms repressing fetal hemoglobin in the adult stage has served as a puzzle of developmental gene regulation as well as a barrier to rational therapeutic design. Recent genome-wide association studies implicated the zinc-finger transcriptional repressor BCL11A in fetal hemoglobin regulation. Extensive genetic analyses have validated BCL11A as a potent repressor of fetal hemoglobin level. Studies of BCL11A exemplify how contextual gene regulation may often be the substrate for trait-associated common genetic variation. These discoveries have suggested novel rational approaches for the β-hemoglobin disorders including therapeutic genome editing.
Copyright © 2015 Elsevier Ltd. All rights reserved.

Slippery Slope

The genetic manipulation of human IVF embryos is set to start in Britain for the first time following a licence application by scientists who want to understand why some women suffer repeated miscarriages.

If the research licence is granted by the Government’s fertility watchdog it will be only the second known occasion in the world where the chromosomes of human embryos have been genetically manipulated using a revolutionary gene-editing technique called Crispr/Cas9.
When Chinese scientists announced earlier this year that they had genetically altered “spare” human IVF embryos using Crispr/Cas9 for research purposes, there was deep concern among many who thought that they had gone too far – the US Government later imposed a moratorium on federally-funded research in America.

Read the article here:
http://www.independent.co.uk/news/science/ivf-embryos-to-be-genetically-manipulated-as-scientists-investigate-repeated-miscarriages-10506064.html

Japan Liberalizes Approval Process for Gene Therapy Treatments

Regenerative medicines in Japan can now get conditional marketing approval based on results from mid-stage, or Phase II, human trials that demonstrate safety and probable efficacy.
Once lagging behind the United States and the European Union on approval times, there is now an approximately three-year trajectory for approvals, according to Frost’s Kumar. That compares with seven to 10 years before. …
Around the world, companies have also faced setbacks while pushing such treatments. In the U.S., Geron Corp., which started the first nation-approved trial of human embryonic stem cells, ended the program in 2011, citing research costs and regulatory complexities. …
While scientists globally have worked for years in this field, treatments have been slow to come to market. But there is hope in Japan that without the political red tape, promising therapies will emerge faster and there will be speedier rewards.

Japan is liberalizing because with their aging population treatments for diseases like Alzheimer’s and Parkinson’s disease are in high demand.

Under the new system, a firm with a gene or regenerative therapy (e.g. stem cells) can get conditional approval with a small trial. Conditional approval means that the firm will be able to sell its procedure while continuing to gather data on efficacy for a period of up to seven years. At the end of the seven year period, the firm must either apply for final marketing approval or withdraw the product.
http://fee.org/anythingpeaceful/japan-liberalizes-regenerative-medicine-and-gene-therapy/

Mitchell Finer, Former Bluebird Bio CSO Lands New Job

The predecessor of Phil Gregory as CSO of Bluebird Bio (BLUE) Mitchell Finer is now Managing Director of MPM Capital.

MPM’s Managing Director Todd Foley states: “The focus of our latest fund is to achieve breakthroughs that will cure previously incurable diseases. Accordingly, cell and gene therapy are extremely important areas of future opportunity for MPM, and Mitch is an acknowledged scientific leader in this space. Our portfolio companies will benefit greatly from his expertise, and we are privileged and tremendously grateful that Mitch has elected to share his considerable talents and experience with us and our portfolio.”
"The addition of Mitch to our team caps a momentous half-year of hiring for MPM in which we've added half a dozen new operating partners with expertise ranging from R&D (Mitch and Patrick Baeuerle) to IP (Greg Sieczkiewicz) to clinical development (Briggs Morrison and Pablo Cagnoni) to M&A and licensing (Tony Rosenberg)," said MPM co-founder Ansbert Gadicke.
For three decades, Mitch has focused on regenerative medicine, cancer immunotherapy and cell and gene therapy, helping to advance niche products from product conception through phase III clinical programs.

 http://www.businesswire.com/news/home/20150915006799/en/MPM-Capital-appoints-Mitchell-H.-Finer-PhD#.VfjeH50o7vY

Dimension Therapeutics Files for IPO

From Firecebiotech.com:
Dimension Therapeutics is preparing to execute the next carefully planned step in its evolution, filing for a $115 million IPO close to 5 months after its crossover round landed. The filing came just days after the FDA accepted Cambridge, MA-based Dimension's IND for its lead gene therapy program, targeting a genetic fix for hemophilia B.
Dimension's lead program for DTX101 uses an AAV vector to deliver Factor IX into hemophilia patients. It's one of several biotechs to focus their first gene therapy programs on hemophilia, which a number of experts believe makes a logical focus for the new wave of upstarts now working in the field.
Gene therapy has been booming over the past two years as developers like bluebird bio ($BLUE) have powered their way back in after the first generation of work was shelved following the emergence of lethal side effects. Biogen ($BIIB) focused its new gene therapy group on hemophilia, alongside Spark Therapeutics ($ONCE), RegenX--which outlicensed original tech to Dimension--and others. But for now there's more promise than performance, as new data start to reveal whether a single-dose fix can work safely.

http://www.fiercebiotech.com/story/gene-therapy-player-dimension-catches-biotech-ipo-wave-files-115m-offering/2015-09-14

First Application of Sangamo's In Vivo Protein Replacement Platform (IVPRP) for Potential Cure of Hemophilia B

From today's press release:
"Hemophilia B is the first clinical application of our IVPRP which can be applied to many other diseases that are currently treated by protein replacement including hemophilia A and lysosomal storage disorders," said Geoff Nichol, M.B., Ch.B., Sangamo's executive vice president of research and development. "Successful review, by the NIH RAC, of the first human in vivo genome editing clinical protocol is a major milestone for Sangamo. We appreciate this careful consideration and unanimous approval of our proposed clinical trial and look forward to the commencement of our Phase 1 study in the near future."

IMPRESSIVE WORK !!

@RNAiAnalyst Showing the Love to Sangamo Today

1. 
   

   $SGMO...btw, extreme gift territory here. just wait when the CRISPR plays IPO+you will start and see value of $SGMO.

Sangamo BioSciences Announces Presentation At The 2015 Morgan Stanley Global Healthcare Conference

Sangamo BioSciences, Inc. (NASDAQ: SGMO) announced today that Edward Lanphier, Sangamo's president and CEO, will provide an update on the progress of Sangamo's ZFP Therapeutic® development programs and an overview of the company's business strategy at 9:55am ET on Friday, September 18, 2015, at the 2015 Morgan Stanley Global Healthcare Conference. The conference is being held in New York, NY

9/9/15 RAC Approves Sangamo Hemophilia F9 Protocol

Tip of the hat to Dr. Holmes.
RAC comments "exciting and innovative and very sophisticated  protocol"
All votes YES

Interesting Tweets from @RNAiAnalyst

Read from bottom

1. Dirk Haussecker ‏@RNAiAnalyst 4h4 hours ago

   $SGMO, however, has IP advantage: 1st mover in a number of Rx areas; plus in ZFN no stepping over each others' toes.

   0 retweets 0 favorites
   

   
   
2. Dirk Haussecker ‏@RNAiAnalyst 4h4 hours ago

   What stuck out is that ZFN/TALEN can do what CRISPR can, but gene k.o. cell line $30-40k vs 1k. does this matter for Rx development? $SGMO

   0 retweets 1 favorite
   

   
   
3. Dirk Haussecker ‏@RNAiAnalyst 4h4 hours ago

   Nice market overview of gene editing in CEN: http://cen.acs.org/articles/93/i35/Genome-Editing-Writ-Large.html … $SGMO

   4h4 hours ago

Reminder - Sangamo Presents F9 Data at RAC meeting Tomorrow 10 am est (SGMO)

Webcast can be found here:
You will be able to view the event at http://videocast.nih.gov when the event is live

Sangamo Biosciences (SGMO) v. RA Capital Final Order and Judgement

As reported by Blackwatch on www.investorvillage.com a settlement has been reached in the RA Capital lawsuit. The document I have access to does  not provide an amount but verifies that Sangamo has proved its claims as written in the complaint.


Sangamo Biosciences, Inc. v. RA Capital Healthcare Fund, L.P. et al


Court New York Southern District Court
Judge Paul A Crotty
Nature of Suit 850 Other Statutes - Securities/Commodities/Exchange
Cause 15:78m(a) Securities Exchange Act


Case # 1:15-cv-03004
Filed Apr 17, 2015
Terminated Aug 20, 2015

Thursday, August 20, 2015

17

17 ORDER AND FINAL JUDGMENT. IT IS HEREBY ORDERED, ADJUDGED AND DECREED THAT: 1. The Court has jurisdiction over the subject matter of this action and over SANGAMO and the Settling Defendants. 2. The Court finds that SANGAMO, through its counsel, has vigorously prosecuted the claims set forth in the Complaint. 3. The Stipulation (a copy of which is annexed hereto as Exhibit 1) is hereby approved as fair, reasonable and adequate and in the best interests of SANGAMO and its shareholders. The parties are directed to consummate the Settlement in accordance with the terms and provisions of the Stipulation. 4. This Order and Final Judgment shall not constitute evidence or an admission by the Settling Defendants or any other person that any transaction giving rise to liability or damages under Section 16(b) occurred, or that any violations of law or acts of other wrongdoing have been committed, and shall not be deemed to create any inference that there is or was liability of any person therefor. The Settling Defendants do not admit, either expressly or implicitly, that they or any one of them is subject to any liability whatsoever by reason of any of the matters alleged in the Complaint or referenced in the Stipulation. The Settling Defendants, on the contrary, expressly deny and dispute the existence of any such liability. 5. The Complaint, each claim for relief therein against the Settling Defendants and all claims for violations of Section 16(b) that were asserted in this Action or could have been asserted in any amended complaint against the Settling Defendants and their Related Parties as defined in paragraph 4 of the Stipulation, are hereby dismissed on the merits, with prejudice and without costs, except as otherwise provided for herein. 6. The Settling Defendants and their Related Parties are hereby discharged and released from any and all liability and damages under or based upon any and all claims, rights, causes of action, suits, matters, demands, transactions and issues, known or unknown, arising out of or relating to the assertions contained in the Complaint in this Action or that could have been asserted in this Action as further set forth in this order. 7. SANGAMO, counsel for SANGAMO and all owners of any security (as defined in Section 3(a)(10) of the Exchange Act) of SANGAMO or of any other security or instrument, the value of which is derived from the value of any SANGAMO equity security, or any of them, either individually, directly, derivatively, representatively or in any other capacity, are permanently barred and enjoined from instituting or prosecuting this Action or any other action, in this or any other court or tribunal of this or any other jurisdiction, any and all claims, rights, causes of action, suits, matters, demands, transactions and issues, known or unknown, arising out of or relating to the assertions contained in the Complaint in this Action or that could have been asserted in this Action as further set forth in this order. 8. Jurisdiction is hereby reserved over all matters relating to the enforcement, administration and performance of the Stipulation. 9. The Clerk of the Court is directed to enter and docket this Order and Final Judgment in this Action. (Signed by Judge Paul A. Crotty on 8/20/2015) (lmb)

Review of Current Gene Therapy Market - Snngamo Mention (SGMO)

Pharmavoice.com has a new online review of the gene therapy market.
Here is the relevant Sangamo excerpt:

Biogen has a collaboration with Sangamo BioSciences in the area of zinc finger nucleases related to hemoglobinopathies, targeting sickle cell disease and beta-thalassemia. The beta-thalassemia program was initiated with a BCL11a knockout strategy, and the sickle cell program already employs the BCL11A enhancer approach.

Both beta-thalassemia and sickle cell manifest several months after birth, when patients’ cells switch from producing functional fetal globin to a mutant form of adult beta-globin, which causes their condition. The development program uses ZFN-mediated genome editing of a patient’s own hematopoietic stem and progenitor cells (HSPCs) to increase production of fetal globin in cells that will ultimately become red blood cells.

Sangamo and Biogen have developed two related but distinct ZFN-mediated genome editing approaches to disrupt critical aspects of the regulatory pathway that, in early infancy, lead to the switch in production from fetal to adult globin.

Initially, the companies developed a strategy for beta-thalassemia that specifically knocked out the gene encoding for the BCL11A transcription factor, a critical regulator of the switch from fetal to adult globin production.

A second approach was initiated for the sickle cell program, which involved the disruption of the more recently described erythroid-specific enhancer of BCL11A expression, a regulatory DNA sequence in the genome that is essential for expression of BCL11A but that is functional exclusively in cells destined to become RBCs.

Dr. Danos says clinical trials for both programs are expected to begin in 2016.

Read the entire article here:

http://www.pharmavoice.com/article/2015-09-gene-therapy/

Extraordinary Volume Today

Huge volume at the close; there was a trade of 1,162,200 .
Total volume for the day 2,784,369
Average volume 1,100,000
Volume precedes price?????