Change to Criteria in HSPC HIV Trial

Safety Study of Zinc Finger Nuclease CCR5-modified Hematopoietic Stem/Progenitor Cells in HIV-1 Infected Patients

Prior to March 24th, 2016

Criteria

Inclusion Criteria:

• HIV-1 R5 seropositive with no evidence of CXCR4-tropic virus.
• On cART with undetectable HIV-1 (<20 gc/ml HIV-1 RNA) for at least 12 months prior to screening evaluations.
• CD4+ T-cell counts ≥200 cells/µL and ≤600 cells/µL.
• No psychosocial conditions that would hinder study compliance and follow-up.
• Absence of clinically significant cardiomyopathy, congestive heart failure

Post March 24th, 2016

Criteria

Inclusion Criteria:

• HIV-1 R5 seropositive with no evidence of CXCR4-tropic virus.
• On cART with undetectable HIV-1 (<20 gc/ml HIV-1 RNA) for at least 12 months prior to screening evaluations.
• CD4+ T-cell counts ≥200 cells/µL and ≤750 cells/µL.
• No psychosocial conditions that would hinder study compliance and follow-up.
• Absence of clinically significant cardiomyopathy, congestive heart failure

Blood - New Publication

Long-term multi-lineage engraftment of genome-edited hematopoietic stem cells after autologous transplantation in nonhuman primates

1. Christopher W. Peterson1,
2. Jianbin Wang2,
3. Krystin K. Norman1,
4. Zachary K. Norgaard1,
5. Olivier Humbert1,
6. Colette K. Tse2,
7. Jenny J. Yan2,
8. Richard G. Trimble2,
9. David A. Shivak2,
10. Edward J. Rebar2,
11. Philip D. Gregory2,
12. Michael C. Holmes2, and
13. Hans-Peter Kiem1,*

Key points

• We are the first to show that genome editing approaches can modify multi-lineage, long-term repopulating cells in a large animal model.
• We demonstrate that genome-edited hematopoietic stem cells engraft with similar kinetics as observed for lentivirus-modified stem cells.

Abstract

Genome editing in hematopoietic stem and progenitor cells (HSPCs) is a promising novel technology for the treatment of many human diseases. Here, we evaluated whether disruption of the CCR5 locus in pigtailed macaque HSPCs by zinc finger nucleases (ZFNs) was feasible. We show that macaque-specific CCR5 ZFNs efficiently induce CCR5 disruption at levels of up to 64% ex vivo, 40% in vivo early post-transplant, and 3–5% in long-term repopulating cells over 6 months following HSPC transplant. These genome-edited HSPCs support multi-lineage engraftment and generate progeny capable of trafficking to secondary tissues including the gut. Using deep sequencing technology, we show that these ZFNs are highly specific for the CCR5 locus in primary cells. Further, we have adapted our clonal tracking methodology to follow individual CCR5 mutant cells over time in vivo, reinforcing that CCR5 gene-edited HSPCs are capable of long-term engraftment. Together, these data demonstrate that genome-edited HSPCs engraft, and contribute to multilineage repopulation after autologous transplantation in a clinically relevant large animal model, an important step toward the development of stem cell-based genome editing therapies for HIV and potentially other diseases.

http://www.bloodjournal.org/content/early/2016/03/15/blood-2015-09-672337?sso-checked=true

New Job Postings at Sangamo

Job Opportunities

The following is a list of open positions with Sangamo BioSciences.
(Updated 03/15/16)

Research

Research Associate III
Research Associate I
Paid Internship Positions

Development

Scientist I/II DNA Bioanalytics
Clinical Trial Assistant
Clinical Trial Manager (in-house)

Technical Operations

Director, Vector Production
Senior Manager / Manager, Quality Control
Analytical Methods Development Scientist (Temp/Contract)

IVPRP - What's next?

Sangamo Slide Shows it's Superiority

Dana Carroll - A Perspective on the State of Genome Editing

http://www.nature.com/mt/journal/v24/n3/full/mt201628a.html

Like the launch of a space probe, the advent of the CRISPR/Cas genome editing platform has caused both excitement and anxiety. The excitement, of course, reflects its high success rate, its simplicity, and its affordability. Its rapid adoption owes much to the groundwork laid by its predecessor nucleases, zinc-finger nucleases (ZFNs), meganucleases, and transcription activator–like effector nucleases (TALENs). All these reagents are able to make specific, targeted breaks in chromosomal DNA and generate both new mutations and intentional sequence changes.

Targeted gene addition in human CD34+ hematopoietic cells for correction of X-linked chronic granulomatous disease.

De Ravin SS¹, Reik A², Liu PQ², Li L³, Wu X⁴, Su L⁴, Raley C⁴, Theobald N¹, Choi U¹, Song AH², Chan A², Pearl JR², Paschon DE², Lee J¹, Newcombe H¹, Koontz S¹, Sweeney C¹, Shivak DA², Zarember KA¹, Peshwa MV⁴, Gregory PD², Urnov FD², Malech HL¹.

Author information

• ¹Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
• ²Sangamo BioSciences, Inc., Richmond, California, USA.
• ³MaxCyte, Inc., Gaithersburg, Maryland, USA.
• ⁴Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick, Maryland, USA.

Abstract

Gene therapy with genetically modified human CD34⁺ hematopoietic stem and progenitor cells (HSPCs) may be safer using targeted integration (TI) of transgenes into a genomic 'safe harbor' site rather than random viral integration. We demonstrate that temporally optimized delivery of zinc finger nuclease mRNA via electroporation and adeno-associated virus (AAV) 6 delivery of donor constructs in human HSPCs approaches clinically relevant levels of TI into the AAVS1 safe harbor locus. Up to 58% Venus⁺ HSPCs with 6-16% human cell marking were observed following engraftment into mice. In HSPCs from patients with X-linked chronic granulomatous disease (X-CGD), caused by mutations in the gp91phox subunit of the NADPH oxidase, TI of a gp91phox transgene into AAVS1 resulted in ∼15% gp91phox expression and increased NADPH oxidase activity in ex vivo-derived neutrophils. In mice transplanted with corrected HSPCs, 4-11% of human cells in the bone marrow expressed gp91phox. This method for TI into AAVS1 may be broadly applicable to correction of other monogenic diseases.

Sangamo BioSciences Announces Presentation At The Cowen And Company 36th Annual Health Care Conference

March 1, 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 progress of Sangamo's ZFP Therapeutic^® development programs and an overview of the company's business strategy at 10:40 am ET on Wednesday, March 9, 2016, at the Cowen and Company 36^th Annual Health Care Conference. The conference is being held in Boston from March 7-9, 2016.