Lab News

The Corn lab and our collaborators have received a $4 million grant from the California Institute for Regenerative Medicine (CIRM) to develop CRISPR-Cas9 genome engineering into a cure for sickle cell disease (SCD).

This generous funding will support the fruitful ongoing collaboration between our lab, physicians and sickle cell experts Mark Walters and David Martin of UCSF Benioff Children’s Hospital Oakland Research Institute (CHORI), and stem cell and gene therapy specialist Don Kohn of UCLA.  The grant is part of CIRM’s Translational Award program, which aims to move “the most promising projects out of the laboratory and into clinical trials in people.” 

We are very grateful for CIRM’s support, which enables us to establish clinical protocols for gene surgery to cure sickle cell disease. CRISPR cures for genetic diseases are rapidly approaching the clinic, and our research will lay the groundwork for a clinical trial in SCD. Our clinical approach will involve removing stem cells from the bone marrow of sickle cell patients, editing the mutated DNA code with CRISPR-Cas9, and putting the corrected cells back into the patient, where they can persist and spawn healthy red blood cells. 

We recently published proof-of-concept sickle gene editing in Science Translational Medicine, and the funding from CIRM will enable us to improve the efficiency of editing, scale up the process, and perform more extensive studies in animals to ensure safety and accuracy before moving into human clinical trials. Mark DeWitt, a postdoc in the lab and first author on the Science Translational Medicine paper, will become the project’s Program Manager, managing research across the three campuses.

For a more in-depth perspective, read Jacob’s blog post on deploying gene editing to tackle sickle cell disease.

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Our lab, in collaboration with globinopathy experts and sickle cell clinicians, have taken a key step toward a cure for sickle cell disease (SCD), using CRISPR-Cas9 genome engineering technology to reverse the disease-causing gene in stem cells from the blood of affected patients. For the first time, the genetic modification occurs in a sufficient proportion of stem cells to produce a substantial benefit in sickle cell patients. SCD primarily afflicts those of African descent and leads to anemia, painful blood blockages, and early death.

In collaboration with the UCSF Benioff Children’s Hospital Oakland Research Institute (CHORI) and the University of Utah School of Medicine, we showed that edited cells persist when transplanted into mice, an important factor in developing a lasting therapy. We’re aiming to improve the efficiency of their approach and perform large-scale studies in mice before attempting it in humans. Our lab hopes to work with Dr. Mark Walters, MD, an expert in curative treatments for sickle cell disease (such as bone marrow transplant and gene therapy), to design and initiate an early-phase clinical trial to test this new treatment within the next five years. Eventually, we hope to re-infuse patients with edited stem cells in order to alleviate symptoms of sickle cell disease.

Selection-Free Genome Editing of the Sickle Cell Mutation in Human Adult Hematopoietic Stem/Progenitor Cells  
Science Translational Medicine | Mark A. DeWitt, et al | October 12, 2016

Sickle hemoglobin polymerizes under low oxygen tensions in the tissues and the red blood cell deforms, which leads to obstruction in the capillaries and painful episodes for the patients
Photo Credit: Frans Kuypers, PhD. RBClab.com, UCSF Benioff Children’s Hospital Oakland

Press Coverage

CRISPR deployed to combat sickle-cell anaemia: Studies in mice highlight the promises — and challenges — of CRISPR–Cas9 gene editing  
Nature | Heidi Ledford | October 12, 2016

3 Gene Editing Approaches for Sickle Cell Disease  
PLoS Blogs | Ricki Lewis | October 13, 2016

CRISPR edits sickle cell mutation: Edited blood stem cells could someday help patients produce healthy red blood cells  
Chemical and Engineering News | Ryan Cross | October 12, 2016

A new gene-editing technique could help treat sickle cell anemia: Scientists hope to have a clinical trial in the next five years  
The Verge | Angela Chen | October 12, 2016

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IGI Co-Director Jonathan Weissman, Scientific Director Jacob Corn, Research Scientist Chong Park, and other colleagues have developed the next generation of guide RNAs (gRNAs) for high-throughput CRISPR screens. Establishing rules for the design of effective gRNAs is critical to making CRISPR activation and repression screens more specific and robust. Based on recent observations that compacted DNA inhibits Cas9 access, the team modified their guide RNA design algorithm to target more open, expanded regions of human and mouse genomes. Taking chromatin, position, and sequence features into account allowed for the design of highly active guide RNA libraries.

gRNA library design tools are available on Github.  The improved gRNA libraries will soon be available on AddGene.

Compact and highly active next-generation libraries for CRISPR-mediated gene repression and activation  
eLife | Jonathan Weissman, Jacob Corn, Chong Park, et al | September 23, 2016

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IGI Researchers have discovered a way to increase the efficiency with which CRISPR-Cas9 technology cuts and disables genes in cells.  In culture, “knockout” cell lines allow researchers to better understand the role of genetic information, and may eventually improve therapies for human genetic diseases.  

Non-homologous DNA increases gene disruption efficiency by altering DNA repair outcomes
Nature Communications | Chris Richardson, Jacob Corn, et al | August 17, 2016

Press Release
CRISPR-Cas9 breaks genes better if you disrupt DNA repair
UC Berkeley News | Robert Sanders | August 17, 2016

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In this new article for the June issue of Discover Magazine, Jeff Wheelwright takes a tour of the Bay Area’s active biotech world, talking with a wide range of researchers – from high-school kids to global corporations – who are embracing CRISPR-Cas9 genetic engineering technology.

The Revolution Will Be Edited: In the San Francisco Bay Area, from global corporations to kids, everyone is embracing the breakthrough gene-editing technology CRISPR 
Discover Magazine | Jeff Wheelwright | May 2, 2016

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The IGI has been awarded a CIRM Inception Award to use gene editing in bone marrow stem cells in order to discover mechanisms that lead to certain types of blood cancers.  The CIRM Inception Awards provide seed funding to support the exploration of transformational ideas that hold the potential to greatly impact the field of human stem cell research.  The IGI will use genetic engineering to determine how mutations frequently observed in the bone marrow stem cells of patients lead to a family of diseases called meyloproliferative neoplasms (MPNs).  The MPN disorders are characterized by over-production of certain blood cells, such as red blood cells or platelets, but it is unclear how patient mutations cause these disorders.  A better understanding of how MPN-associated mutations lead to disease could eventually lead to better therapies for patients suffering from MPN.

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The IGI has been awarded a CIRM grant to develop next-generation sequencing approaches to track gene correction in bone marrow stem cells for the treatment of sickle cell disease. The CIRM Center of Excellence in Stem Cell Genomics (CESCG) Collaborative Research Program (CRP) supports collaborative research projects by providing California scientists with access to cutting-edge genomics and bioinformatics technologies, and expertise and assistance in experimental design and data analysis. Working with CESCG, the IGI will determine how bone marrow stem cells respond to genetic engineering, characterize on- and off-target gene editing in these challenging cells, and work to move research on a gene editing cure for sickle cell disease closer to the clinic.

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IGI Scientific Director Jacob Corn presented this talk on Cas9 genome engineering, from mechanism to therapy during a session entitled “Emergent Technologies to Understand Disease” at the 2016 Institute for Systems Biology International Symposium: Emerging Technologies for Systems Biology.

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IGI Graduate Student Researcher Alan Wang has been awarded a 2016 NSF Graduate Research Fellowship.  Alan received his BA in biology and anthropology from Amherst College in 2012, working with Professor Dominic Poccia to examine the role of diacylglycerol in shaping biological membranes. He was a research assistant at the NIH and UCSF before joining the IGI as a graduate student in May 2015, using Cas9 to study locus specific protein composition. 

Press Release

NSF awards 2016 Graduate Research Fellowships 
National Science Foundation Graduate Research Fellowship Program | March 29, 2016

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IGI Scientific Director Jacob Corn and IGI Research Associate Katelynn Kazane spoke with Seth Shostak and Molly Bentley about CRISPR technology in an interview for Big Picture Science at the SETI Institute.  

Gene-y in a Bottle
Big Picture Science | Seth Shostak and Molly Bentley | March 21, 2016

CRISPR technology enables researchers to change the genetic code by removing and changing the order of genetic information in a cell or organism.  It is now easily accessibly and it is taking the science of genetic modification to new levels of precision and speed.  Other guests on this program include Lee Goldman (Cardiologist, Dean of Columbia University Medical Center, and author of “Too Much of a Good Thing; How Four Key Survival Traits Are Now Killing Us”) and Josiah Zayner (Biohacker and former NASA synthetic biologist).

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