The Vector

Volume 7, Issue 12: December 2018

Editorial Team

Phillip Doerfler, PhD - Editor, The Vector
Melvin Rincon, MD, PhD - Associate Editor, The Vector
Edith Pfister, PhD - Junior Editor, The Vector

Inside This Issue

President's Message
Breaking Through
Society News
Public Policy
Industry News



President's Message

Register Today for the 2019 Annual Meeting

As you may have seen in recent emails from ASGCT, registration for the 2019 Annual Meeting—our 22nd—is now open!

Personally, I’m honored to lead ASGCT through what is already shaping up to be our largest meeting in Society history. The support we receive from the field through attendance, sponsorship, and awards is surpassed only by the enthusiasm of our members and the excitement surrounding the science presented during the meeting. Because of that support, ASGCT is able to offer free registration to Associate Members who are first and presenting authors of abstracts during the Annual Meeting.

Whether or not you’re submitting an abstract, please consider booking your room in the ASGCT room block at the host hotel, the Washington Hilton, sooner rather than later. The ASGCT block sells out well before the meeting every year and is the way ASGCT can guarantee a discounted room rate for the Annual Meeting.

Finally, all of us at ASGCT extend our deepest condolences to the family, friends, and colleagues of Dr. Brian Sorrentino. A pioneer in our field, Dr. Sorrentino led a research team at St. Jude Children’s Hospital developing novel gene therapies for babies born with X-linked severe combined immunodeficiency.

Dr. Phillip Doerfler, editor of The Vector and a colleague of Sorrentino’s at St. Jude, has written a personal, moving remembrance of Sorrentino on behalf of ASGCT which we’ve published in this edition of The Vector and on the ASGCT blog. Thank you, Phillip, for sharing what Brian meant to our field and celebrating his life and accomplishments.

Michele Calos, Ph.D.
ASGCT President

Remembering Dr. Brian Sorrentino

By Phil Doerfler, Ph.D.

It is with great sadness I write to remember a pioneering member of our society. Brian Sorrentino, M.D., passed away in November following his second battle with cancer. Brian was a childhood cancer survivor himself and dedicated his life to offering hope for children with catastrophic disease. He was an exceptional physician-scientist and I have had the good fortune to be a part of the Division of Experimental Hematology, of which Brian was the director since 2001. It is he and my mentor Mitch Weiss, M.D., Ph.D., who made it possible for me to be a postdoc at St. Jude Children’s Research hospital, a position I currently hold, and I cannot help but feel tremendous gratitude.

Brian was a native of New York. He received his medical education at State University of New York at Syracuse, completed an internal medicine residency at the University of North Carolina, followed by training at the National Institutes of Health in hematology/oncology before joining the faculty of St. Jude in 1993. For decades, Brian worked to identify genes which would allow researchers to identify stem cells and to effectively transduce hematopoietic stem cells with lentiviral vectors to treat primary immunodeficiencies.

Through his basic research efforts, he was able to translate his discoveries to clinical application. Brian adamantly pursued gene therapies for X-linked severe combined immunodeficiency (X-SCID). In the past, X-SCID meant early mortality within the first 1-2 years of life. But with Brian and his team’s efforts, the latest lentiviral-based gene therapy for X-SCID has the capability to transform the lives of patients with this and other life-threatening diseases affecting the hematopoietic system. To see how gene and cell therapy is changing the lives of X-SCID patients, I encourage you to view Brian’s presentation at least years’ ASGCT Annual Meeting.

Known the world over, Brian served on the Advisory Council for ASGCT and chaired NIH study sections in the area of hematology. With his tremendous success, he achieved many awards and was recognized for significant contributions to the field. He was a member of American Society of Clinical Investigation and from the International Society of Experimental Hematology he received the McCulloch and Till Lectureship Award. He served on the editorial boards of many journals and held several patents on his work, many of which have been licensed in an effort to continue the success of X-SCID gene therapy beyond clinical trials. Brian was also honored by Inside Memphis Business with the 2017 Innovation Award.

More than anything else, Brian was a friend and mentor to those with whom he interacted. He was passionate about basic and applied research, fostering the growth of trainees whether or not they were part of his lab, and a generous and kind individual. Although he is gone, thanks to Brian’s efforts, patients with X-SCID who received gene therapy are returning home and leading healthy lives. Although his passing is strongly felt at St. Jude, his legacy continues through his colleagues and patients. He will be missed and remembered fondly.

Breaking Through

Long-Term Effects of In Vivo Genome Editing in the Mouse Retina Using Campylobacter jejuni Cas9 Expressed via Adeno-Associated Virus

Dong Hyun Jo,Taeyoung Koo, Chang Sik Cho, Jin Hyoung Kim, Jin-Soo Kim, Jeong Hun Kim


Summary by Edith Pfister, Ph.D.

Viral delivery of genome editing elements, such as CRISPR-Cas9 promises to revolutionize therapies for previously intractable targets. Delivery of Cas9 using adeno-associated viruses (AAVs) can inactivate genes associated with genetic diseases. However, Streptococcus pyogenes derived Cas9 (SpCas9) is large (4.1kb) and the genome packaging capacity of AAV is small (4.8kb), which has made development of AAVs to deliver both SpCas9 and the chimeric guide RNA (sgRNA) more challenging. This can be overcome using minimal promoters and truncated regulatory elements, or by using smaller Cas9 orthologues such as Campylobacter jejuni derived Cas9 (CjCas9, 2.95kb).

Neovascular age-related macular degeneration (AMD) is a leading cause of blindness in adults over 50 and is characterized by the excessive growth of new blood vessels under and within the macula. Vascular endothelial growth factor A (Vegfa) and hypoxia-inducible factor 1 alpha (Hif1a) have been implicated in promoting neovascularization. Kim and colleagues have previously reported that AAV delivery of CjCas9 targeting Vegfa or Hif1a to the mouse retina induces mutations in the retina and in retinal pigment epithelium (RPE) cells, and reduces the area of laser-induced choroidal neovascularization (CNV) 6 weeks after treatment1.

In the current study2, Jo et al. extend upon this work, addressing concerns about the long-term effects of expression of the CRISPR-Cas9 components in vivo and about targeting Hif1a. Previous studies had indicated that deletion of Vegfa in RPE cells leads to loss of blood supply to the outer retina and photoreceptors and to blindness3. Fourteen months after AAV delivery of AAV-CjCas9:Vegfa, the authors observed reduced retinal thickness. In contrast, mice treated with either AAV-CjCas9:Rosa26 or AAV-CjCas9:Hif1a showed no gross histological changes, no increase in the number of apoptotic cells, and no loss of opsin staining. Electroretinography indicates that intravitreal treatment with AAV-CjCas9:Hif1a does not change the functional properties of the retina. Hif1a lies upstream of Vegfa in the control of angiogenesis and the lack of pathological changes with Hif1a targeting confirms that reducing Hif1a is safer and less disruptive than eliminating Vegfa. Furthermore, while the frequency of indels at the targeted locus continues to increase in the period from 6 weeks to 14 months after treatment, long-term expression of AAV-CjCas9:Hif1a or of AAV-CjCas9:Vegfa did not cause an increase in off-target indels at previously identified and predicted off-target sites.

  1. Kim, E. et al. In vivo genome editing with a small Cas9 orthologue derived from Campylobacter jejuni. Nat. Commun. 8, 14500 (2017).
  2. Jo, D. H. et al. Long-Term Effects of In Vivo Genome Editing in the Mouse Retina Using Campylobacter jejuni Cas9 Expressed via Adeno-Associated Virus. Mol. Ther. (2018). doi:10.1016/j.ymthe.2018.10.009
  3. Kurihara, T., Westenskow, P. D., Bravo, S., Aguilar, E. & Friedlander, M. Targeted deletion of Vegfa in adult mice induces vision loss. J. Clin. Invest. 122, 4213–4217 (2012).

Society News

ASGCT Responds to Claims Regarding Germline Gene Editing

Following claims coming out of a conference in China regarding Germline gene-editing and the implantation of gene-edited embryos to achieve a pregnancy, the ASGCT Executive Committee released a statement condemning those actions, whether or not the claims are true.

“ASGCT considers it wholly unacceptable to use these technologies without extensive research into the safety and efficacy of such applications, and the necessary approval by regulatory and government bodies,” the statement reads. “Any announcements of, or claims to have begun such studies in germline gene editing are compromised, both ethically and scientifically.”

Read the full Executive Committee statement on

Abstract Submission is Now Open

With the opening of abstract submission for the 22nd Annual Meeting, we’re officially in #ASGCT19 season. Submit an abstract by January 16 to be eligible for free annual meeting registration, travel awards, and Excellence in Research awards.

Submit an Abstract Online

Public Policy

ASGCT Comments on FDA Gene Therapy Guidance Documents

ASGCT submitted comments to the FDA regarding six draft guidance documents on gene therapy development on Dec. 10. Among its comments, ASGCT recommends:

  • Not needing to test vectors for RCR/RCL that data shows have been free of RCR/RCL.
  • Testing for RCR/RCL post-infusion only in the case of an adverse event.
  • Clarifying by FDA that use of patient registries is an allowable choice for complying with long-term monitoring requirements.
  • Not treating the eye with vehicle control due to ethical concerns.
  • Monitoring for adverse events for 2 – 5 years after exposure to non-integrating gene therapy products for hemophilia, as stated in the draft guidance on long term follow-up.
  • Documenting levels of contaminating host cell DNA and strongly transforming oncogene DNA in products, rather than complying with an arbitrary set limit of 10 ng HC DNA/dose.

Read ASGCT's Recommendations

Congress Passes Sickle Cell Disease Legislation

The Senate version of the Sickle Cell Disease and Other Heritable Blood Disorders Research, Surveillance, Prevention, and Treatment Act of 2018 (S. 2465) passed on the House of Representatives floor this week and headed to the President for signature. ASGCT supports this legislation which expresses support for sickle cell disease (SCD) research and reauthorizes an existing SCD treatment demonstration program. In addition, it authorizes a surveillance program within the Centers for Disease Control and Prevention (CDC) that will fund the collection of information on the prevalence, health outcomes, complications, and treatment of SCD.

Key Advances in Gene Therapy and the Promise for Patients

Last month, ASGCT joined the Bipartisan Policy Center and the Alliance for Regenerative Medicine (ARM) in hosting a roundtable discussion on gene therapy to identify six key areas on which to focus our work. ASGCT Executive Director David Barrett presented on Barriers to Patient Access to Safe, Effective Treatments & Policies to Overcome Them, highlighting reimbursement challenges and potential solutions, including novel payment models. The three organizations will release a report addressing key issues in the field discussed at the event.

Industry News

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22nd Annual Meeting
April 29 – May 2 | Washington D.C.