TRAINING and EDUCATION
FIGURE 1.
Therapeutic Genome Editing
FIGURE 2.
Delivery strategies and target cells for in vivo and ex vivo genome editing.
Genome-Editing Systems
HSCs = hematopoietic stem cells; iPSCs = induced pluripotent stem cells
Source: Hoban MD, Bauer DE. A genome editing primer for the hematologist. Blood. 2016;127:2525-35.
Somatic gene therapy products are classified
as “biological products” and are regulated
by the U.S. Food and Drug Administration’s
(FDA) Center for Biologics Evaluation and
Research. Proposals for gene therapy clinical
trials funded by the National Institutes of
Health (NIH) are reviewed by its Recombi-
nant DNA Advisory Committee (RAC), which
collaborates with the FDA. 6
The FDA is prohibited from reviewing pro-
posals for studies that use germline editing to
alter human embryos. Should this restriction
expire, the National Academies of Sciences,
Engineering, and Medicine proposed strin-
gent criteria for adopting germline editing,
recommending that germline editing research
trials be permitted “only for compelling pur-
poses of treating or preventing serious disease
or disabilities, and only if there is a stringent
oversight system.” 7 However, many scientists
believe that any germline editing using cur-
rent technologies would be dangerous and
unethical. 8
As far as CRISPR/Cas9 is concerned, Dr.
Orkin noted, “There are no ethical concerns
unless one talks about germline editing, which
is not generally thought of at this time for
hematologic disease.”
The Role of CRISPR/Cas9 in Hematology
To date, no commercialized CRISPR/Cas9
products have begun clinical trials in the U.S.
“That being said, there are multiple programs
in development – both in academia and
industry – heading in that direction,” said
Matthew Porteus, MD, PhD, associate profes-
sor of pediatrics at Stanford University in
ASHClinicalNews.org
California, and founder of CRISPR Therapeu-
tics. “We are likely to see clinical trials in 2018
and 2019.” At Stanford, Dr. Porteus’s group is
moving toward a clinical trial for CRISPR/Cas9
gene editing in sickle cell disease (SCD). 9
“It is rather remarkable that the system
was first described as useful in mammalian
cells in 2013, and we learned how to use the
system efficiently in clinically relevant human
cells in 2015,” he added. “The pace to the clin-
ic is amazingly fast given the careful scientific
and regulatory work that needs to be done
before one can give genetically engineered
cells to patients.”
Enhancing Cellular Immunotherapy
To date, the FDA has approved two gene
therapies, both autologous chimeric antigen
receptor (CAR) T-cell immunotherapies for
treating types of leukemia and lymphoma. 10,11
Therapy involves collection of the patient’s
own T cells, genetic modification to express
a CAR that targets tumor cells, and infusion
of modified T cells back into the patient’s
system. 12
These CAR-modified T cells are made
using viral delivery systems, which randomly
insert the CAR gene into the T-cell genome
and may result in unwanted genetic effects.
Scientists are now using CRISPR/Cas9 to
generate CAR T cells and have found that
controlling where CAR integrates can enhance
their potency. 13
CRISPR/Cas9 gene editing also is being
investigated as a tool to enhance CAR T-cell
function by disabling genes that encode inhib-
itory receptors or signaling molecules, such as
programmed cell death protein 1 (PD1). 12 The
first CRISPR/Cas9 clinical trial, initiated in
China in 2016, is doing just that. 14
In the U.S., a proposed CRISPR/Cas9
clinical trial has already been approved by
RAC, but still needs approval from the FDA.
This clinical trial will focus on the safety of
CRISPR/Cas9-modified T cells for the treat-
ment of myeloma, sarcoma, and melanoma.
CRISPR/Cas9 will be used to knock out PD1
as well as the endogenous T-cell receptor. 15
“Such gene editing promises to improve
the potency and specificity of lymphocyte
products and may even enable production of cell
therapies from universal donors,” Daniel Bauer,
MD, PhD, from the department of pediatric he-
matology/oncology at Boston Children’s Hospital
and assistant professor of pediatrics at Harvard
Medical School in Boston, Massachusetts.
CRISPR/Cas9 also could help maximize
efficacy and minimize unwanted toxicity of
cellular immunotherapy in acute myeloid
leukemia (AML). Researchers have proposed
that, by knocking out the AML antigen CD33
in normal hematopoietic stem cells (HSCs),
CD33-directed immunotherapy can be used
against AML without disrupting normal my-
eloid function. 16
Correcting Genetic Defects
While cellular immunotherapy is the first
application of CRISPR/Cas9 being evaluated
in the clinic, Dr. Bauer pointed out that “not
far behind may be applications for CRISPR in
HSCs, where a variety of nonmalignant blood
disorders could be ameliorated by permanent
genetic modification. In addition, genome
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