Research Highlights
Gene Therapy for Hearing Disorders
Efcient delivery of genes to the
mouse inner ear and correction
of hearing loss and balance
symptoms in a mouse model of
a rare genetic hearing disorder
are reported in two papers
published recently in Nature
Biotechnology. Genetic hearing
disorders are estimated to affect
125 million people worldwide
and have been linked to mutations in more than 100 genes. Although
various genetic diseases can be cured in animals and humans using
gene therapy employing viral vectors, scientists have yet to identify a
virus capable of efciently entering the cells of the inner ear (cochlea),
particularly a subset of cells known as outer hair cells, which tune the
responses of inner hair cells to sound waves. Delivery of genes to both
outer and inner hair cells is often needed to confer normal hearing
ability. In the rst paper, Landegger and colleagues show that a syn-
thetic variant of adeno-associated virus efciently delivers a gene en-
coding a uorescent protein to mouse outer and inner hair cells. Safety
studies found that the procedure, including injection through the round
window membrane, had no adverse effects. In the second paper, Pan
and colleagues use the same viral vector to treat mice carrying a mutated
gene responsible for Usher syndrome type IC, a childhood genetic dis-
ease that causes deafness, balance dysfunction, and blindness. Delivery
of a normal copy of the mutated gene, Ush1c, to the cochlea soon after
the mice were born led to high levels of Ush1c protein in outer and inner
hair cells, repair of damaged hair cell bundles, and a robust improve-
ment in hearing and balance behavior. (Nat Biotechnol., Published
online 6 February 2017; http://dx.doi.org/10.1038/nbt.3781 and Nat
Biotechnol., Published online 6 February 2017; http://dx.doi.org/10.
1038/nbt.3801) Image credit Charles Askew and Jeffrey R. Holt.
Hijacking Bacteria to Kill Cancer
Scientists have recruited modi-
ed bacteria to inltrate tumors
and activate the immune system
to kill malignant cells, according
to a study recently appearing in
Science Translational Medicine.
Tumor size decreased below detectable limits in 11 out of 20 mice
that received injections of the engineered strain of bacteria. Zheng
and colleagues made use of attenuated Salmonella typhimurium bacte-
ria as Trojan horses that inltrated the low-oxygen environments
found within tumors. They engineered the bacteria to secrete Vibrio
vulnicus agellin B (FlaB) in tumor tissues; FlaB is an excellent adju-
vant for anticancer immunotherapy because it activates innate immune
responses via the Toll-like receptor 5 (TLR5) signaling pathway. The
FlaB-expressing bacteria were nontoxic and did not invade non-
cancerous tissue. After 3 days post-administration, the numbers of bac-
teria inside tumors were 10,000-fold greater than those found in vital
564 Molecular Therapy Vol. 25 No 3 March 2017
organs. The combination of Salmonella and FlaB synergistically shrank
tumors, prolonged survival, and also prevented metastasis in a mouse
model of human colon cancer. While mice receiving non-FlaB-produc-
ing microorganisms displayed some reductions in cancer burden, their
tumor masses tended to regrow. (Sci Transl Med., Published online 8
February, 2017; http://dx.doi.org/10.1126/scitranslmed.aak9537)
Universal CAR T Cell Therapy Helps Beat
Pediatric Cancer
Two infants diagnosed with a
relapsed form of childhood can-
cer and who had previously
exhausted all other treatment
options remained disease-free
after receiving a rst-in-human
experimental therapy that uses
genetically engineered T cells,
according to a study recently
published in Science Translational Medicine. Such cell-based
approaches have been difcult to implement in young children,
a population in which B cell acute lymphoblastic leukemia (ALL) is
highly prevalent, representing 25% of all pediatric cancer cases in the
US. While modied or chimeric antigen receptor (CAR) T cells have
proven to be highly effective in tackling ALL, these cancer-killing cells
must be generated from each individual patient, which is not feasible for
those who have insufcient quantities of healthy T cells, like very young
children. Instead of ne-tuning the infants own T cells to ght their
cancer, Qasim and colleagues created a universal T cell that eradicated
the leukemia from both subjects blood. They generated universal
CAR19 (UCART19) T cells by lentiviral transduction of non-human
leukocyte antigen-matched donor cells and simultaneous transcription
activator-like effector nuclease (TALEN)-mediated gene editing of a
T cell receptor chain and CD52 gene loci. These off-the-shelf univer-
sal CAR T cells were then used to treat two infants with relapsed refrac-
tory acute lymphocytic leukemia and bridge them to allogeneic stem
cell transplantation. Both babies went into complete remission within
28 days after receiving the therapy and have since remained leuke-
mia-free for 10 and 16 months. (Sci Transl Med., Published online 25
January 2017; http://dx.doi.org/10.1126/scitranslmed.aaj2013)
New 3D Model to Study Tuberculosis
Researchers at the University of
Southampton have developed
an electrostatic encapsulation
technique to create tiny 3D
spheres within which human
cells are infected with tubercu-
losis (TB) bacteria to generate
conditions that more closely
reect events in patients. The
model allows the researchers to further investigate what happens
in a human body when TB develops, with a long-term aim of
www.moleculartherapy.org
Research Highlights
identifying new antibiotic treatments and vaccines. The research
was funded by the Medical Research Council (MRC of the UK)
and is published in mBio and eLife. The 3D sphere can be created
with a collagen matrix so that it more closely resembles the condi-
tions in a human lung. This produces an environment that allows
particular antibiotics that are important in treating patients to kill
the infection, which they cannot do in other 2D model systems.
Additionally, the 3D spheres are able to prolong experiments for
up to 3 weeks, more than four times longer than standard 2D model
systems. This gives researchers more information about how the
infection develops and the effect of different interventions over
time. The next phase of the research will be in collaboration with
the African Health Research Institute in Durban, in a project being
funded by an MRC Global Challenges Research Fund Foundation
Award. Durban has a very high incidence of TB and ideal lab-
oratory infrastructure to introduce the 3D model to study cells
from patients at high risk of tuberculosis. (MBio., Published online
7 February 2017; http://dx.doi.org/10.1128/mBio.02073-16 and
ELife., Published online 7 January 2017; http://dx.doi.org/10.7554/
eLife.21283)
Molecular Therapy Vol. 25 No 3 March 2017 565