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Q&A: GenVec and gene-based medicine
December 2015
EDIT CONNECT
SHARING OPTIONS:
GenVec
is working in the exciting field of gene-based medicine, states the company’s president, CEO and director, Douglas J. Swirsky, and GenVec is dedicated
to developing an array of new therapeutics and vaccines by delivering specific genes to specific cells or tissue types. “We were founded in December
1992 to explore the promise of this area, back during the era when it first became a ‘hot’ area of research. However, as GenVec and everyone else
working in the field soon learned, the challenges for genuine innovation turned out to be greater than expected,” he says.
DDNews: Please describe GenVec, its origins and current mission.
Douglas Swirsky: Today we are riding a new wave of innovation. We’ve developed our own gene delivery platform, AdenoVerse,
that has shown a great deal of promise in allowing us to deliver genes or antigens more effectively than ever before. The therapeutic area that we are
currently putting the greatest focus on is hearing loss, and we have partnered with Novartis, which is conducting a Phase 1/2 study using a drug we developed
to initiate the regrowth of cells in the ear that facilitate hearing. But our sights are set much, much wider. We believe the AdenoVerse gene delivery
platform has applications in everything from cell therapy, regenerative medicine, cancer therapeutics, vaccines and antivirals to gene editing and oncolytics
to therapeutic gene delivery, immunotherapy and nucleic acid therapeutics.
DDNews: What is
AdenoVerse technology and how is it used in development of therapeutics?
Swirsky: Back in the 1990s, it was found that molecular tools called viral vectors—essentially, viruses molecularly engineered
to carry specific genes or antigens into the body—were the ideal delivery method in gene therapy. Trouble was, they didn’t work as well as hoped.
This was even true for what came to be known as the standard “workhorse” tool, the Ad5 adenovector, which was based on a virus that can cause the
common cold in people. In developing our AdenoVerse gene delivery platform, we’ve devised a broad array of new adenovectors that can be uniquely
specialized to address different therapeutic needs. And we are using two separate cell lines to build and manufacture all of our new adenovectors.
DDNews: What were the drawbacks with the original Ad5 adenovector that slowed
development of gene therapy between the 1990s and today?
Swirsky: Work with Ad5 ran into problems with preexisting immunity in patients under certain circumstances that led to a slowdown in
innovation.
DDNews: In what specific ways have you enhanced the
performance of your proprietary adenovectors to succeed?
![]() DDNews:
What have been the major challenges of developing the treatment for hearing loss that you are now working on in collaboration with Novartis?
Swirsky: The Phase 1/2 clinical trial of CGF166, GenVec’s product
candidate for hearing loss and balance disorders, is the first time that a drug—let alone a gene therapy drug—has been delivered directly to the
inner ear. So this was a pioneering effort from the start, and like any first-time effort, we have certainly had to overcome challenges.
We began with the treatment concept for the drug. The data from Huda Zogbi’s lab at Baylor showed the critical role the
atonal gene played in sensory cell development. From this and other data in the field, the regeneration concept emerged. Atonal expression in mammals is a
one-time event during sensory cell development and this key developmental regulator triggers the differentiation of about 30,000 of the cells in the cochlea,
the shell-like structure in the inner ear, into sensorineural cells, also known as “hair cells” for their tiny hair-like projections. These
hair-like projections move when the fluid in the inner ear is disturbed by sound waves or by the motion of walking—and depending on where they are
situated in the inner ear, they pick up those disturbances and transmit them to the auditory nerves, which in turn transmit them to the brain, where these
signals are translated into the sounds we hear and our ability to stay balanced.
However, when the hair cells are
damaged by aging, certain antibiotics or chemotherapeutics, sound trauma or for other reasons, they do not regenerate. During development, the brother cell
to the sensory cell is the supporting cell. This cell develops to the same point as the sensory cell but because it does not express atonal it does not
become a sensory cell. The therapeutic concept was to turn these supporting cells in the developed inner ear into sensory cells to recover function after
damage.
Our collaborators worked hard to design experimental animal models to test this concept. We worked with
several preclinical animal models for deafness and balance disorders that had been established in major academic labs to establish preliminary proof-of-
concept data showing that not only could we regenerate hair cells in the inner ear of test animals, but they did in fact show improvements in balance and in
hearing. These early data showed that sensory cells could be regenerate—that the new sensory cells would hook up to the nervous system, and that they
could send a hearing or balance signal to the brain, reestablishing function.
When we and Novartis began
discussing the kinds of testing that would be needed to determine whether the drug candidate could proceed to studies in humans with the FDA, we had to
answer basically two questions: What is the safety of the vectored drug and what is the dosage?
For the first
question, we used a rat model and were able to show that transfer of the drug was not an apparent short-term or long-term issue. Based on the FDA’s
guidance, we also needed to conduct testing using a large animal model to derive a dosage/volume range that would be acceptable for clinical trial. Given
that this is a first of kind drug, all of these animal models had to be developed as well, and we had to adjust the established surgical approach we planned
to adapt for use in people to allow for size and structural differences in the test animals.
At this point, the
Phase 1/2 study is well underway. It involves a graded increase in volume, because we are using a maximum concentration of drug per microliter. Three
clinical sites with expertise in the kind of surgical procedure required to deliver the drug are recruiting, and safety and efficacy testing is ongoing. We
are proud to have brought this groundbreaking effort this far, and will be very interested to learn more as the data become available.
DDNews:What other therapeutic areas besides hearing loss appear most promising as targets for your
adenovectors, and what is the current status of those programs?
Swirsky: The AdenoVerse gene delivery platform is really extremely flexible, and we are actively seeking opportunities to get
involved with therapeutic gene delivery, gene editing approaches, such as CRISPR/Cas9, oncolytics, cancer therapeutics and nucleic acid therapeutics.
We’re collaborating with TheraBiologics on a cell therapy approach to cancer treatment, leveraging our technology to modifying neural stem cells to
reach their full anticancer potential. We’re also working with the Laboratory of Malaria Immunology and Vaccinology (LMIV) of the National Institutes
of Health on a transmission-blocking vaccine using our adenovectors to deliver novel antigens discovered at LMIV. In addition, we have a multifaceted
collaboration with Washington University at St. Louis to create highly targeted therapeutics and vaccines. And in the past, we worked with the Department of
Homeland Security to produce the first foot and mouth disease vaccine approved for manufacture within the continental U.S. This vaccine, partnered with
Merial, facilitates a vaccinate-to-live strategy for this potentially devastating disease.
DDNews: How do adenovirus vectors deliver genes (i.e., what is the step-by-step process)?
Swirsky: The steps to deliver genes are fairly simple. The adenovirus was developed to do this
extremely efficiently and we take advantage of these steps for our vectors to deliver their payloads. The vector first binds to the cell membrane; it is then
internalized into the cell via a vesicle. The vesicle does two things: it transports the vector particle to the nucleus and it also starts to break down the
vector particle to expose the vector payload. Once it gets to the nucleus, the payload is delivered into the nucleus and the cell machinery in the nucleus
then uses the DNA just like it would any other to make proteins, RNA, etc.
DDNews: What does the
GenVec pipeline hold currently? Are clinical trials underway or being contemplated?
Swirsky: Our drug for hearing loss, CGF166, as we’ve said, is now being tested in a Phase 1/2 clinical study being conducted by
Novartis. The first patient was treated in October 2014, representing the first direct drug delivery to the inner ear. Currently, our drug candidates for
neural stem cell therapeutics, respiratory syncytial virus (RSV), herpes simplex virus 2 (HSV-2), malaria and enterovirus-D68 are in preclinical
development.
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