Researchers from the University of Pennsylvania today announced the
publication of preclinical proof of concept data supporting the
clinical development of a gene-based therapy for the treatment of
X-linked retinitis pigmentosa (XLRP), one of the most common
inherited retinal disorders, which causes progressive vision loss
in boys and young men.
The investigational gene therapy was developed
by Applied Genetic Technologies Corporation (NASDAQ:AGTC), a
biotechnology company conducting human clinical trials of
adeno-associated virus (AAV)-based gene therapies for the treatment
of rare diseases. AGTC is developing a gene-based therapy for XLRP
in collaboration with Biogen.
The study, “Optimization of Retinal Gene Therapy
for X-linked Retinitis Pigmentosa due to RPGR mutations,” appears
in the August issue of Molecular Therapy and was conducted by
researchers from the University of Pennsylvania, the University of
Florida, the University of Alabama, Emory University and AGTC.
Symptoms of XLRP begin with night blindness in young boys,
followed by progressive constriction of the field of vision. Men
with XLRP typically become legally blind at an average age of 45
years. The most common form of XLRP is caused by mutations in the
RPGR gene. The treatment candidate used in the research and
developed by AGTC is designed to provide a functional copy of this
gene. XLRP is one of two lead development programs within AGTC's
collaboration agreement with Biogen, announced in July 2015, along
with X-linked retinoschisis.
“RPGR mutations resulting in XLRP are one of the
most common forms of inherited retinal disease, and patients with
these mutations currently have no treatment options,” said co-lead
study investigator William Beltran, DVM, Ph.D., Associate Professor
of Ophthalmology, University of Pennsylvania School of Veterinary
Medicine. “The results of these studies demonstrate important
progress toward developing an effective therapy for patients living
with this debilitating and progressive disorder.”
To optimize the delivery and expression of a
functional RPGR gene, researchers evaluated two promoter sequences
in non-human primates; one from the IRBP gene and the other from
the GRK1 gene. Results demonstrated that the IRBP promoter drove
transgene expression only in rod photoreceptors, while the GRK1
promoter drove expression in both rod and cone photoreceptors.
Subsequent analyses were conducted in a canine model of XLRP using
vector constructs comprising the GRK1 promoter.
Additional analyses included evaluation of the
safety and effects of a stabilized RPGR sequence delivered with an
AAV2/5 vector (AAV2/5-GRK1-hRPGRstb) in canine models of early- and
mid-stage disease; retinal and visual consequences of low- and
high-dose vector administration at mid-stage disease compared with
vehicle (balanced salt solution) control; and comparison of the
AAV2/5-GRK1-hRPGRstb construct with AAV2/5-GRK1-hRPGRco (a new
full-length stabilized and codon-optimized human RPGR).
Key findings from these analyses include:
- Injection of high or low doses of AAV2/5-GRK1-hRPGRstb to the
eyes of animals with early- or mid-stage disease showed qualitative
and/or quantitative preservation of retinal structure, as
determined by the thickness of the outer nuclear layer (ONL) of the
retina at two years of age. This preservation was not observed in
animals receiving vehicle control. At higher vector doses,
preservation of ONL thickness in animals with early-stage disease
approached that of normal control animals.
- In short-term safety assessments, no ophthalmic alterations
were seen and normal retinal lamination was retained; long-term
safety assessments found no detectable ocular events or differences
in ONL thickness; and electroretinography (ERG) results showed no
difference between treated and untreated regions of the same eye,
and were similar to that of untreated eyes in control animals not
affected by the canine form of XLRP.
- High and low doses of AAV2/5-GRK1-hRPGRstb rescued rod and cone
function, as assessed with ERG at 103 weeks in animals treated at
mid-stage disease compared with vehicle controls, with more
pronounced and statistically significant effects observed at the
high dose.
- High and low doses of AAV2/5-GRK1-hRPGRstb improved
rod-mediated visual behavior in animals with mid-stage disease
compared with vehicle controls, as assessed by maze and obstacle
course testing under multiple illumination conditions, with greater
improvements observed with the high dose.
- Comparison of AAV2/5-GRK1-hRPGRstb with AAV2/5-GRK1-hRPGRco
showed no significant differences in ONL thickness between the two
constructs based on retinal imaging; both vectors preserved ONL
thickness, produced a typical localization of RPGR protein and
corrected rod and cone opsin mislocalization, which is a key
feature of photoreceptor disease.
The researchers conclude that the findings
suggest that an AAV vector carrying a stabilized or a codon
optimized full-length human RPGR gene sequence under the control of
the human GRK1 promoter can be considered for advancement into a
human clinical trial. This warranted further development of the
drug candidate for XLRP.
“These data provide an important foundation for
our XLRP development program,” said Sue Washer, President and CEO
of AGTC. “We are currently conducting studies that will support the
filing of an Investigational New Drug application for our treatment
candidate for XLRP caused by mutations in the RPGR gene, which we
expect to submit to the U.S. Food and Drug Administration in the
third quarter of 2017.”
About AGTC
AGTC is a clinical-stage biotechnology company that uses its
proprietary gene therapy platform to develop products designed to
transform the lives of patients with severe diseases, with an
initial focus in ophthalmology. AGTC's lead product candidates are
designed to treat inherited orphan diseases of the eye, caused by
mutations in single genes that significantly affect visual function
and currently lack effective medical treatments.
AGTC's product pipeline includes ophthalmology programs in
X-linked retinoschisis (XLRS), X-linked retinitis pigmentosa
(XLRP), achromatopsia, wet age-related macular degeneration, and an
optogenetics program with Bionic Sight. AGTC's non-ophthalmology
programs include its adrenoleukodystrophy program and its otology
program, which is in pre-clinical development, and the company
expects to advance several otology product candidates into clinical
development in the next few years. Each of AGTC's XLRS, XLRP and
adrenoleukodystrophy programs is partnered with Biogen. AGTC
employs a highly-targeted approach to selecting and designing its
product candidates, choosing to develop therapies for indications
having high unmet medical need that it believes are clinically
feasible and present commercial opportunities. AGTC has a
significant intellectual property portfolio and extensive expertise
in the design of gene therapy products including capsids, promoters
and expression cassettes, as well as, expertise in the formulation,
manufacture and physical delivery of gene therapy products.
Forward Looking Statements
This release contains forward-looking statements that reflect
AGTC's plans, estimates, assumptions and beliefs. Forward-looking
statements include information concerning possible or assumed
future results of operations, business strategies and operations,
preclinical and clinical product development and regulatory
progress, potential growth opportunities, potential market
opportunities and the effects of competition. Forward-looking
statements include all statements that are not historical facts and
can be identified by terms such as "anticipates," "believes,"
"could," "seeks," "estimates," "expects," "intends," "may,"
"plans," "potential," "predicts," "projects," "should," "will,"
"would" or similar expressions and the negatives of those terms.
Actual results could differ materially from those discussed in the
forward-looking statements, due to a number of important factors.
Risks and uncertainties that may cause actual results to differ
materially include, among others: no gene therapy products have
been approved in the United States and only two such products have
been approved in Europe; AGTC cannot predict when or if it will
obtain regulatory approval to commercialize a product candidate;
uncertainty inherent in the regulatory review process; risks and
uncertainties associated with drug development and
commercialization; factors that could cause actual results to
differ materially from those described in the forward-looking
statements are set forth under the heading "Risk Factors" in the
Company's Annual Report on Form 10-K for the fiscal year ended June
30, 2016, as updated by the Company’s Quarterly Report on Form 10-Q
for the fiscal quarter ended March 31, 2017, as filed with the SEC.
Given these uncertainties, you should not place undue reliance on
these forward-looking statements. Also, forward-looking statements
represent management's plans, estimates, assumptions and beliefs
only as of the date of this release. Except as required by law, we
assume no obligation to update these forward-looking statements
publicly or to update the reasons actual results could differ
materially from those anticipated in these forward-looking
statements, even if new information becomes available in the
future.
IR/PR CONTACTS:
David Carey (IR)
Lazar Partners Ltd.
T: (212) 867-1768
dcarey@lazarpartners.com
Lazar Partners for AGTC (PR)
T: (212) 867-1762
AGTC_PR@lazarpartners.com
CORPORATE CONTACTS:
Stephen Potter
Chief Business Officer
Applied Genetic Technologies Corporation
T: (617) 413-2754
spotter@agtc.com
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