MeiraGTx Holdings plc (Nasdaq: MGTX), a vertically integrated,
clinical stage gene therapy company, today announced the Company
will exhibit nine poster presentations at the American Society of
Gene and Cell Therapy (ASGCT) 2023 Annual Meeting, which is being
held from May 16-20, 2023, in Los Angeles, CA.
“Our presentations at this year’s ASGCT Annual Meeting reflect
the significant progress made in our novel gene and cell therapy
platforms, including promoter discovery and development,
manufacturing technology as well as several in vivo proof of
concept efficacy studies using our riboswitch platform,” said
Alexandria Forbes, Ph.D., president and chief executive officer of
MeiraGTx. “Our riboswitch gene control platform allows us to
precisely control the expression of any gene in a tight dose
response to oral small molecules and to control gene expression to
a very high dynamic range, from undetectable at baseline to levels
generally greater than the maximum expression of the unregulated
vector expressing the same gene. Importantly, we are presenting
data on in vivo dose dependent efficacy of our riboswitch in animal
models. We demonstrate efficacy of vector-delivered human growth
hormone, rescuing B.little mice by controlling hGH expression in a
periodic fashion with an oral small molecule, and data
demonstrating control of tumor burden by regulating anti-HER2
antibody in tight dose response to an orally dosed small-molecule
inducer.” Dr. Forbes continued, “We are also presenting data
demonstrating precise regulation of CAR levels on CAR-Ts, with the
unprecedented ability to intermittently switch CAR on to low
receptor density levels, which results in increased CAR-T potency,
decreased exhaustion markers and increased safety when directly
compared to CAR-T with constitutively expressed CAR. These
three examples, along with data on our promoter discovery platforms
presented at ASGCT, provide support for the broad applicability of
our gene regulation technology across multiple therapeutic targets
for gene and cell therapy.”
The posters will be available on the Posters and Publications
page of the Company’s website after the respective presentation
session has concluded.
The details of the poster presentations are
below:
Poster #764 Riboswitch-regulated chimeric
antigen receptor (RiboCAR) enhances T cell activitySession
Date/Time: 5/17/2023 12:00PM PTSession
Title: Wednesday Poster Session
Chimeric antigen receptor (CAR)-T cell therapy is a promising
treatment for certain cancers and the level of CAR molecule
expression is important for CAR-T cell activation, durability, and
anti-cancer activities. RiboCAR is a synthetic riboswitch-based
gene regulation system for precise regulation of CAR expression
levels in CAR-T cell therapy via orally available small molecule.
RiboCAR contains a synthetic mammalian ON riboswitch in the coding
sequence of the CAR transgene, in which the aptamer functions as a
sensor for a specific novel small molecule inducer. We demonstrate
that with a bioavailable small molecule inducer, CAR-T activity can
be precisely tuned and “remotely” controlled in vivo. This precise
control of CAR levels provides a system for improving the efficacy
and durability of CAR-T as well as a safety mechanism for CAR-T
cell therapy in comparison to current therapies with constitutively
active CAR expression.
Poster #1245: Towards Ultra Scale-down AAV
Production in Microtiter Plates Session Date/Time:
5/18/2023 12:00 PM PTSession Title: Thursday
Poster Session
High-throughput screening methods have become an integral part
of research and development in the biopharmaceutical industry due
to their low cost, ease of operation, and high degree of
parallelization. This study scaled down a transient
transfection-based adeno-associated virus (AAV) production process
from a 250 mL stirred tank reactor (STR) to a 24-deep square well
(DSW) for serotypes AAV2, AAV5, and AAV8. A tightly controlled
transfection step with sufficient mixing was identified as playing
a decisive role in achieving scalable productivity, resulting in a
reduction of the intra-plate coefficient of variance from 60% to
under 30%, proving the suitability of the platform for large
early-stage screening studies. These findings illustrate a viable
method for high-throughput early-stage AAV process development.
Poster #1277: Development of rationally
designed CAG-based promoters for use in gene therapySession
Date/Time: 5/19/2023 12:00 PM PTSession
Title: Friday Poster Session
The promoter is an essential cis-regulatory element in any
DNA-based gene therapy. It directly controls gene transcription and
thereby therapeutic protein expression. Current gene therapy
clinical trials mostly use cellular CAG or viral CMV promoters. To
improve promoter efficacy we designed a series of 82 new CAG
promoter variants by systematically introducing modifications to
each of the promoter elements and testing them in different in
vitro and in vivo models. In HEK293T cells, 67 CAG promoter
variants were found to be stronger than the original CAG with the
strongest promoter exhibiting a 13-fold improvement in potency. Two
CAG promoter variants, based on improved in vitro activity and
smaller size (~40% size reduction), were administered by tail vein
injection into C57BL/6 mice. Expression in the liver improved by up
to 4-fold compared to the original CAG promoter. Four MGTx variants
are ~800 bp smaller than CAG but exhibit 15-fold higher expression
in primary mouse hepatocytes. Our CAG promoter library provides
promising options for the development of next-generation gene
therapies.
Poster #1399: AAV-mediated
riboswitch-controlled delivery of anti-HER2 antibody suppresses
HER2-positive tumorigenesisSession Date/Time:
5/19/2023 12:00 PM PTSession Title: Friday Poster
Session
Controlled expression of delivered transgenes may be critical
for optimized, safe, and effective genetic medicines. AAV-mediated
gene transfer is a promising therapy for many diseases. However,
excessive amounts of transgene from unregulated vectors may limit
the breadth of applicability of gene therapy. A specific and
precise mechanism for gene control via orally delivered small
molecules with high dynamic range and gene expression at least as
high as unregulated genes would provide a safe and effective gene
therapy approach to a broad range of disease areas. We developed a
regulated anti-HER2 antibody gene that addresses the potential
safety concerns associated with excessive and long-term expression
of therapeutic antibodies. The expression of the anti-HER2 antibody
gene is controlled by riboswitch via a small molecule inducer. The
induced anti-HER2 antibody is efficacious in suppressing HER2+
tumor growth and prolonging tumor-free survival in a
dose-responsive fashion to the oral small molecule inducer. Our
results indicate that synthetic mammalian riboswitch works
efficiently in vivo and can provide precise control of therapeutic
antibody expression, achieving high levels of antibody expression
and rapid tumor suppression in a dose-dependent manner.
Poster #1433: AAV-mediated, small
molecule-riboswitch-controlled delivery of growth hormone rescues
growth in GH-deficient B.little mice Session
Date/Time: 5/19/2023 12:00 PM PTSession
Title: Friday Poster Session
AAV-mediated gene transfer holds promise as a therapy for
various diseases, but unregulated protein expression from vectors
can lead to unwanted side effects and reduced efficacy. We present
the development of an optimized vectorized human growth hormone
gene, whose expression is specifically and precisely in
dose-response to a bespoke oral small molecules inducer via a
synthetic mammalian riboswitch. Our gene expression platform
utilizes a riboswitch, an RNA element that contains an aptamer as a
sensor for a small molecule ligand/inducer. In the absence of the
small molecule inducer in vitro, the growth hormone (GH) gene
containing the riboswitch does not express growth hormone protein.
In the presence of the small molecule inducer, growth hormone is
robustly produced in a precise inducer dose-dependent manner. When
the GH gene with riboswitch was delivered into the muscles of
GH-deficient B.little mice via AAV-mediated local intramuscular
injection, the oral small molecule inducer treatment resulted in
increased body weight and body length of the mice. The improvement
of the animal growth in B.little mice indicates that the induction
of expression of growth hormone achieves a therapeutic level in
these animals and demonstrates for the first time rescue of GH
deficiency via the delivery of a small molecule inducer of a
locally delivered gene therapy rather than repeated injection of
exogenously produced synthetic growth hormone. Our data provide
evidence that our riboswitch platform provides an efficacious and
safe platform for delivering GH via gene expression control.
Poster #1446: Development of in vitro neuronal
cytotoxicity models for neurodegenerative disease gene therapy
R&DSession Date/Time: 5/19/2023 12:00 PM
PTSession Title: Friday Poster Session
Neurological disorders such as Alzheimer’s Disease, Parkinson’s
Disease, Amyotrophic Lateral Sclerosis (ALS), and Frontal Temporal
Dementia (FTD) are the second leading cause of death worldwide,
with millions of new diagnoses each year. ALS alone affects 1 in
50,000 people per year worldwide, calling for increased demand for
efficient therapies. Cytoplasmic mislocalization and the subsequent
accumulation and aggregation of transactive response DNA-binding
protein 43 kDa (TDP-43) is a hallmark of ALS and, in most cases,
represents a reliable post-mortem diagnostic marker. We propose two
cellular models of TDP-43-induced cytotoxicity mediated by
adeno-associated virus (AAV) transduction. Primary cortical mouse
neurons were transduced with AAV containing TDP-43 and cytotoxicity
was tracked over time. Dose-dependent cytotoxicity, as well as
changes in morphology, were observed in the TDP-43-transduced
neurons. The same experiment was conducted using ReNcells, an
immortalized human neural progenitor cell line. Treating ReNcells
with AAV-TDP-43 resulted in dose-dependent cytotoxicity determined
by LDH activity and AO/PI staining. Our data demonstrate that these
in vitro models have the potential to be used in high throughput
screens and functional potency assays for neuroprotective gene
therapy development.
Poster #1466: Identification of Novel
Inflammation-Inducible Promoters Using a Hybrid-Barcoded SuRETM
LibrarySession Date/Time: 5/19/2023 12:00 PM
PTSession Title: Friday Poster Session
AAV-based gene therapy vectors are promising candidates for the
treatment of inflammatory disease, resulting from a biological
response of the immune system triggered by a variety of different
factors. Regulatory elements, including promoters and enhancers,
are engineered for use in AAV vectors to optimize the strength,
kinetics, and specificity of transgene expression. The
incorporation of promoters inducible by inflammation will help to
reduce the risk of side effects due to overexpression of and/or
continuous exposure to the anti-inflammatory therapeutic protein by
such AAV vectors. The Survey of Regulatory Elements (SuRE)
methodology was applied to identify new cis-regulatory elements in
the human genome. The best-performing elements were combined with
the NFkB-CMV promoter to generate a new barcoded library,
consisting of ~40,000 new hybrid combinations, each of around 600
bp in size. The new barcoded hybrid library was subsequently used
in a second round of screening in HT1080 cells. The best-performing
hybrid elements were selected for further analysis in the context
of the AAV2 genome upon plasmid transfection and AAV transduction,
with luciferase as the reporter protein. Primary cells and
different cell lines were used to determine the strength and
inducible character of the new hybrid promoters. The expression
profiles from plasmids and AAV viruses revealed a number of new
hybrid promoter elements that displayed improved inducibility
and/or higher expression under inflammatory conditions compared to
the reference NFkB-CMV promoter.
Poster #1499: Understanding the factors that
influence capsid-column affinity and peak profile in AEX-HPLC to
measure empty:full ratioSession Date/Time:
5/19/2023 12:00 PM PTSession Title: Friday Poster
Session
Anion exchange chromatography by HPLC is an analytical technique
that can be used to determine the empty and full capsid content of
adeno-associated viral (AAV) vector drug products. AEX columns have
a positively charged resin which has a high affinity for negatively
charged ions (anions). Under certain conditions, AAV capsids will
bind to the column and the introduction of a salt gradient will
alter the ionic strength, causing the bound empty capsids to elute
first from the column shortly followed by full capsids. Developing
a reproducible empty:full method can be challenging due to factors
like sample preparation, mobile phase components, pH, conductivity,
salt concentration, and temperature which influence the binding
efficiency of AAV capsids onto the column and the elution of the
empty and full capsids during the salt gradient. Data collected
during the development of an AEX empty:full method demonstrates the
effects of small method changes on capsid-column affinity and peak
profile. AEX results are also compared to results of other
orthogonal analytical techniques such as VG/VP ratio, AUC, cIEF,
CryoEM, and mass photometry.
Poster #1623: Multiple In Vitro Differentiated
Skeletal Muscle Models for Screening of Synthetic Muscle Promoters
for Gene TherapySession Date/Time: 5/19/2023 12:00
PM PTSession Title: Friday Poster Session
Gene therapy for inherited musculoskeletal disorders in skeletal
muscle has been challenging due to the target’s large size and the
need for high systemic vector doses of adeno-associated virus (AAV)
for therapeutic efficacy, which has resulted in dose-limiting
toxicity and immunogenic responses. However, muscle tissue is an
effective target for the therapeutic production of secretory
proteins through the local delivery of viral vectors containing
therapeutic transgenes. We established multiple in vitro
differentiated myotube models of skeletal muscle for a more
efficient evaluation of engineered muscle promoters for gene
therapy and their characterization by transcriptomics and
immunofluorescence analyses. We tested a set of in-house
proprietary muscle promoters in these models and compared them
against known reference muscle promoters currently used in clinical
trials of AAV-delivered treatment for muscular dystrophies. Top
performing candidates from our rationally designed compact
muscle-based promoters were evaluated in vitro and in vivo, with
our results showing higher transgene expression compared to
reference muscle promoters. MGTx-M24, a top candidate demonstrated
higher potency in vivo than promoters used in clinical trials,
which validates the relevance of our models. Collectively, these
results show we have established a robust platform to screen
engineered promoters for applications to skeletal muscle gene
therapies.
About MeiraGTx
MeiraGTx (Nasdaq: MGTX) is a vertically integrated, clinical
stage gene therapy company with six programs in clinical
development and a broad pipeline of preclinical and research
programs. MeiraGTx has core capabilities in viral vector design and
optimization and gene therapy manufacturing, and a transformative
gene regulation platform technology that allows precise,
dose-responsive control of gene expression by oral small molecules
with dynamic range that can exceed 5000-fold. Led by an experienced
management team, MeiraGTx has taken a portfolio approach by
licensing, acquiring, and developing technologies that give depth
across both product candidates and indications. MeiraGTx’s initial
focus is on three distinct areas of unmet medical need: ocular
diseases, including both inherited retinal diseases as well as
large degenerative ocular diseases, neurodegenerative diseases, and
severe forms of xerostomia. Though initially focusing on the eye,
central nervous system, and salivary gland, MeiraGTx plans to
expand its focus to develop additional gene therapy treatments for
patients suffering from a range of serious diseases.
For more information, please visit www.meiragtx.com.
Forward Looking StatementThis press release
contains forward-looking statements within the meaning of the
Private Securities Litigation Reform Act of 1995. All statements
contained in this press release that do not relate to matters of
historical fact should be considered forward-looking statements,
including, without limitation, statements regarding our product
candidate development and our pre-clinical data and reporting of
such data and the timing of results of data, as well as statements
that include the words “expect,” “will,” “intend,” “plan,”
“believe,” “project,” “forecast,” “estimate,” “may,” “could,”
“should,” “would,” “continue,” “anticipate” and similar statements
of a future or forward-looking nature. These forward-looking
statements are based on management’s current expectations. These
statements are neither promises nor guarantees, but involve known
and unknown risks, uncertainties and other important factors that
may cause actual results, performance or achievements to be
materially different from any future results, performance or
achievements expressed or implied by the forward-looking
statements, including, but not limited to, our incurrence of
significant losses; any inability to achieve or maintain
profitability, raise additional capital, repay our debt
obligations, identify additional and develop existing product
candidates, successfully execute strategic priorities, bring
product candidates to market, expansion of our manufacturing
facilities and processes, successfully enroll patients in and
complete clinical trials, accurately predict growth assumptions,
recognize benefits of any orphan drug designations, retain key
personnel or attract qualified employees, or incur expected levels
of operating expenses; the impact of the COVID-19 pandemic on the
status, enrollment, timing and results of our clinical trials and
on our business, results of operations and financial condition;
failure of early data to predict eventual outcomes; failure to
obtain FDA or other regulatory approval for product candidates
within expected time frames or at all; the novel nature and impact
of negative public opinion of gene therapy; failure to comply with
ongoing regulatory obligations; contamination or shortage of raw
materials or other manufacturing issues; changes in healthcare
laws; risks associated with our international operations;
significant competition in the pharmaceutical and biotechnology
industries; dependence on third parties; risks related to
intellectual property; changes in tax policy or treatment; our
ability to utilize our loss and tax credit carryforwards;
litigation risks; and the other important factors discussed under
the caption “Risk Factors” in our Quarterly Report on Form 10-Q for
the quarter ended March 31, 2023, as such factors may be updated
from time to time in our other filings with the SEC, which are
accessible on the SEC’s website at www.sec.gov. These and other
important factors could cause actual results to differ materially
from those indicated by the forward-looking statements made in this
press release. Any such forward-looking statements represent
management’s estimates as of the date of this press release. While
we may elect to update such forward-looking statements at some
point in the future, unless required by law, we disclaim any
obligation to do so, even if subsequent events cause our views to
change. Thus, one should not assume that our silence over time
means that actual events are bearing out as expressed or implied in
such forward-looking statements. These forward-looking statements
should not be relied upon as representing our views as of any date
subsequent to the date of this press release.
Contacts
Investors:MeiraGTxInvestors@meiragtx.com
or
Media:Jason Braco, Ph.D.LifeSci
Communicationsjbraco@lifescicomms.com
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