AVROBIO leading industry in combining use of
two safety assays to evaluate genotoxicity risk prior to moving
into clinical trials
New safety assay uses machine learning
algorithms and transcriptional profile data designed to assess the
genotoxicity risk of integrating vectors
AVROBIO, Inc. (Nasdaq: AVRO), a leading clinical-stage gene
therapy company working to free people from a lifetime of genetic
disease, today reported favorable data on the combined use of two
state-of-the-art assays to evaluate the genotoxicity risk of
integrating vectors used in hematopoietic stem cell (HSC) gene
therapy prior to clinical use, at the 29th Annual Congress of the
European Society of Gene & Cell Therapy (ESGCT), Oct. 11-14,
2022 in Edinburgh, Scotland.
In collaboration with Professor Axel Schambach, Ph.D., Institute
of Experimental Hematology, Hannover Medical School, Germany,
AVROBIO is pioneering the use of two advanced preclinical
cell-based assays -- in vitro immortalization (IVIM) assay and the
novel surrogate assay for genotoxicity assessment (SAGA) -- to
evaluate viral vectors before they move into clinical programs.
Together these assays are designed to assess which vectors are less
likely to exhibit genotoxic behavior and monitor if these vectors
activate proto-oncogenes (genes that may lead to cancer).
“Our work provides insight into the early molecular events of
genotoxicity following HSC transduction with integrating vectors
and presents a powerful machine-learning approach to prospectively
estimate the genotoxicity risk of integrating vectors for gene
therapy,” said Professor Schambach, also associated with the
Division of Hematology/Oncology, Boston Children’s Hospital and
Harvard Medical School, Boston, MA, whose work includes data on
more than 30 commonly used vectors. “These assays enable
preclinical risk assessment of gene therapy vectors, potentially
paving the way for safer gene therapy vectors used in clinical
trials.”
AVROBIO uses these assays to inform vector selection during
preclinical development. In addition, to date, AVROBIO has seen no
cases of insertional oncogenesis in any of its clinical
programs.
“Safety is at the forefront of our work at AVROBIO and
incorporated in the development of our plato® platform, which
includes our advanced vector design, optimized for safety as well
as transgene expression and protein uptake,” said AVROBIO President
and CEO Geoff MacKay. “Combining these assays helps assess vector
genotoxicity risk early in preclinical development and further
reaffirms that not all lentiviral vectors are designed the
same.”
IVIM/SAGA as screening tools during lentiviral vector
selection
In its research, AVROBIO used the two assays in combination to
determine the potential genotoxicity risk of six lentiviral
vectors. Five of the vectors used the EF1 α short promoter (EFS),
while the sixth vector used the modified enhancer/promoter of the
murine myeloproliferative sarcoma virus, or MND, promoter. Vectors
were compared to a non-transduced mock control and a positive
genotoxic control, the non-SIN gamma-retroviral vector (RSF91).
The in vitro immortalization (IVIM) assay quantifies the risk of
vector-induced cellular transformation. The technique assesses
genotoxicity by determining how likely a vector is to insert near
and activate proto-oncogenes, such as MECOM, and lead to an
over-proliferation of cells. In this study, to quantify the risk of
vector-induced cellular transformation, mouse hematopoietic stem
and progenitor cell (HSPC) proliferation was monitored after
transduction. IVIM determined that the five EFS vectors drove cell
growth in a manner indistinguishable from non-transduced cells. The
vector using the MND promoter, however, exhibited cell growth that
was statistically significantly different from non-transduced cells
and similar to the positive genotoxic control.
The second and newer assay assesses genotoxicity more directly.
The novel surrogate assay for genotoxicity assessment (SAGA) relies
on the observation that genotoxic vectors induce a unique gene
expression signature that is linked to stemness and oncogenesis in
mouse HSPCs. Machine learning algorithms developed from
transcriptional data of known genotoxic vectors are used to
estimate the transformational potential of candidate vectors. The
SAGA assay can evaluate vectors with known genotoxic potential with
an accuracy of 90.9%. In this study, SAGA data showed that the five
vectors with EFS promoters were statistically distinct from the
genotoxic positive control and therefore displayed lower genotoxic
risk, whereas four of nine (44%) samples from cells transduced with
a lentiviral vector containing an MND internal promoter had gene
enrichment scores associated with insertional oncogenesis.
These findings enable the estimation of clinically translatable
insertional oncogenesis risk of integrating vectors during
preclinical development. AVROBIO uses the EFS promoter in its
clinical programs.
The Hannover Medical School team working with Professor
Schambach and Michael Rothe, Ph.D., has previously published their
data in Molecular Therapy.
About AVROBIO
Our vision is to bring personalized gene therapy to the world.
We target the root cause of genetic disease by introducing a
functional copy of the affected gene into patients’ own
hematopoietic stem cells (HSCs), with the goal to durably express
the therapeutic protein throughout the body, including the central
nervous system. Our first-in-class pipeline includes clinical
programs for cystinosis and Gaucher disease type 1, as well as
preclinical programs for Gaucher disease type 3, Hunter syndrome
and Pompe disease. Our proprietary plato® gene therapy platform is
designed to be scaled to support late-stage clinical development
and commercialization globally. We are headquartered in Cambridge,
Mass. For additional information, visit avrobio.com, and follow us
on Twitter and LinkedIn.
Forward-Looking Statements
This press release contains forward-looking statements,
including statements made pursuant to the safe harbor provisions of
the Private Securities Litigation Reform Act of 1995. These
statements may be identified by words and phrases such as “aims,”
“anticipates,” “believes,” “could,” “designed to,” “estimates,”
“expects,” “forecasts,” “goal,” “intends,” “may,” “plans,”
“possible,” “potential,” “seeks,” “will,” and variations of these
words and phrases or similar expressions that are intended to
identify forward-looking statements. These forward-looking
statements include, without limitation, statements regarding our
business strategy for and the potential therapeutic benefits of our
preclinical and clinical product candidates, the potential benefits
of the IVIM/SAGA preclinical assays, including the potential to
evaluate or assess possible genotoxicity risk during preclinical
development and in vector selection, statements regarding
preclinical or clinical trial results, anticipated benefits of our
gene therapy platform including potential impact on our
commercialization activities, the expected benefits and results of
our implementation of the plato platform in our clinical trials and
gene therapy programs, and the expected safety profile of our
preclinical and investigational gene therapies. Any such statements
in this press release that are not statements of historical fact
may be deemed to be forward-looking statements. Results in
preclinical or early-stage clinical trials may not be indicative of
results from later stage or larger scale clinical trials and do not
ensure regulatory approval. You should not place undue reliance on
these statements, or the scientific data presented.
Any forward-looking statements in this press release are based
on AVROBIO’s current expectations, estimates and projections about
our industry as well as management’s current beliefs and
expectations of future events only as of today and are subject to a
number of risks and uncertainties that could cause actual results
to differ materially and adversely from those set forth in or
implied by such forward-looking statements. These risks and
uncertainties include, but are not limited to, the risk that any
one or more of AVROBIO’s product candidates will not be
successfully developed or commercialized, the risk of cessation or
delay of any ongoing or planned clinical trials of AVROBIO or our
collaborators, the risk that AVROBIO may not successfully recruit
or enroll a sufficient number of patients for our clinical trials,
the risk that AVROBIO may not realize the intended benefits of our
gene therapy platform, including the features of our plato®
platform, the risk that our product candidates or procedures in
connection with the administration thereof will not have the safety
or efficacy profile that we anticipate, the risk that prior
results, such as signals of safety, activity or durability of
effect, observed from preclinical or clinical trials, will not be
replicated or will not continue in ongoing or future studies or
trials involving AVROBIO’s product candidates, the risk that we
will be unable to obtain and maintain regulatory approval for our
product candidates, the risk that the size and growth potential of
the market for our product candidates will not materialize as
expected, risks associated with our dependence on third-party
suppliers and manufacturers, risks regarding the accuracy of our
estimates of expenses and future revenue, risks relating to our
capital requirements and needs for additional financing, risks
relating to clinical trial and business interruptions resulting
from the COVID-19 outbreak or similar public health crises,
including that such interruptions may materially delay our
enrollment and development timelines and/or increase our
development costs or that data collection efforts may be impaired
or otherwise impacted by such crises, and risks relating to our
ability to obtain and maintain intellectual property protection for
our product candidates. For a discussion of these and other risks
and uncertainties, and other important factors, any of which could
cause AVROBIO’s actual results to differ materially and adversely
from those contained in the forward-looking statements, see the
section entitled “Risk Factors” in AVROBIO’s most recent Annual or
Quarterly Report, as well as discussions of potential risks,
uncertainties and other important factors in AVROBIO’s subsequent
filings with the Securities and Exchange Commission. AVROBIO
explicitly disclaims any obligation to update any forward-looking
statements except to the extent required by law.
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Investors: Christopher F. Brinzey Westwicke, an ICR
Company 339-970-2843 chris.brinzey@westwicke.com
Media: Kit Rodophele Ten Bridge Communications
617-999-9620 krodophele@tenbridgecommunications.com
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