Scribe Therapeutics Presents Data Demonstrating Highly Potent Gene Editing In Vivo, Including Saturated Editing of Hepatocytes in NHPs, by an Engineered XE Genome Editor; Showcases Novel Epigenetic Editing Capabilities at 2024 ASGCT Annual Meeting
2024年5月11日 - 5:02AM
ビジネスワイヤ(英語)
- Engineering of X-Editors (XE), Scribe’s proprietary genome
editing platform, for potency and specificity enables XE to become
the first non-Cas9-based molecule to achieve saturating levels of
editing in the NHP liver (exceeding 75% whole liver editing)
without any detectable off-targets
- Data also highlight the ability of XE to achieve safe and
saturated levels of editing in transduced photoreceptors in the
mouse retina and rescue of visual response in a mouse model for
autosomal dominant retinitis pigmentosa (adRP)
- Unveiling of critical and comprehensive engineering of
Epigenetic Long-Term X-Repressors (ELXR), Scribe’s novel epigenetic
editing platform, for greater potency
Scribe Therapeutics Inc. (Scribe), a genetic medicines company
unlocking the potential of CRISPR to transform human health,
presented data on its X-Editor (XE) and Epigenetic Long-Term
X-Repressor (ELXR) technologies at the 27th American Society of
Gene & Cell Therapy (ASGCT) Annual Meeting taking place in
Baltimore, MD, and virtually.
The data described in the company’s oral presentations and
poster session showcase the dramatic potency, safety, and
specificity of the novel XE genome editing and ELXR epigenetic
editing platforms and the company's developments in successfully
advancing these technologies into large animal models, including
non-human primates.
“A major challenge in the field has been to achieve saturating
levels of genome editing, at therapeutically relevant doses, with
molecules that have better safety and delivery characteristics than
CRISPR-Cas9—this has not been possible to date,” said Benjamin
Oakes, Ph.D., co-founder and Chief Executive Officer of Scribe.
“For the first time, Scribe has demonstrated that the holistic
engineering of a wholly unique and highly potent CRISPR enzyme can
enable this goal. We have demonstrated that our XE platform can
achieve editing rates of greater than 75% in the liver of NHPs,
theoretically targeting all hepatocytes, while not displaying any
detectable off-target effects in primary human cells.”
“Furthermore, we were thrilled to unveil a taste of the
engineering behind Scribe’s ELXR epigenetic editing platform and
present data elucidating the effectiveness of our comprehensive
engineering approach compared to previous methodologies,” Dr. Oakes
said. “We believe this positions Scribe as the only company to have
engineered, from the ground up, novel CRISPR genome editing and
epigenetic editing platforms that can meet and often exceed the
field’s expectations regarding therapeutically relevant potency and
specificity.”
Additional highlights on the developments of the XE platform and
application in vivo include:
Presentation: Engineering CasX to Create a Gene Editor
with Potent Activity in Non-Human Primates
- Using a variety of holistic engineering approaches, Scribe has
created X-Editor molecules that are >100 steps in sequence space
removed and >100-fold more potent than the naturally occurring
CRISPR predecessors
- XE achieves at or near-saturating levels of editing across a
broad range of tissue types, including the eye, CNS, cardiac and
skeletal muscle, and liver using either AAV or LNP
- XE is highly potent in non-human primate studies, achieving
>75% editing in the liver and saturating editing at
<1.5mg/kg
- When tested at different sites, XE is highly specific,
demonstrating no detectable off-target editing at doses 10-fold
higher than the effective dose in primary human hepatocytes
- Scribe continues to expand the XE platform by engineering
molecules with customizable genomic targetability by modifying the
PAM recognition of the XE platform
Presentation: AAV-Mediated Delivery of a Novel
CasX-Editor Molecule Achieves Allele-Specific and Potent Editing of
P23H Rhodopsin in a Mouse Model of Retinitis Pigmentosa
- XE and AAV cargo engineering enables safe and selective XE
delivery and editing in rod photoreceptors when administered
subretinally
- Scribe demonstrates for the first time the use of XE to achieve
allele-specific editing of the P23H.RHO locus, in an in vitro
system and a phenotypically relevant in vivo model. This novel gene
editing strategy selectively targets the P23H SNP in the RHO gene
and rescues photoreceptor structure and visual function three
months post-treatment
- Further engineering of the XE molecule improves molecule
potency and therapeutic window in vivo
- The findings illustrate the potential for XE not only to treat
P23H.RHO-related adRP, but also, more broadly, other forms of
ophthalmic disease and autosomal dominant disorders in an
allele-specific manner
Highlights on ELXR, Scribe’s epigenetic editing technology:
Presentation: Comprehensive Engineering of a CasX-Based
Repressor to Create Highly Potent Epigenetic Editors
- Leveraging its CRISPR by Design™ approach, Scribe engineers
wholly novel epigenetic editors that potently silence gene
expression without permanently altering the underlying genome
- The company’s epigenetic editing technology incorporates a
catalytically inactive version of its proprietary XE platform
tethered to epigenetic repressor domains
- To identify novel epigenetic effector domains more potent than
the repressive domains widely used in conventional Cas9-based
epigenetic editors, Scribe built and queried a library of 30,000
distinct effector domains from across the tree of life. These
effector domains were each fused to the catalytically inactive XE
molecule
- Through this high-throughput functional bioprospecting, Scribe
identified novel and compact repressive effector domains that were
significantly more potent than the widely used repressive
domains
- Use of these novel repressive effector domains enables the
generation of Scribe’s proprietary Epigenetic Long-Term
X-Repressors (ELXRs), which exhibit robust targeting and repressive
activity
- Compared with Cas9-based CRISPRoff systems, ELXR more potently
and durably represses a therapeutically relevant target in vivo
when delivered via mRNA in a single dose of LNP
About Scribe Therapeutics
Scribe Therapeutics is revolutionizing the development of
optimized in vivo CRISPR-based genetic medicines designed to become
standard of care treatments for patients suffering from highly
prevalent diseases. Our CRISPR by Design™ approach engineers
bacterial immune systems into a premier suite of genome and
epigenome editing tools built for unique molecular advantages in
activity, specificity and deliverability that translate into safer
and more effective genetic therapies. Co-founded by Nobel Prize
winner Jennifer Doudna and backed by leading life sciences
investors, Scribe is engineering the future of genetic medicine. To
learn more, visit www.scribetx.com.
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Investor Contact: Stern IR for Scribe Therapeutics
investors@scribetx.com
Media Contact: Thermal for Scribe Therapeutics
media@scribetx.com