Taysha Gene Therapies Presents New Preclinical In-vitro Data on TSHA-102 in Rett Syndrome Supporting miRARE Regulation of MECP2 Expression at the European Society of Gene & Cell Therapy (ESGCT) 30th Annual Congress
October 24 2023 - 8:00AM
Taysha Gene Therapies, Inc. (Nasdaq: TSHA), a clinical-stage gene
therapy company focused on developing and commercializing AAV-based
gene therapies for the treatment of monogenic diseases of the
central nervous system (CNS), today announced new preclinical in
vitro data on TSHA-102 in Rett syndrome as part of a poster
presentation at the European Society of Gene & Cell Therapy
(ESGCT) 30th Annual Congress. TSHA-102 is a self-complementary
intrathecally delivered AAV9 investigational gene transfer therapy
that utilizes a novel miRNA-Responsive Auto-Regulatory Element
(miRARE) technology designed to mediate levels of MECP2 in the CNS
on a cell-by-cell basis without risk of overexpression. These data
demonstrate the function of the miRARE-RHD1pA regulatory element
and its impact on MECP2 transgene and protein expression in human
and mouse cell lines, providing further support for the regulatory
control of miRARE.
“Appropriate control of MECP2 transgene expression based on
cellular levels of MeCP2 is fundamental to the development of a
safe and effective gene therapy for Rett syndrome, given the mosaic
pattern of MECP2 silencing in females with Rett syndrome,” said
Sukumar Nagendran, M.D., President, and Head of R&D of Taysha.
“These new in vitro data recapitulating our in vivo findings in
neonatal mice further our mechanistic understanding of how the
miRARE technology controls post-transcriptional MECP2 expression
and reinforce the potential of TSHA-102 to address the root cause
of Rett syndrome. We look forward to reporting available clinical
data from the two adult patients dosed with TSHA-102 in the
low-dose cohort of the REVEAL Phase 1/2 adult trial in mid-November
and expect to dose the first pediatric patient with TSHA-102 in
first quarter of 2024.”
The preclinical study presented at ESGCT used human (2v6.11) and
mouse (N2a) cell culture models to explore the function of miRARE
and its impact on MECP2 transgene and protein expression in the
presence or absence of cellular MeCP2 using both viral AAV9
transduction and plasmid transfection containing either
miRARE-regulated or SV40 (unregulated) elements.
In vitro data showed
post-transcriptional gene silencing by miRARE in response to
cellular MeCP2 levels can be recapitulated in human and mouse cell
lines:
- miRARE controlled dose-dependent transgene expression of MeCP2
protein via a similar mechanism in both human and mouse cell
lines
- miRARE partially silenced transgene expression in neuronal and
non-neuronal cell lines; the expression and subsequent
downregulation were 4-5-fold higher in neuronal cell lines,
supporting tissue-specific expression of MeCP2
- Transgene protein expression was highest in homozygous cells
and slightly greater than wild-type in heterozygous cells,
demonstrating transgene expression of MeCP2 protein is sensitive to
cellular levels of MeCP2 and increases in human cells with both
endogenous MECP2 copies disrupted
- Transgene silencing occurred in part by inducing mRNA decay but
more substantially by reducing miniMeCP2 protein accumulation,
suggesting that the miRARE technology also acts in cis to prevent
translation
About TSHA-102TSHA-102 is a self-complementary
intrathecally delivered AAV9 investigational gene transfer therapy
in clinical evaluation for Rett syndrome. TSHA-102 utilizes a novel
miRNA-Responsive Auto-Regulatory Element (miRARE) platform designed
to mediate levels of MECP2 in the CNS on a cell-by-cell basis
without risk of overexpression. TSHA-102 has received Fast Track
designation and Orphan Drug and Rare Pediatric Disease designations
from the FDA and has been granted Orphan Drug designation from the
European Commission.
About Rett SyndromeRett syndrome is a rare
neurodevelopmental disorder caused by mutations in the X-linked
MECP2 gene, which is a gene that’s essential for neuronal and
synaptic function in the brain. The disorder is characterized by
intellectual disabilities, loss of communication, seizures, slowing
and/or regression of development, motor and respiratory impairment,
and shortened life expectancy. Rett syndrome primarily occurs in
females and is one of the most common genetic causes of severe
intellectual disability. Currently, there are no approved
disease-modifying therapies that treat the genetic root cause of
the disease. Rett syndrome caused by a pathogenic/likely pathogenic
MECP2 mutation is estimated to affect between 15,000 and 20,000
patients in the U.S., EU and UK.
About Taysha Gene TherapiesTaysha Gene
Therapies (Nasdaq: TSHA) is on a mission to eradicate monogenic CNS
disease. With a singular focus on developing curative medicines, we
aim to rapidly translate our treatments from bench to bedside. We
have combined our team’s proven experience in gene therapy drug
development and commercialization with the world-class UT
Southwestern Gene Therapy Program. Together, we leverage our fully
integrated platform with a goal of dramatically improving patients’
lives. More information is available at www.tayshagtx.com.
Forward-Looking StatementsThis press release
contains forward-looking statements within the meaning of the
Private Securities Litigation Reform Act of 1995. Words such as
“anticipates,” “believes,” “expects,” “intends,” “projects,”
“plans,” and “future” or similar expressions are intended to
identify forward-looking statements. Forward-looking statements
include statements concerning the potential of TSHA-102 to
positively impact quality of life and alter the course of disease
in the patients we seek to treat and our research, development and
regulatory plans for TSHA-102, including timing of expected
clinical data and the dosing of additional patients.
Forward-looking statements are based on management’s current
expectations and are subject to various risks and uncertainties
that could cause actual results to differ materially and adversely
from those expressed or implied by such forward-looking statements.
Accordingly, these forward-looking statements do not constitute
guarantees of future performance, and you are cautioned not to
place undue reliance on these forward-looking statements. Risks
regarding our business are described in detail in our Securities
and Exchange Commission (“SEC”) filings, including in our Annual
Report on Form 10-K for the full-year ended December 31, 2022, and
our Quarterly Report on Form 10-Q for the quarter ended June 30,
2023, both of which are available on the SEC’s website at
www.sec.gov. Additional information will be made available in other
filings that we make from time to time with the SEC. Such risks may
be amplified by the impacts of the COVID-19 pandemic. These
forward-looking statements speak only as of the date hereof, and we
disclaim any obligation to update these statements except as may be
required by law.
Company Contact:Hayleigh Collins Director, Head
of Corporate CommunicationsTaysha Gene Therapies,
Inc.hcollins@tayshagtx.com
Media Contact:Carolyn HawleyCanale
Communicationscarolyn.hawley@canalecomm.com
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