Cellectis (the “Company”) (Euronext Growth: ALCLS - NASDAQ: CLLS),
a clinical-stage biotechnology company using its pioneering
gene-editing platform to develop life-saving cell and gene
therapies, announced today the publication of a new research paper
in Molecular Therapy – Methods & Clinical Development,
demonstrating the efficacy of its TALEN-mediated gene correction of
mutated PIK3CD gene in APDS1 T-cells.
The research work described in this article was
jointly conducted by Imagine Institute and Cellectis teams.
About APDS1:
Activated phosphoinositide 3-kinase δ syndrome
(also known as APDS type 1 or APDS1) is a rare but devastating
disease caused by gain-of-function mutations in the PIK3CD gene and
resulting in a combined immunodeficiency.
Approved treatments for APDS1 consist in
prophylactic measures including long term antibiotics and Ig
(immunoglobulin) replacement therapy.
Allogeneic hematopoietic stem/progenitor cell
(HSPC) transplantation has been proposed as a definitive treatment
for APDS1. However, the lack of compatible donor as well as graft
failure, graft instability, and poor graft function are still major
challenges that must be overcome to reach a positive therapeutic
outcome. Thus, so far there are neither optimal nor long-term
therapeutic solutions for APDS1 patients and new alternative
treatments are highly regarded.
The study published here aims at exploring an
alternative therapeutic strategy by correcting the mutated PIK3CD
gene associated to APDS1 by gene editing. This article describes a
TALEN®-mediated gene insertion strategy that allows targeted
correction of the dominant gain-of-function mutation of the PIK3CD
gene by insertion of a functional sequence in a precise manner.
Results show efficient gene insertion in APDS1 patients’ T-cells,
normalization of PI3K signaling and rescue of T-cell cytotoxic
functions.
Preclinical results demonstrated
that:
- The PIK3CD gene can be efficiently
corrected by TALEN®-mediated gene insertion of the functional
PIK3CD DNA sequence vectorized by AAV, in healthy donor and APDS1
patient T-cells.
- TALEN®-mediated PIK3CD gene
correction rescues PI3K signaling in APDS1 patient T-cells.
- TALEN®-mediated PIK3CD gene
correction normalizes the transcriptomic status of APDS1 patient
CD8+ T-cells and rescues their cytolytic activity.
In summary, we demonstrate that the PIK3CD
dominant gain of function mutation associated to APDS1 can be
successfully corrected in APDS1 patient T-cells using TALEN® gene
editing and AAV-based DNA repair matrix. This correction rescues
the cytolytic function of APDS1 T-cells, normalizes their
intracellular phospho-AKT levels found at basal and at activated
states as well as the transcriptomic signature of certain genes
involve in T-cells’ cytolytic function, activation, and
fitness.
“This successful demonstration of PIK3CD gene
correction warrants the development of a gene therapy approach to
treat p110δ dysregulations in a long-term fashion. This
proof-of-concept study paves the way for the future development of
a bona fide gene surgery candidate to potentially cure APDS1” said
Julien Valton, Ph.D., Vice President Gene Therapy at Cellectis.
Rescuing the Cytolytic Function of APDS1
Patient T-cells via TALEN-mediated PIK3CD Gene
Correction
Poggi L.1,2, Chentout L.1,2, Lizot S.3, Boyne A.
4, Juillerat A.4, Moiani A.3, Luka M.5,6, Carbone. F 5,6, Ménager M
M. 5,6, Cavazzana M.1,7, Duchateau P.4, Valton J.3*, Kracker
S.1,2*
1 Université de Paris Cité, Imagine Institute,
Paris, France2 Laboratory of Human Lymphohematopoiesis, INSERM UMR
1163, Paris, France 3 Cellectis, 8 rue de la Croix Jarry, 75013
Paris, France 4 Cellectis, Inc., 430 East 29th Street, New York, NY
10016, USA. 5 Université de Paris Cité, Imagine Institute,
Laboratory of Inflammatory Responses and Transcriptomic Networks in
Diseases, Atip-Avenir Team, INSERM UMR 1163, F-75015 Paris, France6
Labtech Single-Cell@Imagine, Imagine Institute, INSERM UMR 1163,
F-75015 Paris, France.7 Biotherapy Clinical Investigation Center,
Groupe Hospitalier Universitaire Ouest, Assistance
Publique-Hôpitaux de Paris, INSERM, Paris, France
* Corresponding authors Julien Valton and Sven
Kracker (julien.valton@cellectis.com and sven.kracker@inserm.fr,
respectively)
About Cellectis
Cellectis is a clinical-stage biotechnology
company using its pioneering gene-editing platform to develop
life-saving cell and gene therapies. Cellectis utilizes an
allogeneic approach for CAR-T immunotherapies in oncology,
pioneering the concept of off-the-shelf and ready-to-use
gene-edited CAR T-cells to treat cancer patients, and a platform to
make therapeutic gene editing in hemopoietic stem cells for various
diseases. As a clinical-stage biopharmaceutical company with over
23 years of experience and expertise in gene editing, Cellectis is
developing life-changing product candidates utilizing TALEN®, its
gene editing technology, and PulseAgile, its pioneering
electroporation system to harness the power of the immune system in
order to treat diseases with unmet medical needs. Cellectis’
headquarters are in Paris, France, with locations in New York, New
York and Raleigh, North Carolina. Cellectis is listed on the Nasdaq
Global Market (ticker: CLLS) and on Euronext Growth (ticker:
ALCLS).
Forward-looking Statements
This press release contains “forward-looking”
statements within the meaning of applicable securities laws,
including the Private Securities Litigation Reform Act of 1995.
Forward-looking statements may be identified by words such as
“anticipate,” “expect,” “plan,” “could” and “will,” or the negative
of these and similar expressions. These forward-looking statements,
which are based on our management’s current expectations and
assumptions and on information currently available to management,
include statements about the potential benefit and potential
development of the Company’s preclinical product candidates. These
forward-looking statements are made in light of information
currently available to us and are subject to numerous risks and
uncertainties, including with respect to the numerous risks
associated with biopharmaceutical product candidate development.
Furthermore, many other important factors, including those
described in our Annual Report on Form 20-F and the financial
report (including the management report) for the year ended
December 31, 2022 and subsequent filings Cellectis makes with the
Securities Exchange Commission from time to time, as well as other
known and unknown risks and uncertainties may adversely affect such
forward-looking statements and cause our actual results,
performance or achievements to be materially different from those
expressed or implied by the forward-looking statements. Except as
required by law, we assume no obligation to update these
forward-looking statements publicly, or to update the reasons why
actual results could differ materially from those anticipated in
the forward-looking statements, even if new information becomes
available in the future.
For further information on Cellectis, please
contact:
Media contact:
Patricia Sosa Navarro, Chief of Staff to the CEO, +33 (0)7 76 77
46 93, media@cellectis.com
Investor Relations contacts:
Arthur Stril, Chief Business Officer, +1 (347) 809 5980,
investors@cellectis.com
Ashley R. Robinson, LifeSci Advisors, +1 617 430 7577
- APDS1_scientific_article_PR_ENGLISH_VF.pdf
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