Cellectis and Imagine Institute Publish A Proof-Of-Concept Study of a Gene Surgery Candidate to Treat Activated Phosphoinositide 3-Kinase Δ Syndrome Type 1 (APDS1)
Published on October 12, 2023
October 12, 2023 - New York, NY – 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, France
2 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, France
6 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)