MOLECULAR IMMUNOLOGY AND BIOTHERAPIES

 

 


ABOUT US

 

We are specialized in the gene therapy of the immune and hematopoietic systems with two goals : one is to develop new treatments based on gene-modified immune or blood cells, another is to control unwanted immune host reactions in gene therapy.

 

We have developed lentiviral vectors and hematopoietic stem cell-based gene therapies to treat primary immune or blood disorders in collaboration with international colleagues. Recent publications report the results of phase I/II studies for the gene therapy of Wiskott Aldrich syndrome, a rare immune deficit with thrombopenia, for X-linked chronic granulomatous disease, an immune deficit with hyperinflammation requiring stable myeloid correction, for Fanconi Anemia type A a genetic form of DNA repair defect leading to stem cell aplasia. Currently we are developing a gene therapy for Artemis-SCID. Technological aspects are studied to improve transduction levels, to measure genomic insertions and to replace gene transfer by CRISPR genome editing. We explore the use of umbilical cord blood for the gene therapy of sickle cell disease in an ongoing non-interventional clinical study at the Evry hospital CHSF (clinicaltrials.gov, NCT 03876821). For this project we collaborate with the accelerator of technological research in genomic therapy (ART-TG), an innovation platform which is specialized in ex vivo genomic engineering for immunotherapy or hematology (https://insermus35.wixsite.com/art-tg). 

 

We are also interested in understanding the immunogenicity of gene therapy vectors and the tolerance of the host to long-term gene correction. We previously reported that unwanted epigenetic changes can occur in target cells following their infection by vectors and are currently exploring the causative mechanisms. We have also reported on the immunogenicity of rAAV or lentiviral vectors in vivo. We seek to develop gene therapy vectors that are invisible to the immune system and particulary to the adaptative immune system, enabling redosing. We chose to work with lentiviral vectors in vivo and have endogenized the particles using syncytins which are endogenous glycoproteins. Several applications of these vectors are being studied. In particular, lentiviral particles pseudotyped with syncytins promote efficient transduction of B cells. A current project funded by ANR is focused on B cell-mediated gene transfer with these new tools in the perspective of B cell-mediated immunotherapy.  

 

HIGHLIGHTS

 

January 2020. Publication in Nature Medicine of X-CGD gene therapy trial results.  

Lentiviral gene therapy for X-linked chronic granulomatous disease. Kohn DB, Booth C, Kang EM, Pai SY, Shaw KL, Santilli G, Armant M, Buckland KF, Choi U, De Ravin SS, Dorsey MJ, Kuo CY, Leon-Rico D, Rivat C, Izotova N, Gilmour K, Snell K, Dip JX, Darwish J, Morris EC, Terrazas D, Wang LD, Bauser CA, Paprotka T, Kuhns DB, Gregg J, Raymond HE, Everett JK, Honnet G, Biasco L, Newburger PE, Bushman FD, Grez M, Gaspar HB, Williams DA, Malech HL, Galy A, Thrasher AJ; Net4CGD consortium. Nat Med. 2020 Jan 27. doi: 10.1038/s41591-019-0735-5. [Epub ahead of print] PMID: 31988463

 

September 2019. Publication in Nature Medicine of the Fanconi Anemia A gene therapy study results. Successful engraftment of gene-corrected hematopoietic stem cells in non-conditioned patients with Fanconi anemia. Río P, Navarro S, Wang W, Sánchez-Domínguez R, Pujol RM, Segovia JC, Bogliolo M, Merino E, Wu N, Salgado R, Lamana ML, Yañez RM, Casado JA, Giménez Y, Román-Rodríguez FJ, Álvarez L, Alberquilla O, Raimbault A, Guenechea G, Lozano ML, Cerrato L, Hernando M, Gálvez E, Hladun R, Giralt I, Barquinero J, Galy A, García de Andoín N, López R, Catalá A, Schwartz JD, Surrallés J, Soulier J, Schmidt M, Díaz de Heredia C, Sevilla J, Bueren JA. Nat Med. 2019 Sep;25(9):1396-1401. doi: 10.1038/s41591-019-0550-z. Epub 2019 Sep 9. PMID: 31501599 

 

August 2019. Manuscript accepted for publication in Molecular Therapy Methods and Clinical Development. "Biosafety studies of a clinically-applicable lentiviral vector for the gene therapy of Artemis-SCID". by Sabine Charrier, Chantal Lagresle-Peyrou, Valentina Poletti, Michael Rothe, Grégory Cédrone, Bernard Gjata, Fulvio Mavilio, Alain Fischer, Axel Schambach, Jean-Pierre de Villartay, Marina Cavazzana, Salima Hacein-Bey-Abina, Anne Galy.

 

July 2019. Manuscript accepted for publication in Molecular Therapy Methods and Clinical Development

"Temporary reduction of membrane CD4 with the antioxidant MnTBAP is sufficient to prevent immune responses induced by gene transfer" by Sylvie Da Rocha, Jérémy Bigot, Fanny Onodi, Jérémie Cosette, Guillaume Corre, Jérôme Poupiot, David Fenard, Bernard Gjata, Anne Galy*, and Thi My Anh Neildez* (* co-corresp.) 

 

June 2019. Partner of the hospital-university network "IRIS", a laureate of the "RHU 2019" call for proposal.  Notre laboratoire est partenaire du projet lauréat IRIS « La thérapie génique des maladies héréditaires monogéniques du système immunitaire » coordonné par M. Cavazzana, Institut Imagine, Paris. 

 

Publication of preclinical data for the gene therapy of X-CGD

Brendel Cet al. Hum Gene Ther Clin Dev. 2018 Jun;29(2):69-79. doi: 10.1089/humc.2017.245. 

 

Celebration of the first gene therapy CGD-treated patient in Boston Children Hospital [Bost.Child.Hosp. website online article]

 

SUPPORT

Ongoing

  • ANR SYNB (in collaboration with Université of Limoges and EFS Rennes)
  • IRS Biotheralliance-UPSAY, Université Paris Saclay
  • DIM Therapie Génique Région Ile-de-France

Recently expired

  • EC FP7 Health: Net4CGD "Gene therapy for chronic granulomatous disease" project
  • Genopole ATIGE
  • France Lymphome Espoir