公开(公告)号：US20230190956A1

公开(公告)日：2023-06-22

申请号：US17996987

申请日：2021-04-23

Applicant: INSERM (Institut National de la Santé et de la Recherche Médicale) ,  Genethon ,  Université d'Evry-Val-d'Essonne

Inventor： Fisson SYLVAIN

IPC: A61K48/00 ,  A61K38/16 ,  A61P27/02

CPC classification number: A61K48/005 ,  A61K48/0083 ,  A61K48/0075 ,  A61K38/162 ,  A61P27/02 ,  C12N2750/14133 ,  C12N2750/14143

Abstract: Despite the eye's immune-privileged status, a secondary loss of vision in some patients treated with AAV led the inventors to question the immunogenicity of AAV vectors after a subretinal injection. The inventors thus characterized anti-transgene and anti-capsid immune responses induced in the periphery after the subretinal AAV injection. Different doses of AAV8 encoding reporter proteins fused with the HY male antigen were injected at day 0 into the subretinal space of adult immunocompetent C57BL/6 female mice. Subretinal AAV injection induced a dose-dependent proinflammatory immune response to the transgene product, correlated with local transgene expression. In order to trigger a subretinal-associated immune inhibition (SRAII) mechanism, some mice were co-injected subretinally at day 0 with AAV and HY peptides. Interestingly, this subretinal co-injection of AAV8 with peptides of the transgene product modulated the anti-transgene T-cell immune response, even at high dose of vector (5.1010 vg). This immunodulation was also confirmed in a pathophysiological murine model of retinal degeneration. The inventors also demonstrated that injection of AAV8 in the subretinal space induces proinflammatory peripheral immune responses to the transgene and the capsid that could be counteracted y co-injection with transgene peptides. Accordingly, the object of the present invention is to provide methods for preventing induction of immune responses to the transgene product and the AAV capsid after ocular gene therapy.

公开(公告)号：US11427836B2

公开(公告)日：2022-08-30

申请号：US16604648

申请日：2018-04-11

Applicant: INSERM (INSTITUT NATIONAL DE LA SANTÉ ET DE LA RECHERCHE MÉDICALE) ,  UNIVERSITÉ D'EVRY-VAL-D'ESSONNE ,  GENETHON ,  FONDAZIONE ISTITUTO ITALIANO DI TECNOLOGIA ,  FONDAZIONE TELETHON

Inventor： Federico Mingozzi ,  Giuseppe Ronzitti ,  Andrea Contestabile ,  Laura Cancedda

IPC: C12N15/113 ,  C12N15/86 ,  A61K45/06 ,  C12Q1/68

Abstract: An RNA interference (RNAi) strategy is provided based on use of artificial microRNA (amiR) to reduce NKCC1 expression. In particular, a method is provided that achieves neuron-specific expression of specific amiR against NKCC1 by using a human Synapsin promoter to drive transgene expression.

公开(公告)号：US20200261589A1

公开(公告)日：2020-08-20

申请号：US16757591

申请日：2018-10-19

Applicant: Genethon ,  Institut National de la Santé et de la Recherche Médicale ,  Université d'Evry val d'Essonne

Inventor： Anne Galy ,  Maxime Ferrand

IPC: A61K47/64 ,  A61K9/127 ,  A61K45/06 ,  A61K9/00 ,  A61K35/76 ,  A61K47/69 ,  A61P21/00

Abstract: The invention relates to a pharmaceutical composition for targeting drug delivery including gene delivery to regenerating muscle tissue, comprising at least a therapeutic drug or gene, associated to a syncytin protein, and its use in the prevention and/or treatment of muscle injuries or diseases, in particular in gene therapy of said diseases using lentiviral vector particles or lentivirus-like particles pseudotyped with syncytin protein.

公开(公告)号：US20230357769A1

公开(公告)日：2023-11-09

申请号：US18246270

申请日：2021-09-21

Applicant: INSERM (INSTITUT NATIONAL DE LA SANTÉ ET DE LA RECHERCHE MÉDICALE) ,  ASSISTANCE PUBLIQUE-HÔPITAUX DE PARIS (APHP) ,  FONDATION IMAGINE ,  UNIVERSITÉ D'EVRY VAL D'ESSONNE ,  UNIVERSITÉ DE PARIS

Inventor： Annarita MICCIO ,  Fulvio MAVILIO ,  Mario AMENDOLA ,  Marina CAVAZZANA ,  Megane BRUSSON

IPC: C12N15/113 ,  C12N15/86 ,  A61K35/28 ,  A61P7/06

CPC classification number: C12N15/113 ,  C12N15/86 ,  A61K35/28 ,  A61P7/06 ,  C12N2310/141 ,  C12N2310/531 ,  C12N2740/15043

Abstract: Gene therapy of SCO is based on the transplantation of genetically modified HSCs. Several LV approaches based on gene addition consist in transducing patient HSCs with a lentiviral vector expressing an anti-sickling β-like globin chain such as use of βAS3 HBB anti-sickling variants. Here, the inventors have improved the design of the LV-AS3 vector to treat SCO patients. These LVs allow the simultaneous expression of the potent anti-sickling βAS3-globin and an artificial miR (amiR) silencing the βS-globin. The reduction of βS-globin levels will increase the incorporation of βAS3-globin in Hb tetramers, which should increase the proportion of corrected RBCs in SCO patients. The inventors selected the best-performing miRs, and modified the therapeutic βAS3-globin transgene by inserting silent mutations to avoid the recognition by the amiR and the silencing of the transgene.

公开(公告)号：US20220017919A1

公开(公告)日：2022-01-20

申请号：US17295093

申请日：2019-11-19

Applicant: INSERM (Institut National de la Santé et de la Recherche Médicale) ,  Université de Paris ,  Assistance Publique-Hôpitaux de Paris (APHP) ,  Fondation Imagine ,  Université d'Evry-Val-d'Essonne ,  Ecole Pratique des Hautes Etudes ,  Medizinische Hochschule Hannover

Inventor： Isabelle ANDRE ,  Emmanuelle SIX ,  Florence BELLIER ,  Marianne DELVILLE ,  Marina CAVAZZANA ,  Mario AMENDOLA ,  Axel SCHAMBACH

IPC: C12N15/86 ,  C07K14/705 ,  C07K14/47 ,  C12N5/0783 ,  A61K35/17

Abstract: IPEX (Immune dysregulation Polyendocrinopathy X linked) syndrome is a primary immunodeficiency caused by mutations in the gene encoding the transcription factor forkhead box P3 (FOXP3), which leads to the loss of function of thymus-derived CD4+CD25+ regulatory T (tTreg) cells. Preclinical and clinical studies suggest that T cell gene therapy approaches designed to selectively restore the repertoire of Treg cells by transfer of wild type FOXP3 gene is a promising potential cure for IPEX. However, there is still a need for a vector that can be used efficiently for the preparation of said Treg cells. The inventors thus compared 6 different lentiviral constructs according to 4 criteria (vector titers, level of transduction of human CD4+ T cells, level of expression of FOXP3 and ΔLNGFR genes, degree of correlation between both expression) and selected one construct comprising a bidirectional PGK-EF1a promoter that showed remarkable efficiency.

公开(公告)号：US20220380807A1

公开(公告)日：2022-12-01

申请号：US17861676

申请日：2022-07-11

Applicant: INSERM (INSTITUT NATIONAL DE LA SANTÉ ET DE LA RECHERCHE MÉDICALE) ,  UNIVERSITÉ D'EVRY-VAL-D'ESSONNE ,  GENETHON ,  FONDAZIONE ISTITUTO ITALIANO DI TECNOLOGIA ,  FONDAZIONE TELETHON

Inventor： Federico Mingozzi ,  Giuseppe Ronzitti ,  Andrea Contestabile ,  Laura Cancedda

IPC: C12N15/86 ,  A61K45/06 ,  C12N15/113

Abstract: The invention relates to an RNA interference (RNAi) strategy based on the use of artificial microRNA (amiR) to reduce NKCC1 expression. In particular, the invention relates to a vector that achieves neuron-specific expression of specific amiR against NKCC1 by using a human Synapsin promoter to drive transgene expression.

公开(公告)号：US20220280655A1

公开(公告)日：2022-09-08

申请号：US17605524

申请日：2020-04-23

Applicant: INSERM (INSTITUT NATIONAL DE LA SANTÉ ET DE LA RECHERCHE MÉDICALE) ,  Assistance Publique-Hôpitaux de Paris ,  Genethon ,  Sorbonne Université ,  Universite de Paris ,  Université d'Evry-Val-d'Essonne ,  Universite Paris XIII Paris-Nord Villetaneuse

Inventor： Jessica Zucman-Rossi ,  Jean-Charles Nault ,  Tiziana La Bella ,  Giuseppe Ronzitti ,  Sandrine Imbeaud ,  Patrice Vidal

IPC: A61K48/00 ,  C12N7/00 ,  C12N15/86

Abstract: Adeno-associated virus (AAV) is a defective mono-stranded DNA virus, endemic in human population (35-80%). Recurrent clonal AAV2 insertions are associated with the pathogenesis of rare human hepatocellular carcinoma (HCC) developed on normal liver. The aimed of the inventors was to characterize the natural history of AAV infection in the liver. Viral DNA was thus quantified in tumor and non-tumor liver tissues of 1461 patients. Presence of episomal form and viral mRNA expression were analyzed using a DNAse/TaqMan based assay and quantitative RT-PCR. In silico analyses using viral capture data explored viral variants and new clonal insertions. AAV DNA was detected in 21% of the patients equally distributed in 2 major viral subtypes: one similar to AAV2, the other hybrid between AAV2 and AAV13 sequences. Thus the inventors provided an integrated analysis of the wild type AAV infection in the liver with the identification of viral genotypes, molecular forms, helper virus relationship and viral integrations. These findings are important to understand wild type AAV biology and particularly relevant considering the large usage of AAV vector in liver-targeted gene therapy. Thus, the present invention relates to new adeno-associated virus (AAV) variants and uses thereof for gene therapy.

公开(公告)号：US20220160788A1

公开(公告)日：2022-05-26

申请号：US17441466

申请日：2020-03-20

Applicant: INSERM (INSTITUT NATIONAL DE LA SANTÉ ET DE LA RECHERCHE MÉDICALE) ,  UNIVERSITÉ D'EVRY-VAL-D'ESSONNE ,  ASSISTANCE PUBLIQUE-HÔPITAUX DE PARIS (APHP) ,  UNIVERSITÉ DE PARIS ,  FONDATION IMAGINE

Inventor： Annarita MICCIO ,  Mario AMENDOLA ,  Mégane BRUSSON ,  Marina CAVAZZANA ,  Fulvio MAVILIO

IPC: A61K35/545 ,  C12N15/86 ,  C12N15/113 ,  C12N5/0735 ,  A61K35/28 ,  A61K38/17 ,  A61P7/06

Abstract: The #β-hemoglobinopathies #β-thalassemia (BT) and sickle cell disease (SCD) are the most frequent genetic disorders worldwide. These diseases are caused by mutations causing reduced or abnormal synthesis of the β-globin chain of the adult hemoglobin (Hb) tetramer. Here, the inventors intend to improve HSC-based gene therapy for β-thalassemia and SCD by developing an innovative, highly infectious LV vector expressing a potent anti-sickling β-globin transgene and a second biological function either increasing fetal γ-globin expression (for β-thalassemia and SCD). More particularly, the inventors have designed a novel lentivirus (LV), which carry two different functions: βAS3 gene addition and gene silencing. This last strategy allows the re-expression of the fetal γ-globin genes (HBG1 and HBG2) and production of the endogenous fetal hemoglobin (HbF). Elevated levels of HbF and HbAS3 (Hb tetramer containing βAS3-globin) will benefit the β-hemoglobinopathy phenotype by increasing the total amount of β-like globin that will: (i) reduce the alpha precipitates and improve the alpha/non alpha ratio in β-thalassemia, and (ii) reduce the sickling in SCD. This combined strategy will improve the β-hemoglobinopathy phenotype at a lower vector copy number (VCN) per cell compared to a LV expressing the βAS3 alone.

公开(公告)号：US20250020490A1

公开(公告)日：2025-01-16

申请号：US18711493

申请日：2022-11-16

Applicant: UNIVERSITÉ D'EVRY VAL D'ESSONNE

Inventor： Samer ALFAYAD ,  Mohamad KARDOFAKI ,  Maya SLEIMAN ,  Richard ARLOT

IPC: G01D5/245 ,  F15B15/28

Abstract: A cylinder actuator includes two elements mobile one relative to the other along an axis of movement and a position sensor configured to measure the relative position of the two elements, the position sensor comprising a multi-pole magnetic strip secured to a first of the two elements and a sensitive element sensitive to magnetic-field variations and secured to a second of the two elements, the multi-pole magnetic strip having an alternation of north and south poles extending in an interval that defines a measurement range for the measurement of the relative position along the axis of movement, the sensitive element being arranged in such a way as to detect variations in the magnetic field in the vicinity of the multi-pole magnetic strip along the axis of movement within the interval.

公开(公告)号：US20230416675A1

公开(公告)日：2023-12-28

申请号：US18038734

申请日：2020-11-25

Applicant: INSERM (INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE) ,  SORBONNE UNIVERSITE ,  UNIVERSITÉ D'EVRY-VAL-D'ESSONNE ,  CENTRE D'ETUDE DES CELLULES SOUCHES (CECS) ,  UNIVERSITÉ PARIS-SACLAY

Inventor： Stéphane NEDELEC ,  Cécile MARTINAT ,  Vincent MOUILLEAU ,  Célia VASLIN

IPC: C12N5/0793

CPC classification number: C12N5/0619 ,  C12N2506/45 ,  C12N2501/41 ,  C12N2501/19 ,  C12N2501/115 ,  C12N2501/16 ,  C12N2501/119 ,  C12N2501/415

Abstract: The present invention relates to the targeted engineering of specific cell populations. Motoneurons (MN) subtypes display differential vulnerabilities in diseases and in spinal injuries. Engineered MNs of specific rostro-caudal identity represent an important resource for cell therapy approaches. However, these strategies remain impeded by slow and inefficient targeted differentiations due to the imprecise control over cell fate specification in vitro. The inventors now used an embryoid body-based differentiation of hPSC and showed that the HOX clock expression can be controlled to generate subtypes of spinal MNs. Thus, the present invention relates to an in vitro or an ex vivo method for producing spinal neuronal subtypes comprising exposing axial progenitors to retinoic acid (RA), an agonist of Hedgehog signalling pathway, and optionally a FGFR agonist and/or an activator of the TGF pathway, wherein more and more caudal motor neurons identities are obtained by delayed exposure to RA and/or by exposure to RA in combination with the FGFR agonist and/or the activator of the TGF pathway.