专利检索 ap:("INSERM (INSTITUT NATIONAL DE LA SANTÉ ET DE LA RECHERCHE MÉDICALE)" OR "ASSISTANCE PUBLIQUE-HÔPITAUX DE PARIS (APHP)" OR "FONDATION IMAGINE" OR "UNIVERSITÉ PARIS CITÉ") AND inv:"Pascale DE LONLAY-DEBENEY" 第 1 页

1.

发明申请
GENE THERAPY FOR MAPLE SYRUP URINE DISEASE 有权

公开(公告)号：US20230136699A1

公开(公告)日：2023-05-04

申请号：US17904124

申请日：2021-02-26

申请人： INSERM (INSTITUT NATIONAL DE LA SANTÉ ET DE LA RECHERCHE MÉDICALE) , ASSISTANCE PUBLIQUE-HÔPITAUX DE PARIS (APHP) , FONDATION IMAGINE , UNIVERSITÉ PARIS CITÉ

发明人： Manuel SCHIFF , Marina CAVAZZANA , Pascale DE LONLAY-DEBENEY , Marcelo SIMON SOLA , Clément PONTOIZEAU , Chris OTTOLENGHI

IPC分类号： C12N9/02 , C12N15/86 , A61P3/00 , A61P13/00 , A61K38/44

摘要： Maple syrup urine disease (MSUD) is a rare autosomal recessive disease with an incidence that is caused by a defective activity of the branched-chain 2-keto acid dehydrogenase (BCKD) leading to accumulation of branched-chain amino acids (BCAA) leucine, isoleucine, valine and their corresponding alpha-ketoacids (BCKA) in tissues and body fluids. The inventors herein characterized the Bckdha−/− mouse and Bckdhb−/− mouse recapitulating the classical forms of MSUD. As a proof of concept, they developed a (liver-directed) AAV gene therapy based on the transfer of human BCKDHA (hBCKDHA) or BCKDHB (hBCKDHB) mediated by AAV8 during immediate neonatal period in Bckdha−/− or Bckdhb−/− mice. The inventors demonstrated that hBCKDHA gene transfer completely rescued the lethal early-onset phenotype of Bckdha−/− mice allowing long-term survival to age 12 months, at which they were systematically sacrificed, without overt phenotypic abnormalities. They also demonstrated that hBCKDHB gene transfer exhibited similar survival and a normal growth without overt phenotypic abnormalities at age 3 months, with a dramatic improvement of the biochemical phenotype. The present invention relates to a method of treating MSUD by gene therapy.

2.

发明申请
USE OF LOW DOSES OF HYDROXYCHLOROQUINE FOR THE TREATMENT OF LIPIN-1 DEFICIENCY 有权

公开(公告)号：US20230066065A1

公开(公告)日：2023-03-02

申请号：US17797265

申请日：2021-02-04

申请人： Institut National de la Santé et de la Recherche Médicale (INSERM) , Assistance Publique-Hôpitaux de Paris (APHP) , Centre National de la Recherche Scientifque (CNRS) , Fondation Imagine , Université Paris Cité

发明人： Pascale DE LONLAY-DEBENEY , Peter VAN ENDERT , Sebastian MONTEALEGRE , Caroline TUCHMANN-DURAND , Laure CACCAVELLI , Marine MADRANGE , Perrine RENARD

IPC分类号： A61K31/4706 , A61P3/00

摘要： Lipin-1 deficiency is a rare, life-threatening condition that causes severe rhabdomyolysis episodes (RM) triggered by febrile illness and effort. Now, the inventors treated 10 patients with LPIN1 mutations with hydroxychloroquine (HCQ) in an off open-label use phases 1 and 2 study, to assess safety, clinical, and biological effects of the drug. A first inclusion group of patients were treated with oral HCQ at a dose of 6.5 mg/Kg/day in one intake, not exceeding 400 mg/day. Five patients have not presented any new acute RM under treatment, except for 2 patients experimented one and two episodes of RM respectively despite HCQ in a context of gastroenteritis. Plasma levels of HCQ were in the range of 400 ng/ml except in the two patients who experimented RM, in whom the plasma HCQ levels were higher (1000 ng/ml). With a therapeutic adjustment, in order to maintain plasma levels of HCQ under 700 ng/ml, in a new group of patients, two patients did not suffer from new acute RM under treatment. HCQ had not seem to have benefit effect for one patient. Thus, the inventors describe the first human experience with HCQ for Lipin-1 disease. The results allow the inventors to propose low doses of HCQ as a long-term treatment to prevent further relapses in this severe disease.

3.

发明申请
METHODS FOR DETERMINING WHETHER A PATIENT SUFFERING FROM RHABDOMYOLYSIS ACHIEVES A RESPONSE WITH A TLR9 ANTAGONIST 有权

公开(公告)号：US20210087633A1

公开(公告)日：2021-03-25

申请号：US16633912

申请日：2018-07-26

申请人： INSERM (INSTITUTE NATIONAL DE LA SANTÉ ET DE LA RECHERCHE MÉDICALE) , FONDATION IMAGINE , UNIVERSITÉ DE PARIS , ASSISTANCE PUBLIQUE-HÔPITAUX DE PARIS (APHP) , CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE (CNRS)

发明人： Pascale DE LONLAY-DEBENEY , Peter VAN ENDERT , Marine MADRANGE , Yamina HAMEL , François-Xavier MAUVAIS

IPC分类号： C12Q1/6883 , C12Q1/686

摘要： The inventors initially participated to the identification of LPIN1 mutations as a cause for massive rhabdomyolysis episodes in children, triggered by febrile illness. The inventors have suggested that TLR9 antagonists would be suitable for the treatment of rhabdomyolysis (WO2017085115). The inventors thus treated 2 patients with lipin-1 disease by a TRL9 antagonist (hydroxychloroquine). They showed that the accumulation of mtDNA in plasma of the two patients before treatment decreases under treatment. When the treatment was stopped, the accumulation of mtDNA reappeared, then normalized when treatment was resumed. Accordingly, the present invention relates to a method for determining whether a patient suffering from rhabdomyolysis achieves a response with a TLR9 antagonist comprising determining the amount of mitochondrial DNA (mtDNA) in a blood sample obtained from the patient (e.g. by PCR).