公开(公告)号：US20250073353A1

公开(公告)日：2025-03-06

申请号：US18803700

申请日：2024-08-13

Applicant: SPARK THERAPEUTICS, INC.

Inventor： Xavier ANGUELA

IPC: A61K48/00 ,  A61K9/51 ,  A61K38/37 ,  A61P7/02 ,  C12N15/86

Abstract: Methods of using vectors comprising nucleic acid and nucleic acid variants encoding FVIII protein are disclosed. In particular embodiments, a method of treating a human having hemophilia A includes administering a recombinant adeno-associated virus (rAAV) vector comprising a nucleic acid encoding Factor VIII (FVIII) or nucleic acid variant encoding Factor VIII (FVIII) having a B domain deletion (hFVIII-BDD). In some aspects, a nucleic acid variant has 95% or greater identity to SEQ ID NO:7 and/or a nucleic acid variant has no more than 2 cytosine-guanine dinucleotides (CpGs). In other aspects, a rAAV vector is administered to the human at a dose of less than about 6×1012 vector genomes per kilogram (vg/kg).

公开(公告)号：US20210371877A1

公开(公告)日：2021-12-02

申请号：US15733246

申请日：2018-12-18

Applicant: SPARK THERAPEUTICS, INC.

Inventor： Andrew William SHAW ,  Xavier ANGUELA

IPC: C12N15/86 ,  A61K9/08 ,  A61K9/107 ,  A61K9/51 ,  C12N15/88

Abstract: A composition includes an adeno-associated vims (AAV) vector in a lipid nanoparticle (LNP). The AAV vector can include a heterologous nucleic acid sequence, optionally an inverted terminal repeat (ITR) positioned 5′ of the heterologous nucleic acid sequence and an ITR positioned 3′ of the heterologous nucleic acid sequence. The AAV vector can further include expression control elements (e.g., a promoter and/or enhancer), and intron, and/or or a polyadenylation signal.

公开(公告)号：US20210363192A1

公开(公告)日：2021-11-25

申请号：US17050362

申请日：2019-04-26

Applicant: SPARK THERAPEUTICS, INC.

Inventor： Xavier ANGUELA ,  Sean ARMOUR ,  Nicholas KEISER ,  Suryanarayan SOMANATHAN ,  Mustafa N. YAZICIOGLU

IPC: C07K14/005 ,  C12N7/00 ,  C12N15/86 ,  C12N15/113

Abstract: The invention provides modified adeno-associated virus (AAV) capsid proteins. Modified AAV capsid proteins include, for example, capsid proteins modified to have a peptide insertion comprising a nuclear localization signal (NLS) sequence, capsid proteins modified to have an amino acid substitution at an RXXL site or a (L/P)PXY site, where X can be any amino acid, and capsid proteins modified to have one or more particular amino acid positions substituted with a different amino acid.

公开(公告)号：US20200237930A1

公开(公告)日：2020-07-30

申请号：US16635957

申请日：2018-08-01

Applicant: SPARK THERAPEUTICS, INC.

Inventor： Xavier ANGUELA

IPC: A61K48/00 ,  A61K38/37 ,  C12N15/86 ,  A61K9/51 ,  A61P7/02

Abstract: Methods of using vvectors comprising nucleic acid and nucleic acid variants encoding FVIII protein are disclosed. In particular embodiments, a method of treating a human having hemophilia A includes administering a recombinant adeno-associated virus (rAAV) vector comprising a nucleic acid encoding Factor VIII (FVIII) or nucleic acid variant encoding Factor VIII (FVIII) having a B domain deletion (hFVIII-BDD). In some aspects, a nucleic acid variant has 95% or greater identity to SEQ ID NO:7 and/or a nucleic acid variant has no more than 2 cytosine-guanine dinucleotides (CpGs). In other aspects, a rAAV vector is administered to the human at a dose of less than about 6×1012 vector genomes per kilogram (vg/kg).

公开(公告)号：US20180312571A1

公开(公告)日：2018-11-01

申请号：US15772025

申请日：2016-10-31

Applicant: SPARK THERAPEUTICS, INC.

Inventor： Xavier ANGUELA ,  Sam Hsien-i SHEN

IPC: C07K14/755 ,  C12N15/86 ,  A61K38/37 ,  A61K45/06

CPC classification number: A61K38/37 ,  A61K45/06 ,  A61K48/0066 ,  C07K14/755 ,  C12N7/00 ,  C12N15/86 ,  C12N2710/10342 ,  C12N2710/10343 ,  C12N2750/14122 ,  C12N2750/14143 ,  C12N2750/14145

Abstract: CpG reduced nucleic acid variants encoding FVIII protein and methods of use thereof are disclosed. In particular embodiments, CpG reduced nucleic acid variants encoding FVIII are expressed more efficiently by cells, are secreted at increased levels by cells over wild-type Factor VIII proteins, exhibit enhanced expression and/or activity over wild-type Factor VIII proteins or are packaged more efficiently into viral vectors.

公开(公告)号：US20170216408A1

公开(公告)日：2017-08-03

申请号：US15462660

申请日：2017-03-17

Applicant: SPARK THERAPEUTICS, INC.

Inventor： Xavier ANGUELA ,  Sam Hsien-I SHEN

IPC: A61K38/37 ,  A61K45/06 ,  C07K14/755 ,  A61K48/00 ,  C12N15/86 ,  C12N7/00

CPC classification number: C07K14/755 ,  A61K38/37 ,  A61K45/06 ,  A61K48/00 ,  A61K48/0066 ,  C12N7/00 ,  C12N15/86 ,  C12N2710/10342 ,  C12N2710/10343 ,  C12N2750/14122 ,  C12N2750/14143 ,  C12N2750/14145

Abstract: CpG reduced nucleic acid variants encoding FVIII protein and methods of use thereof are disclosed. In particular embodiments, CpG reduced nucleic acid variants encoding FVIII are expressed more efficiently by cells, are secreted at increased levels by cells over wild-type Factor VIII proteins, exhibit enhanced expression and/or activity over wild-type Factor VIII proteins or are packaged more efficiently into viral vectors.

公开(公告)号：US20220362408A1

公开(公告)日：2022-11-17

申请号：US17250712

申请日：2019-08-23

Applicant: SPARK THERAPEUTICS, INC.

Inventor： Xavier ANGUELA ,  Liron ELKOUBY

IPC: A61K48/00 ,  C07K14/755 ,  C12N15/86 ,  C12N7/00 ,  C07K14/775 ,  A61P7/04 ,  A61K9/00 ,  C07K14/81

Abstract: The invention provides expression cassettes. In certain embodiments, an expression cassette comprises (a) a regulatory element at least 90% identical to the sequence of any of SEQ ID NOs:2-67, and (b) a nucleic acid sequence encoding a Factor VIII protein having a B domain deletion (FVIII-BDD), where the nucleic acid sequence of (a) is at least 90% identical to the sequence of SEQ ID NO:77, where the regulatory element is operably linked to the nucleic acid sequence, and where no intron is present between the regulatory element and the nucleic acid sequence encoding FVIII-BDD, or where no more than 0-107 nucleotides of untranslated nucleic acid is between the regulatory element and the nucleic acid sequence encoding FVIII-BDD. In certain embodiments, expression cassettes contain sequence elements having CpG(s) substituted with CpT, CpA, TpG, or ApG at the same position(s) or has CpG reduced nucleic acid sequences.

公开(公告)号：US20220011308A1

公开(公告)日：2022-01-13

申请号：US17309261

申请日：2019-11-15

Applicant: SPARK THERAPEUTICS, INC.

Inventor： Klaudia KURANDA ,  Xavier ANGUELA ,  Federico MINGOZZI

IPC: G01N33/569 ,  G06F17/18

Abstract: Disclosed herein are methods for analyzing for or detecting the presence of non-antibody inhibitors and/or enhancers of adeno-associated virus (AAV) vector cell transduction in a biological sample from a subject. Also disclosed herein are methods for analyzing for, or detecting the presence of, AAV binding antibodies that inhibit, reduce or decrease AAV vector cell transduction in a biological sample from a subject. The methods rely, in part, on the use of empty capsid AAV particles to absorb AAV binding antibodies, to detect enhancers or inhibitors of AAV vector cell transduction, when present, in a biological sample analyzed for AAV neutralizing antibodies (NAbs).

公开(公告)号：US20210222141A1

公开(公告)日：2021-07-22

申请号：US17055523

申请日：2019-05-15

Applicant: SPARK THERAPEUTICS, INC.

Inventor： Xavier ANGUELA ,  Sean ARMOUR ,  Jayme NORDIN

IPC: C12N9/26 ,  C12N15/86 ,  A61K48/00

Abstract: The invention provides nucleic acids encoding acid a-glucosidase (GAA). In certain embodiments, nucleic acids have greater than about 86% sequence identity to a sequence selected from the group consisting of any of the sequences set forth as SEQ ID NOs:1-5. In certain embodiments, nucleic acids encoding acid a-glucosidase (GAA) contain less than 127 CpG dinucleotides. Expression cassettes, vectors, cells and cell lines and methods of using such nucleic acids encoding acid a-glucosidase (GAA) are also provided.