公开(公告)号：US20220106592A1

公开(公告)日：2022-04-07

申请号：US17419171

申请日：2019-12-31

Applicant: RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL

Inventor： Scott Quenton Harper ,  Afrooz Rashnonejad

IPC: C12N15/11 ,  C12N9/22 ,  A61K38/46 ,  C12N15/86 ,  A61P21/00 ,  A61K31/713 ,  C12N15/90 ,  A61K31/7105

Abstract: RNA interference-based products and methods for inhibiting the expression of the double homeobox 4 (DUX4) gene on human chromosome 4q35 are disclosed. The disclosure includes the Cas13 protein silencing of RNA, wherein Cas13 is specifically targeted to a DUX4 region of interest using a sequence- specific guide RNA (gRNA). Recombinant adeno-associated viruses of the disclosure deliver DNAs encoding inhibitory gRNAs that are constructed with Cas13 direct repeats to knock down the expression of DUX4. The methods have application in the treatment of muscular dystrophies including, but not limited to, facioscapulohumeral muscular dystrophy (FSHD), and other disorders associated with elevated DUX4 expression, including cancer.

公开(公告)号：US20240285638A1

公开(公告)日：2024-08-29

申请号：US18573684

申请日：2022-06-24

Applicant: RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL

Inventor： Scott Quenton Harper ,  Jocelyn Eidahl ,  Lindsay Wallace ,  Renatta Knox

IPC: A61K31/52 ,  A61K31/192 ,  A61P21/00

CPC classification number: A61K31/52 ,  A61K31/192 ,  A61P21/00

Abstract: Disclosed herein are methods and uses for treating, ameliorating, delaying the progression of, and/or preventing a muscular dystrophy or a cancer including, but not limited to, facioscapulohumeral muscular dystrophy (FSHD) or a sarcoma. More particularly, disclosed herein are methods of using small molecule protein arginine methylation (PRMT) inhibitors, and uses of these inhibitors, for inhibiting methylation of amino acids, e.g., arginine, in the double homeobox 4 (DUX4) protein. Even more particularly, the disclosure provides methods of using such methylation inhibitors or arginine methylation inhibitors for inhibiting methylation of the DUX4 protein resulting in reduced DUX4-activated cell death, including reduced DUX4-activated muscle cell death and/or reduced DUX4 target gene activation. The disclosure provides, in some aspects, methods of using protein methylation inhibitors including, but not limited to salvianolic acid A (SAA), or a derivative thereof, or adenosine dialdehyde (ADOX), or a derivative thereof for inhibiting methylation of arginine residues of the DUX4 protein in cells in vitro, ex vivo, or in vivo in the cells of a subject at risk of or suffering from a muscular dystrophy or a cancer associated with DUX4 overexpression.

公开(公告)号：US11939579B2

公开(公告)日：2024-03-26

申请号：US17729751

申请日：2022-04-26

Applicant: RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL

Inventor： Scott Quenton Harper

IPC: C12N15/63 ,  A61K9/00 ,  A61P21/00 ,  C07H21/02 ,  C12N7/00 ,  C12N15/113 ,  A61K48/00 ,  C12Q1/70

CPC classification number: C12N15/113 ,  A61K9/0019 ,  A61P21/00 ,  C07H21/02 ,  C12N7/00 ,  A61K48/00 ,  C12N2310/141 ,  C12N2320/32 ,  C12N2330/51 ,  C12N2710/10043 ,  C12Q1/70

Abstract: The present invention relates to a tissue-specific promoter system for expressing microRNA (miRNA) for RNA interference-based methods of gene therapy. In these systems, the miRNA will inhibit gene expression or replace natural miRNA expression using microRNA.

公开(公告)号：US11802291B2

公开(公告)日：2023-10-31

申请号：US16299456

申请日：2019-03-12

Applicant: RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL

Inventor： Scott Quenton Harper ,  Jian Liu ,  Sara Coppens ,  Lindsay Wallace

IPC: C12N15/86 ,  C12N15/113 ,  C12N15/09 ,  C12N15/63 ,  C12N15/11

CPC classification number: C12N15/86 ,  C12N15/113 ,  C12N2310/11 ,  C12N2310/141 ,  C12N2320/30 ,  C12N2330/51 ,  C12N2750/00032 ,  C12N2750/14132 ,  C12N2750/14143

Abstract: The present invention relates to RNA interference-based methods for inhibiting the expression of the DUX4 gene, a double homeobox gene on human chromosome 4q35. Recombinant adeno-associated viruses of the invention deliver DNAs encoding microRNAs that knock down the expression of DUX4. The methods have application in the treatment of muscular dystrophies such as facioscapulohumeral muscular dystrophy.

公开(公告)号：US20220333115A1

公开(公告)日：2022-10-20

申请号：US17231963

申请日：2021-04-15

Applicant: RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL ,  THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK

Inventor： Scott Quenton Harper ,  Wayne N. Frankel

IPC: C12N15/113 ,  C12N15/86 ,  A61K31/713

Abstract: RNA interference-based methods and products for inhibiting the expression of pathogenic dynamin-1 variants are provided. Delivery vehicles such as recombinant adeno-associated viruses deliver DNAs encoding RNAs that inhibit the expression of the dynamin-1 variants. The methods treat, for example, developmental and epileptic encephalopathies.

公开(公告)号：US11345913B2

公开(公告)日：2022-05-31

申请号：US16089860

申请日：2017-03-31

Applicant: RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL

Inventor： Scott Quenton Harper

IPC: C12N15/63 ,  C12N15/113 ,  C07H21/02 ,  A61P21/00 ,  A61K9/00 ,  C12N7/00 ,  C12Q1/70 ,  A61K48/00

Abstract: The present invention relates to a tissue-specific promoter system for expressing microRNA (miRNA) for RNA interference-based methods of gene therapy. In these systems, the miRNA will inhibit gene expression or replace natural miRNA expression using microRNA.

公开(公告)号：US20220033823A1

公开(公告)日：2022-02-03

申请号：US17269741

申请日：2019-08-22

Applicant: RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL

Inventor： Nicolas Sebastien Wein ,  Scott Quenton Harper ,  Kelly Reed Clark

IPC: C12N15/113 ,  C12N15/86

Abstract: The present disclosure relates to RNA interference-based methods for inhibiting the expression of the dystrophia myotonia protein kinase (DMPK) gene. Recombinant adeno-associated viruses of the disclosure deliver DNAs encoding inhibitory RNAs that knock down the expression of DMPK or interfere with the expression of the CTG repeat associated with myotonic dystrophy type-1 (DM1). The methods have application in the treatment of myotonic dystrophies, including DM1, and other disorders associated with aberrant DMPK expression.

公开(公告)号：US11180755B2

公开(公告)日：2021-11-23

申请号：US16079426

申请日：2017-02-24

Applicant: RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL

Inventor： Scott Quenton Harper ,  Nicolas Wein

IPC: C12N15/113 ,  C12Q1/68 ,  A61P21/00 ,  C12N15/864

Abstract: The present invention relates to methods for shifting the splicing profile of the DUX4 gene, a double homeobox gene on human chromosome 4q35. Recombinant adeno-associated viruses of the invention deliver DNAs encoding U7-based small nuclear RNAs to induce DUX4 exon-skipping and the expression of shortened forms of DUX4. The methods have application in the treatment of muscular dystrophies such as facioscapulohumeral muscular dystrophy.