University of Pennsylvania

University of Massachusetts

The General Hospital Corporation

Massachusetts Eye and Ear Infirmary

Sichuan University

The Clinic for Special Children

Adrenas Therapeutics, Inc.

Columbia University

Guangping Gao

James M Wilson

Mauricio R Alvira

Jun Xie

Phillip D Zamore

Luc H Vandenberghe

Terence Flotte

Luk H Vandenberghe

Dan Wang

Michael R Green

Phillip Tai

Soumitra Roy

Sanchita Bhatnagar

Manas Kumar Santra

Zuoshang Xu

Hemant Khanna

Hongwei Zhang

Hongyan Wang

Yi Lu

Jianzhong Ai

Qiang Zheng

Jung Min Kim

Li Zhong

Dominic Gessler

Patricia K Donahoe

Robert H Brown, Jr

Yuquan Wei

Demetrios Vavvas

Miguel Sena Esteves

Xun Xu

David Pepin

Mien Van Hoang

Shaoyong Li

Umrao Monani

Hong Li

Qiang Wei

Guangchao Xu

Li Luo

Wei Zhan

Xu Xun

Manish Muhuri

Sachin Chaugule

Jae-Hyuck Shim

Yeon-Suk Yang

Tessa Mercedes Simone

Jiaming Wang

Elisabet C Mandon

Gyongyi Szabo

Kevin A Strauss

Pierre Bougneres

Abhishek Satishchandran

Jaime Antonio Rivera-Perez

Darryl De Vivo

Kristin Engelstad

James N Wilson

Plillip D Zamore

Michael Green

Mauricio 4417 Pine Street Alvira

Aspects of the disclosure relate to compositions and methods useful for treating ocular ciliopathies, for example Leber congenital amaurosis (LCA). In some embodiments, the disclosure provides isolated nucleic acids comprising a transgene encoding a CEP290 protein fragment, and methods of treating ocular ciliopathies using the same.

Minigene therapy

In some aspects the disclosure provides compositions and methods for promoting expression of functional BCKDHA protein, which is the E1-alpha subunit of the branched-chain alpha-keto acid (BCAA) dehydrogenase complex, in a subject. In some aspects the disclosure provides compositions and methods for promoting expression of functional BCKDHB protein, which is the E1-beta subunit of the branched-chain alpha-keto acid (BCAA) dehydrogenase complex, in a subject. In some aspects the disclosure provides compositions and methods for promoting expression of functional BCKDHA and BCKDHB proteins, in a subject. In some embodiments, the disclosure provides methods of treating a subject having Maple Syrup Urine Disease (MSUD).

AAV-mediated gene therapy for maple syrup urine disease (MSUD)

In some aspects the disclosure relates to recombinant adeno-associated virus (rAAV) vectors and rAAVs (e.g., viral particles) engineered to express a transgene comprising an inhibitory nucleic acid (e.g., an artificial miRNA, amiRNA) having a pri-miRNA scaffold and a guide strand that targets a human target gene.

Modified AAV constructs and uses thereof

In some aspects, the disclosure relates to methods for improving titer and yield of viral vector production. In some embodiments, the methods comprise transient silencing of transgene expression during packaging of a viral vector.

Viral vector production

Disclosed herein are recombinant adeno-associated viral vectors expressing 21-hydroxylase (21OH) protein and related uses for treating 21OH deficiency.

Adeno-associated virus gene therapy for 21-hydroxylase deficiency

In some aspects, the disclosure relates to compositions and methods for modulating (e.g., increasing and/or decreasing) bone mass in a subject. In some aspects, the disclosure provides isolated nucleic acids, and vectors such as rAAV vectors, configured to express transgenes that promote (e.g., increase) or inhibit (e.g., decrease) activity, differentiation, or function of certain types of bone cells, for example osteoblasts, osteoclasts, osteocytes, etc. In some embodiments, the isolated nucleic acids and vectors described by the disclosure are useful for treating disorders and conditions associated with increased bone mass (e.g., osteopetrosis) or decreased bone mass (e.g., osteoporosis).

Gene therapeutics for treating bone disorders

The present disclosure relates to the field of rAAV delivery of transgenes. In some aspects, the disclosure relates to RNAi. Provided herein are recombinant adeno-associated virus (rAAV) vectors comprising modified ITRs. In some embodiments, the modified ITRs comprise a sequence encoding a shRNA, miRNA, or AmiRNA.

In some aspects, the disclosure provides recombinant AAV and nucleic acid constructs having novel inverted terminal repeats (ITRs), cap, and/or rep genes. In some aspects, the disclosure relates to gene transfer methods using rAAVs described herein.

Use of inverted terminal repeats (ITRS) from adeno-associated virus serotypes 8 and RH.39 in gene therapy vectors

The disclosure in some aspects relates to recombinant adeno-associated viruses having nuclease grafted to one or more capsid proteins. In some aspects, the disclosure relates to isolated AA V capsid proteins having terminally grafted nucleases and isolated nucleic acids encoding the same. Recent approaches to delivering nucleases to cells for gene editing have focused on delivering of expression vectors engineered to express the nucleases in target cells. However, these approaches have proved to be problematic in many instances due to genotoxicity resulting from to prolonged expression of gene editing system in vivo. To prevent such off-target genotoxicity due to prolonged presence of a gene editing system, several studies explored delivery of mRNA or protein instead of delivering the gene coding for the nucleases in cell culture.

Compositions and methods for transient delivery of nucleases

The disclosure, in some aspects, relates to methods and compositions for recombinant adeno-associated virus (rAAV)-mediated delivery of genome editing molecules to a pre-implantation embryo.

Recombinant adeno-associated viruses for delivering gene editing molecules to embryonic cells

The disclosure relates, in some aspects, to compositions and methods for treating corneal disease (e.g., corneal neovascularization. In some embodiments, the disclosure relates to rAAV-mediated delivery of an cornea-associated transgene to a subject. In some embodiments, the rAAV transduces the corneal tissue of a subject.

Anti-angiogenic miRNA therapeutics for inhibiting corneal neovascularization

The invention in some aspects relates to recombinant adeno-associated viruses having distinct tissue targeting capabilities. In some aspects, the invention relates to gene transfer methods using the recombinant adeno-associate viruses. In some aspects, the invention relates to isolated AAV capsid proteins and isolated nucleic acids encoding the same.

AAV's and uses thereof

The invention in some aspects relates to isolated nucleic acids, compositions, and kits useful for identifying adeno-associated viruses in cells. In some aspects, the invention provides kits and methods for producing somatic transgenic animal models using recombinant AAV (rAAV) to an animal having at least one transgene that expresses a small interfering nucleic acid or at least one binding site for a miRNA.

Isolation of novel AAV's and uses thereof

The disclosure in some aspects relates to methods and compositions for repairing mutations (e.g., compound heterozygous mutations) that are widely found in patients having certain diseases (e.g., monogenic recessive diseases). In some aspects, the disclosure provides a method for targeted allelic exchange using recombinant gene editing complex.

Repairing compound heterozygous recessive mutations by allele exchange

Growing community of inventors

Westborough, MA, United States of America

Guangping Gao