The present invention features a dual vector system for disrupting and replacing a target gene comprising a mutation (e.g., dominant, recessive mutation). Embodiments of the invention may also provide compositions comprising the dual vector system, and methods of using the dual vector system, including but not limited to methods of modifying the genome of a cell, methods of genomic editing, and methods of treating cells or a subject suffering from a genetic disease comprising a mutation.

Provided herein are compositions that include at least two different nucleic acid vectors, where each of the at least two different vectors includes a coding sequence that encodes a different portion of an otoferlin protein, and the use of these compositions to treat hearing loss in a subject.

A vector system for expressing a transgene in a cell, the vector system comprising a first vector and a second vector, wherein: (a) the first vector comprises in a 5′ to 3′ direction: a promoter; an intron; a 5′ end portion of the transgene coding sequence (CDS); a splice donor sequence; and a first recombinogenic region; (b) the second vector comprises in a 5′ to 3′ direction: a second recombinogenic region; a splice acceptor sequence; and a 3′ end portion of the transgene CDS; wherein the 5′ end portion and the 3′ end portion together constitute the transgene CDS, and wherein the intron is not capable of homologous recombination with the splice donor sequence to excise the 5′ end portion of the transgene CDS.

The present invention relates to the field of recombinant viral vectors suitable for the delivery of therapeutic genes in vivo. Described is an adeno-associated virus (AAV) vector comprising (i) a human growth hormone intron 3 (hGHi3) sequence (ii) a synapsin promoter sequence and/or (iii) a progranulin 3′ untranslated region (UTR) sequence, operably coupled to a polynucleotide sequence encoding a polypeptide of interest. Specific use of such a vector lies in the enhanced expression of a polypeptide of interest, such as progranulin (PGRN), to treat subjects who have a genetic mutation or intrinsic polypeptide level that is below a physiologically normal level.

Provided herein are compositions and methods of using a bicistronic vector for treating or preventing a lysosomal storage disorder (LSD) in a subject. The disclosed compositions comprise a bicistronic vector comprising a promoter, an Internal Ribosome Entry Site (IRES), a polynucleotide encoding a lysosomal enzyme and a polynucleotide encoding a modified GlcNAc-1 phosphotransferase (GlcNAc-1 PTase). The present methods comprise administering to the subject a pharmaceutical composition comprising the bicistronic vector as disclosed herein.

Provided herein are methods and agents for modulating the signaling pathway and components thereof that are responsible for assembly and disassembly of synapses in neurons, including amyloid beta (Aβ) mediated synaptotoxicity and synapse loss. Also provided herein are methods for screening and identifying candidate agents capable of modulating synapse formation and (Aβ) mediated synaptotoxicity.

The object of the present invention is to provide a polynucleotide which can be inserted into an expression vector and can enhance the transcriptional activity of a predetermined promoter under heart failure.

The object is achieved by an enhancer polynucleotide comprising a polynucleotide consisting of a sequence having 80% or more identity with a sequence represented by SEQ ID NO: 1, or a polynucleotide consisting of a sequence having 80% or more identity with a sequence represented by SEQ ID NO: 2, wherein the enhancer polynucleotide responds to heart failure (where the enhancer polynucleotide excludes a polynucleotide having the same sequence as a sequence represented by SEQ ID NO: 13 and a polynucleotide having the same sequence as a sequence represented by SEQ ID NO: 12).

Described herein are methods of prolonging or reactivating organogenesis in a subject in need thereof (e.g., a subject that has impaired organ function such as a prematurely born infant). The methods comprise increasing the expression or activity of Lin28A or Lin28B proteins, inhibiting the expression or activity of let-7 family microRNAs, and/or inhibiting the expression or activity of Dis3L2 exonuclease.

The present invention concerns an expression system for systemic administration comprising a sequence encoding a FKRP protein, and: —a promoter sequence allowing the expression at a therapeutically acceptable level of FKRP in the skeletal muscles and a target sequence of an miRNA expressed in the heart; or—a promoter sequence allowing the expression at a therapeutically acceptable level of FKRP in the skeletal muscles and presenting a promoter activity at a toxically acceptable level in the heart; and its use for the treatment of various diseases linked to FKRP deficiencies.

Provided is a method for preparing a diabetic dog model by means of gene editing technology, a diabetic dog model prepared therefrom, as well as cells and issues thereof. The method comprises the following steps: (1) obtaining a dog fertilized egg cell, which comprises a point mutation in GCK gene, for a diabetic dog model by means of gene editing; and (2) transplanting the dog fertilized egg cell into one fallopian tube of a female dog, in which both fallopian tubes have been flushed, to prepare a diabetic dog model comprising a point mutation in GCK gene.