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).

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 herein are combination therapies involving co-expression of an E2 subunit of a branched-chain alpha-keto acid dehydrogenase (BCKDH) from a skeletal muscle-targeted rAAV.hDBT vector and a liver-targeted rAAV.hDBT vector. Also provided herein are combination therapies wherein an E1a and/or an E1b subunit of the BCKDH complex is expressed from muscle and/or liver following rAAV-mediated delivery targeted to these tissues. Further provided is a pharmaceutical composition comprising a rAAV as described herein in a formulation buffer, and a method of treating a human subject diagnosed with MSUD.

Methods for the treatment and prevention of laminopathies and diseases characterised by hyperlipidemia through LING complex inhibition are disclosed. In particular, LING complex disruption by expression of dominant-negative LING complex proteins alleviates pathophysiology in Lmna mutation-associated muscular dystrophy, progeria, and dilated cardiomyopathy. In addition, LING complex disruption by expression of dominant-negative LING complex proteins also alleviates pathophysiology in mouse models of atherosclerosis and familial hypercholesterolemia.

Disclosed is an erythroid-specific human β-globin gene promoter and a human β-globin-expressing recombinant sequence, and use thereof, which belongs to the technical field of genetic engineering. An erythroid-specific human β-globin gene promoter with a nucleotide sequence set forth in SEQ ID NO: 1 is provided in the present disclosure, which may achieve high-efficiency and erythroid-specific initiation of the expression of a functional gene. A recombinant sequence specifically expressing human β-globin in erythroid cells is also provided in the present disclosure, which is human β-globin locus control region (LCR) HS 3-1+β-globin gene promoter+β-globin gene+β-globin gene enhancer.

Disclosed herein are novel variants of KCVN2 and their use, for example, in methods of treating a subject with a retinal disorder, such as CDSRR.

The present invention provides an isolated nucleic acid molecule comprising, or consisting of, the nucleic acid sequence of SEQ ID NO:1 or a nucleic acid sequence of at least 1000 bp having at least 80% identity to said sequence of SEQ ID NO:1, wherein said isolated nucleic acid molecule specifically leads to the expression in cells of the retinal pigment epithelium of a gene when operatively linked to a nucleic acid sequence coding for said gene.

The present disclosure provides, among other things, a recombinant adeno-associated virus (rAAV) vector comprising an AAV8 capsid and a codon-optimized sequence encoding a human phenylalanine hydroxylase (PAH) enzyme. The disclosure also provides a method of treating a subject having phenylketonuria (PKU), comprising administering to the subject in need thereof a recombinant adeno-associated vims (rAAV) vector comprising an AAV8 capsid, and a promoter operably linked to a nucleic acid sequence that encodes PAH, and wherein administering results in a decrease in phenylalanine level in the subject.

This present disclosure provides adeno-associated viral vectors, recombinant adeno-associated vims (rAAV), and methods of their use in gene therapy for treating CDKL5 deficiency disorder (CDD). Also provided are pharmaceutical compositions comprising an rAAV of the invention and a pharmaceutically acceptable carrier or excipient. These pharmaceutical compositions may be useful in gene therapy for the treatment of CDD caused by mutations in CDKL.

Methods are disclosed for polarizing macrophages to become M2 macrophages. Methods also are disclosed for treating type 1 diabetes in a subject. These methods include administering to the subject a vector comprising a macrophage specific promoter operably linked to a nucleic acid molecule encoding TNF-alpha-induced protein 8-like 2 (TIPE2) protein. In some embodiments, the vector is administered locally to a pancreas of the subject. In further embodiments, compositions are disclosed including a) a vector comprising a macrophage specific promoter operably linked to a nucleic acid molecule encoding TNF-alpha-induced protein 8-like 2 (TIPE2) protein; b) a buffer; and c) a contrast dye for endoscopic retrograde cholangiopancreatography.