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AssigneeAgency for Science, Technology and Research
InventorsColin Lawson Stewart, Jinfen Chai, Yin Loon Lee, Brian Edmund Burke
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The present invention relates to use of expression vectors and other compounds in methods to disrupt the LInker of Nucleoskeleton and Cytoskeleton (LINC) complex, uncoupling the nucleus from its linkage to the cytoskeleton, resulting in amelioration of diseases caused by one or more Lmna mutations, so-called laminopathies. More particularly, the invention relates to the expression of dominant negative SUN domain protein and/or dominant negative KASH domain protein to disrupt, for example, the LINC complex in cardiomyocytes for suppressing disease progression in dilated cardiomyopathy (DCM).
A(n) isolated nucleic acid molecule, wherein the nucleic acid molecule comprises an expression vector and a transgene, whereby the transgene is operably linked to the expression vector, wherein expression of the transgene in a transfected cell results in disruption of a LInker of Nucleoskeleton and Cytoskeleton (LINC) complex in the transfected cell.
The nucleic acid molecule of any one of the preceding claims, wherein the expression vector is a virus expression vector.
The nucleic acid molecule of any one of the preceding claims, wherein the adeno-associated virus expression vector (AAV) has cardiac tropism/is cardiotropic.
The nucleic acid molecule of any one of the preceding claims, wherein in the AAV vector is selected from the group consisting of AAV9 (serotype 9), AAV1 (serotype 1), AAV6 (serotype 6), AAV8 (serotype 8), AAV28, and AAV9.45.
The nucleic acid molecule of any one of the preceding claims, wherein in the AAV vector is AAV9 (serotype 9).
The nucleic acid molecule of any one of the preceding claims, wherein transgene comprises nucleic acid sequences for expressing a lumenal domain of a SUN domain-containing protein, an N-terminal signal sequence, a signal peptidase cleavage site, and a C-terminal targeting peptide sequence.
The nucleic acid molecule of any one of the preceding claims, wherein the transgene further comprises nucleic acid sequences for expressing an N-terminal signal sequence, a signal peptidase cleavage site, and a C-terminal targeting peptide sequence.
The nucleic acid molecule of any one of the preceding claims, wherein the transgene comprises nucleic acid sequences for expressing an N-terminal signal sequence, a signal peptidase cleavage site, and a C-terminal targeting peptide sequence, and either the luminal domain of the SUN domain-containing protein or the SUN domain.
The nucleic acid molecule of any one of the preceding claims, wherein the transgene is a humanised or human transgene.
The nucleic acid molecule of any one of the preceding claims, wherein expression of the transgene results in the disruption of the protein-protein interaction between SUN and KASH of the LINC complex.
The nucleic acid molecule of any one of the preceding claims, wherein the AAV vector is formulated for delivery into the myocardium of a subject.
The nucleic acid molecule of any one of the preceding claims for use in treating a disease caused by one or more Lmna mutations in a subject.
The nucleic acid molecule of any one of the preceding claims for use in treating cardiovascular disease in a subject.
A method of screening for drug candidates capable of inhibiting the interaction of the proteins of a LINC complex in a cell, which comprises:
Dependencies are inferred from the claim text.