JP-2025516226-A5 -

Dates

Publication Date

20260511

Application Date

20230426

Description

The breadth and scope of this disclosure are not limited by any of the exemplary embodiments described above, but are defined solely by the following claims and their equivalents. This disclosure relates, for example, to the following: [1] A method for reducing or avoiding the expression of a heterologous protein in the liver of a subject in need thereof, comprising administering to the subject lipid nanoparticles comprising (i) one or more lipids and (ii) a replicon derived from the Venezuelan encephalitis (VEE) virus ("VEE replicon"), wherein the VEE replicon comprises a nucleic acid sequence encoding the heterologous protein. [2] The method according to [1], wherein reducing the expression means, compared to a reference subject (for example, a subject administered the corresponding lipid nanoparticles but whose replicon is not a VEE replicon), (i) reducing the amount of the heterologous protein expressed in the liver, (ii) reducing the duration of expression of the heterologous protein in the liver, or (iii) the method according to [1], comprising both (i) and (ii). [3] The method according to [2], wherein, after the administration, the amount of the heterologous protein expressed in the liver is reduced by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% compared to that of the reference subject. [4] The method according to [3], wherein, after the administration, the liver does not express the heterologous protein. [5] The method according to [2] or [3], wherein, after the administration, the duration of expression of the heterologous protein in the liver is reduced by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or about 100% compared to that of the reference subject. [6] The method according to any one of the claims [1] to [5], wherein, after the administration, the heterologous protein is expressed in the non-liver tissue of the subject, and the non-liver tissue is selected from the spleen, lung, tumor, or a combination thereof. [7] The method according to [6], wherein, after the administration, the amount of the heterologous protein expressed in the non-liver tissue is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% or more compared to that observed in the reference non-liver tissue. [8] The method according to [6] or [7], wherein, after the administration, the duration of expression of the heterologous protein in the non-liver tissue is at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% compared to that observed in the reference non-liver tissue. [9] A method for selectively expressing a heterologous protein in non-liver tissue in a subject requiring such expression, comprising administering to the subject lipid nanoparticles comprising (i) one or more lipids and (ii) a replicon derived from the Venezuelan encephalitis (VEE) virus ("VEE replicon"), wherein the VEE replicon comprises a nucleic acid sequence encoding the heterologous protein. [10] The method according to [9], wherein the amount of the heterologous protein expressed in the non-liver tissue after the administration is at least about 2 times, at least about 3 times, at least about 4 times, at least about 5 times, at least about 6 times, at least about 7 times, at least about 8 times, at least about 9 times, at least about 10 times, at least about 15 times, at least about 20 times, at least about 25 times, at least about 30 times, at least about 35 times, at least about 40 times, at least about 45 times, or at least about 50 times greater than the corresponding amount observed in the liver of the subject. [11] The method according to [9] or [10], wherein, after the administration, the duration of expression of the heterologous protein in the non-liver tissue is at least about 2 times, at least about 3 times, at least about 4 times, at least about 5 times, at least about 6 times, at least about 7 times, at least about 8 times, at least about 9 times, at least about 10 times, at least about 15 times, at least about 20 times, at least about 25 times, at least about 30 times, at least about 35 times, at least about 40 times, at least about 45 times, or at least about 50 times longer than the corresponding duration observed in the liver of the subject. [12] The method according to any one of the claims [9] to [11], wherein the non-liver tissue includes the spleen, the lungs, or both. [13] A