Claims for Patent: RE48267

Summary for Patent: RE48267

Title:	Variants of C-type natriuretic peptide
Abstract:	The present disclosure provides variants of C-type natriuretic peptide (CNP), pharmaceutical compositions comprising CNP variants, and methods of making CNP variants. The CNP variants are useful as therapeutic agents for the treatment of diseases responsive to CNP, including but not limited to bone-related disorders, such as skeletal dysplasias (e.g., achondroplasia), and vascular smooth muscle disorders (e.g., restenosis and arteriosclerosis).
Inventor(s):	Wendt; Daniel J. (Novato, CA), Long; Shinong (Novato, CA), Castillo; Sianna (Novato, CA), Price; Christopher P. (Munich, DE), Aoyagi-Scharber; Mika (Novato, CA), Vellard; Michel Claude (Novato, CA), Okhamafe; Augustus O. (Concord, CA)
Assignee:	BioMarin Pharmaceutical Inc. (Novato, CA)
Application Number:	15/646,822
Patent Claims:	1. A variant of C-type natriuretic peptide (CNP) selected from the group consisting of: TABLE-US-00045 (SEQ ID NO: 179) GDLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMS GLGC (Gly-CNP53); (SEQ ID NO: 185) PDLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMS GLGC (Pro-CNP53); (SEQ ID NO: 190) MDLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMS GLGC (Met-CNP53) (SEQ ID NO: 180) DLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSNS GLGC [CNP-53(M48N)]. .]. .[.2. A pharmaceutical composition comprising a CNP variant of claim 1, and a pharmaceutically acceptable excipient, carrier or diluent..]. .[.3. The composition of claim 2, which is a lyophilized formulation prepared from a formulation that comprises a citric acid/citrate buffer or an acetic acid/acetate buffer having a pH from about 4 to about 6..]. .[.4. The composition of claim 3, wherein the lyophilized formulation is prepared from a formulation that further comprises (a) an isotonicity-adjusting agent or a bulking agent or (b) an antioxidant..]. .[.5. A method of treating a bone-related disorder or skeletal dysplasia, comprising administering a CNP variant to a subject in need thereof, wherein the CNP variant is a CNP variant according to claim 1, and wherein the bone-related disorder or skeletal dysplasia is selected from the group consisting of achondroplasia, hypochondroplasia, short stature, dwarfism and homozygous achondroplasia..]. .[.6. A method for recombinant production of a CNP variant, comprising culturing in a medium a host cell comprising a first polynucleotide encoding a CNP variant polypeptide linked to a second polynucleotide encoding a cleavable peptide or protein under conditions that result in expression of a fusion polypeptide encoded by the polynucleotides, wherein the fusion polypeptide comprises the CNP variant polypeptide directly linked to the cleavable peptide or protein or indirectly linked thereto via a linker, herein the CNP variant is selected from the group consisting of: TABLE-US-00046 (SEQ ID NO: 179) GDLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMS GLGC (Gly-CNP53); (SEQ ID NO: 185) PDLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMS GLGC (Pro-CNP53); (SEQ ID NO: 190) MDLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMS GLGC (Met-CNP53); (SEQ ID NO: 180) DLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSNS GLGC [CNP-53(M48N)]. .]. .[.7. The method of claim 6, wherein the cleavable peptide or protein is selected from the group consisting of histidine tags, human transcription factor TAF12, TAF12 fragments, TAF12 histone fold domain, mutants of TAF12 and fragments thereof, TAF12(C/A), TAF12(D/E), TAF12(4D/4E), TAF12 (6D/6E), TAF12(10D/10E), TAF12(C/A & D/E), TAF12 (C/A & 4D/4E), TAF12(C/A & 6D/6E), TAF12(C/A & 10D/10E), ketosteroid isomerase, maltose-binding protein, .beta.-galactosidase, glutathione-S-transferase, thioredoxin, chitin-binding domain, BMP-2, BMP-2 mutants, BMP-2(C/A), and mutants and fragments thereof..]. .[.8. The method of claim 6, wherein the host cell is bacterial..]. .[.9. The method of claim 6, wherein the fusion polypeptide is expressed as a soluble protein or as an inclusion body..]. .[.10. The method of claim 6, further comprising isolating the expressed fusion polypeptide from the host cell or culture medium..]. .[.11. The method of claim 10, further comprising contacting the isolated fusion polypeptide with a cleaving agent selected from the group consisting of formic acid, cyanogen bromide (CNBr), hydroxylamine, protein self cleavage, Factor Xa, enterokinase, ProTEV, and SUMO protease..]. .[.12. A CNP variant produced according to the method of claim 6, wherein the CNP variant is selected from the group consisting of: TABLE-US-00047 (SEQ ID NO: 179) GDLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMS GLGC (G1y-CNP53)); (SEQ ID NO: 185) PDLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMS GLGC (Pro-CNP53)); (SEQ ID NO: 190) MDLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMS GLGC (Met-CNP53)); (SEQ ID NO: 180) DLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSG LGC [CNP-53(M48N)]). .]. .[.13. A method of increasing long bone growth, comprising administering a CNP variant according to claim 1 to a subject in need thereof, where the administration increases long bone growth..]. .[.14. A CNP variant according to claim 1 useful for increasing long bone growth or treating achondroplasia, hypochondroplasia, short stature, dwarfism, or homozygous achondroplasia in a subject in need thereof..]. .Iadd.15. A macromolecule capable of releasing a CNP variant comprising a synthetic polymeric group coupled to the CNP variant through a hydrolysable linkage, wherein the CNP variant is selected from the group consisting of: TABLE-US-00048 (SEQ ID NO: 145) PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Pro-Gly-CNP37); (SEQ ID NO: 158) RLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-40); (SEQ ID NO: 159) LLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-39); (SEQ ID NO: 160) LQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-38); (SEQ ID NO: 60) QEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-37); (SEQ ID NO: 161) EHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-36); (SEQ ID NO: 162) HPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-35); (SEQ ID NO: 163) PNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-34); (SEQ ID NO: 164) NARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-33); (SEQ ID NO: 165) ARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-32); (SEQ ID NO: 166) RKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-31); (SEQ ID NO: 167) KYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-30); (SEQ ID NO: 182) QEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC [CNP37(M32N)]; (SEQ ID NO: 186) PQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Pro-CNP37); (SEQ ID NO: 192) MQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Met-CNP37); (SEQ ID NO: 75) GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Gly-CNP37); (SEQ ID NO: 181) GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC [Gly-CNP37(M32N)]; (SEQ ID NO: 191) MGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Met-Gly-CNP37); (SEQ ID NO: 144) GHKSEVAHRFKGANKKGLSKGCFGLKLDRIGSMSGLGC (HSA-CNP27); (SEQ ID NO: 36) GANRRGLSRGCFGLKLDRIGSMSGLGC [CNP27(K4,5,9R)]; (SEQ ID NO: 36) PEGIK-GANRRGLSRGCFGLKLDRIGSMSGLGC [PEG1K-CNP27(K4,5,9R)]; (SEQ ID NO: 36) PE012-GANRRGLSRGCFGLKLDRIGSMSGLGC [PEO12-CNP27(K4,5,9R)]; and (SEQ ID NO: 36) PEO24-GANRRGLSRGCFGLKLDRIGSMSGLGC [PEO24-CNP27(K4,5,9R)], and wherein hydrolysis of the hydrolysable linkage releases the CNP variant. .Iaddend. .Iadd.16. The macromolecule of claim 15, wherein the synthetic polymeric group comprises a hydrophilic polymeric moiety. .Iaddend. .Iadd.17. The macromolecule of claim 16, wherein the hydrophilic polymeric moiety comprises polyethylene glycol (PEG). .Iaddend. .Iadd.18. A sustained release CNP variant formulation comprising a synthetic polymeric group coupled to the CNP variant through a hydrolysable linkage, wherein the CNP variant is selected from the group consisting of: TABLE-US-00049 (SEQ ID NO: 145) PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Pro-Gly-CNP37); (SEQ ID NO: 158) RLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-40); (SEQ ID NO: 159) LLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-39); (SEQ ID NO: 160) LQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-38); (SEQ ID NO: 60) QEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-37); (SEQ ID NO: 161) EHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-36); (SEQ ID NO: 162) HPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-35); (SEQ ID NO: 163) PNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-34); (SEQ ID NO: 164) NARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-33); (SEQ ID NO: 165) ARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-32); (SEQ ID NO: 166) RKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-31); (SEQ ID NO: 167) KYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-30); (SEQ ID NO: 182) QEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC [CNP37(M32N)]; (SEQ ID NO: 186) PQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Pro-CNP37); (SEQ ID NO: 192) MQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Met-CNP37); (SEQ ID NO: 75) GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Gly-CNP37); (SEQ ID NO: 181) GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC [Gly-CNP37(M32N)]; (SEQ ID NO: 191) MGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Met-Gly-CNP37); (SEQ ID NO: 144) GHKSEVAHRFKGANKKGLSKGCFGLKLDRIGSMSGLGC (HSA-CNP27); (SEQ ID NO: 36) GANRRGLSRGCFGLKLDRIGSMSGLGC [CNP27(K4,5,9R)]; (SEQ ID NO: 36) PEGIK-GANRRGLSRGCFGLKLDRIGSMSGLGC [PEG1K-CNP27(K4,5,9R)]; (SEQ ID NO: 36) PE012-GANRRGLSRGCFGLKLDRIGSMSGLGC [PEO12-CNP27(K4,5,9R)]; and (SEQ ID NO: 36) PEO24-GANRRGLSRGCFGLKLDRIGSMSGLGC [PEO24-CNP27(K4,5,9R)]. .Iaddend. .Iadd.19. The sustained release formulation of claim 18, wherein the synthetic polymeric group comprises a hydrophilic polymeric moiety. .Iaddend. .Iadd.20. The sustained release formulation of claim 19, wherein the hydrophilic polymeric moiety comprises polyethylene glycol (PEG)..Iaddend. .Iadd.21. A method of stimulating cGMP production in a cell expressing natriuretic peptide receptor B (NPR-B) comprising contacting the cell expressing NPR-B with a CNP variant selected from the group consisting of: TABLE-US-00050 (SEQ ID NO: 145) PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Pro-Gly-CNP37); (SEQ ID NO: 158) RLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-40); (SEQ ID NO: 159) LLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-39); (SEQ ID NO: 160) LQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-38); (SEQ ID NO: 60) QEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-37); (SEQ ID NO: 161) EHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-36); (SEQ ID NO: 162) HPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-35); (SEQ ID NO: 163) PNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-34); (SEQ ID NO: 164) NARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-33); (SEQ ID NO: 165) ARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-32); (SEQ ID NO: 166) RKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-31); (SEQ ID NO: 167) KYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-30); (SEQ ID NO: 182) QEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC [CNP37(M32N)]; (SEQ ID NO: 186) PQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Pro-CNP37); (SEQ ID NO: 192) MQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Met-CNP37); (SEQ ID NO: 75) GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Gly-CNP37); (SEQ ID NO: 181) GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC [Gly-CNP37(M32N)]; (SEQ ID NO: 191) MGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Met-Gly-CNP37); (SEQ ID NO: 144) GHKSEVAHRFKGANKKGLSKGCFGLKLDRIGSMSGLGC (HSA-CNP27); (SEQ ID NO: 36) GANRRGLSRGCFGLKLDRIGSMSGLGC [CNP27(K4,5,9R)]; (SEQ ID NO: 36) PEGIK-GANRRGLSRGCFGLKLDRIGSMSGLGC [PEG1K-CNP27(K4,5,9R)]; (SEQ ID NO: 36) PE012-GANRRGLSRGCFGLKLDRIGSMSGLGC [PEO12-CNP27(K4,5,9R)]; and (SEQ ID NO: 36) PEO24-GANRRGLSRGCFGLKLDRIGSMSGLGC [PEO24-CNP27(K4,5,9R)]. .Iaddend. .Iadd.22. A method of overcoming cell growth arrest induced by a constitutively active mutant fibroblast growth factor receptor 3 (FGFR-3) comprising contacting a cell expressing the constitutively active FGFR-3 with a CNP variant selected from the group consisting of: TABLE-US-00051 (SEQ ID NO: 145) PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Pro-Gly-CNP37); (SEQ ID NO: 158) RLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-40); (SEQ ID NO: 159) LLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-39); (SEQ ID NO: 160) LQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-38); (SEQ ID NO: 60) QEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-37); (SEQ ID NO: 161) EHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-36); (SEQ ID NO: 162) HPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-35); (SEQ ID NO: 163) PNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-34); (SEQ ID NO: 164) NARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-33); (SEQ ID NO: 165) ARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-32); (SEQ ID NO: 166) RKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-31); (SEQ ID NO: 167) KYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-30); (SEQ ID NO: 182) QEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC [CNP37(M32N)]; (SEQ ID NO: 186) PQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Pro-CNP37); (SEQ ID NO: 192) MQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Met-CNP37); (SEQ ID NO: 75) GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Gly-CNP37); (SEQ ID NO: 181) GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC [Gly-CNP37(M32N)]; (SEQ ID NO: 191) MGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Met-Gly-CNP37); (SEQ ID NO: 144) GHKSEVAHRFKGANKKGLSKGCFGLKLDRIGSMSGLGC (HSA-CNP27); (SEQ ID NO: 36) GANRRGLSRGCFGLKLDRIGSMSGLGC [CNP27(K4,5,9R)]; (SEQ ID NO: 36) PEGIK-GANRRGLSRGCFGLKLDRIGSMSGLGC [PEG1K-CNP27(K4,5,9R)]; (SEQ ID NO: 36) PE012-GANRRGLSRGCFGLKLDRIGSMSGLGC [PEO12-CNP27(K4,5,9R)]; and (SEQ ID NO: 36) PEO24-GANRRGLSRGCFGLKLDRIGSMSGLGC [PEO24-CNP27(K4,5,9R)]. .Iaddend. .Iadd.23. A method of treating a bone-related disorder or skeletal dysplasia, comprising administering a macromolecule capable of releasing a CNP variant comprising a synthetic polymeric group coupled to the CNP variant through a hydrolysable linkage, wherein the CNP variant is selected from the group consisting of: TABLE-US-00052 (SEQ ID NO: 145) PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Pro-Gly-CNP37); (SEQ ID NO: 158) RLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-40); (SEQ ID NO: 159) LLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-39); (SEQ ID NO: 160) LQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-38); (SEQ ID NO: 60) QEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-37); (SEQ ID NO: 161) EHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-36); (SEQ ID NO: 162) HPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-35); (SEQ ID NO: 163) PNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-34); (SEQ ID NO: 164) NARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-33); (SEQ ID NO: 165) ARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-32); (SEQ ID NO: 166) RKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-31); (SEQ ID NO: 167) KYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-30); (SEQ ID NO: 182) QEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC [CNP37(M32N)]; (SEQ ID NO: 186) PQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Pro-CNP37); (SEQ ID NO: 192) MQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Met-CNP37); (SEQ ID NO: 75) GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Gly-CNP37); (SEQ ID NO: 181) GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC [Gly-CNP37(M32N)]; (SEQ ID NO: 191) MGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Met-Gly-CNP37); (SEQ ID NO: 144) GHKSEVAHRFKGANKKGLSKGCFGLKLDRIGSMSGLGC (HSA-CNP27); (SEQ ID NO: 36) GANRRGLSRGCFGLKLDRIGSMSGLGC [CNP27(K4,5,9R)]; (SEQ ID NO: 36) PEGIK-GANRRGLSRGCFGLKLDRIGSMSGLGC [PEG1K-CNP27(K4,5,9R)]; (SEQ ID NO: 36) PE012-GANRRGLSRGCFGLKLDRIGSMSGLGC [PEO12-CNP27(K4,5,9R)]; and (SEQ ID NO: 36) PEO24-GANRRGLSRGCFGLKLDRIGSMSGLGC [PEO24-CNP27(K4,5,9R)], and wherein hydrolysis of the hydrolysable linkage releases the CNP variant. .Iaddend. .Iadd.24. The method of claim 23, wherein the bone-related disorder or skeletal dysplasia is selected from the group consisting of achondroplasia, hypochondroplasia, short stature, dwarfism and homozygous achondroplasia. .Iaddend. .Iadd.25. The method of claim 24, wherein the synthetic polymeric group comprises a hydrophilic polymeric moiety. .Iaddend. .Iadd.26. The method of claim 25, wherein the hydrophilic polymeric moiety comprises polyethylene glycol (PEG). .Iaddend. .Iadd.27. A method of treating a bone-related disorder or skeletal dysplasia, comprising administering a sustained CNP variant release formulation comprising a synthetic polymeric group coupled to the CNP variant through a hydrolysable linkage, wherein the CNP variant is selected from the group consisting of: TABLE-US-00053 (SEQ ID NO: 145) PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Pro-Gly-CNP37); (SEQ ID NO: 158) RLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-40); (SEQ ID NO: 159) LLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-39); (SEQ ID NO: 160) LQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-38); (SEQ ID NO: 60) QEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-37); (SEQ ID NO: 161) EHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-36); (SEQ ID NO: 162) HPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-35); (SEQ ID NO: 163) PNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-34); (SEQ ID NO: 164) NARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-33); (SEQ ID NO: 165) ARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-32); (SEQ ID NO: 166) RKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-31); (SEQ ID NO: 167) KYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-30); (SEQ ID NO: 182) QEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC [CNP37(M32N)]; (SEQ ID NO: 186) PQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Pro-CNP37); (SEQ ID NO: 192) MQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Met-CNP37); (SEQ ID NO: 75) GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Gly-CNP37); (SEQ ID NO: 181) GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC [Gly-CNP37(M32N)]; (SEQ ID NO: 191) MGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Met-Gly-CNP37); (SEQ ID NO: 144) GHKSEVAHRFKGANKKGLSKGCFGLKLDRIGSMSGLGC (HSA-CNP27); (SEQ ID NO: 36) GANRRGLSRGCFGLKLDRIGSMSGLGC [CNP27(K4,5,9R)]; (SEQ ID NO: 36) PEGIK-GANRRGLSRGCFGLKLDRIGSMSGLGC [PEG1K-CNP27(K4,5,9R)]; (SEQ ID NO: 36) PE012-GANRRGLSRGCFGLKLDRIGSMSGLGC [PEO12-CNP27(K4,5,9R)]; and (SEQ ID NO.36) PEO24-GANRRGLSRGCFGLKLDRIGSMSGLGC [PEO24-CNP27(K4,5,9R)]. .Iaddend. .Iadd.28. The method of claim 27, wherein the bone-related disorder or skeletal dysplasia is selected from the group consisting of achondroplasia, hypochondroplasia, short stature, dwarfism and homozygous achondroplasia. .Iaddend. .Iadd.29. The method of claim 28, wherein the synthetic polymeric group comprises a hydrophilic polymeric moiety. .Iaddend. .Iadd.30. The method of claim 29, wherein the hydrophilic polymeric moiety comprises polyethylene glycol (PEG). .Iaddend. .Iadd.31. The macromolecule of claim 15, wherein the CNP variant is selected from the group consisting of TABLE-US-00054 (SEQ ID NO: 145) PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Pro-Gly-CNP37); (SEQ ID NO: 160) LQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-38); (SEQ ID NO: 75) GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Gly-CNP37) (SEQ ID NO: 159) LLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-39); and (SEQ ID NO: 60) QEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-37). .Iaddend. .Iadd.32. The macromolecule of claim 15, wherein the CNP variant is TABLE-US-00055 (SEQ ID NO: 160) LQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-38). .Iaddend. .Iadd.33. The macromolecule of claim 32, wherein the synthetic polymeric group comprises a hydrophilic polymeric moiety. .Iaddend. .Iadd.34. The macromolecule of claim 33, wherein the hydrophilic polymeric moiety comprises polyethylene glycol (PEG). .Iaddend. .Iadd.35. The macromolecule of claim 15, wherein the CNP variant is selected from the group consisting of TABLE-US-00056 (SEQ ID NO: 75) GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Gly-CNP37) and TABLE-US-00057 (SEQ ID NO: 160) LQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-38). .Iaddend. .Iadd.36. The macromolecule of claim 35, wherein the synthetic polymeric group comprises a hydrophilic polymeric moiety. .Iaddend. .Iadd.37. The macromolecule of claim 36, wherein the hydrophilic polymeric moiety comprises polyethylene glycol (PEG). .Iaddend. .Iadd.38. The macromolecule of claim 15, wherein the CNP variant comprises an amino acid sequence at least 95% identical to TABLE-US-00058 (SEQ ID NO: 75) GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Gly-CNP37). .Iaddend. .Iadd.39. The macromolecule of claim 15, wherein the CNP variant comprises an amino acid sequence at least 95% identical to TABLE-US-00059 (SEQ ID NO: 60) QEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-37). .Iaddend. .Iadd.40. The sustained release formulation of claim 18, wherein the CNP variant is selected from the group consisting of TABLE-US-00060 (SEQ ID NO: 145) PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Pro-Gly-CNP37); (SEQ ID NO: 160) LQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-38); (SEQ ID NO: 75) GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Gly-CNP37). (SEQ ID NO: 159) LLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-39); and (SEQ ID NO: 60) QEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-37). .Iaddend. .Iadd.41. The sustained release formulation of claim 18, wherein the CNP variant is TABLE-US-00061 (SEQ ID NO: 160) LQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-38). .Iaddend. .Iadd.42. The sustained release formulation of claim 41, wherein the synthetic polymeric group comprises a hydrophilic polymeric moiety. .Iaddend. .Iadd.43. The sustained release formulation of claim 42, wherein the hydrophilic polymeric moiety comprises polyethylene glycol (PEG). .Iaddend. .Iadd.44. The sustained release formulation of claim 18, wherein the CNP variant is selected from the group consisting of TABLE-US-00062 (SEQ ID NO: 75) GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Gly-CNP37) and (SEQ ID NO: 160) LQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-38). .Iaddend. .Iadd.45. The sustained release formulation of claim 44, wherein the synthetic polymeric group comprises a hydrophilic polymeric moiety. .Iaddend. .Iadd.46. The sustained release formulation of claim 45, wherein the hydrophilic polymeric moiety comprises polyethylene glycol (PEG). .Iaddend. .Iadd.47. The sustained release formulation of claim 18, wherein the CNP variant comprises an amino acid sequence at least 95% identical to TABLE-US-00063 (SEQ ID NO: 75) GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Gly-CNP37). .Iaddend. .Iadd.48. The sustained release formulation of claim 18, wherein the CNP variant comprises an amino acid sequence at least 95% identical to TABLE-US-00064 (SEQ ID NO: 60) QEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-37). .Iaddend. .Iadd.49. The method of claim 21, wherein the CNP variant is selected from the group consisting of TABLE-US-00065 (SEQ ID NO: 145) PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Pro-Gly-CNP37); (SEQ ID NO: 160) LQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-38); (SEQ ID NO: 75) GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Gly-CNP37) (SEQ ID NO: 159) LLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-39); and (SEQ ID NO: 60) QEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-37). .Iaddend. .Iadd.50. The method of claim 21, wherein the CNP variant is TABLE-US-00066 (SEQ ID NO: 160) LQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-38). .Iaddend. .Iadd.51. The method of claim 21, wherein the CNP variant is selected from the group consisting of TABLE-US-00067 (SEQ ID NO: 75) GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Gly-CNP37) and (SEQ ID NO: 160) LQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-38). .Iaddend. .Iadd.52. The method of claim 21, wherein the CNP variant comprises an amino acid sequence at least 95% identical to TABLE-US-00068 (SEQ ID NO: 75) GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Gly-CNP37). .Iaddend. .Iadd.53. The method of claim 21, wherein the CNP variant comprises an amino acid sequence at least 95% identical to TABLE-US-00069 (SEQ ID NO: 60) QEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-37). .Iaddend. .Iadd.54. The method of claim 22, wherein the CNP variant is selected from the group consisting of TABLE-US-00070 (SEQ ID NO: 145) PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Pro-Gly-CNP37); (SEQ ID NO: 160) LQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-38); (SEQ ID NO: 75) GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Gly-CNP37) (SEQ ID NO: 159) LLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-39); and (SEQ ID NO: 60) QEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-37). .Iaddend. .Iadd.55. The method of claim 22, wherein the CNP variant is TABLE-US-00071 (SEQ ID NO: 160) LQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-38). .Iaddend. .Iadd.56. The method of claim 22, wherein the CNP variant is selected from the group consisting of TABLE-US-00072 (SEQ ID NO: 75) GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Gly-CNP37) and (SEQ ID NO: 160) LQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-38). .Iaddend. .Iadd.57. The method of claim 22, wherein the CNP variant comprises an amino acid sequence at least 95% identical to TABLE-US-00073 (SEQ ID NO: 75) GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Gly-CNP37). .Iaddend. .Iadd.58. The method of claim 22, wherein the CNP variant comprises an amino acid sequence at least 95% identical to TABLE-US-00074 (SEQ ID NO: 60) QEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-37) .Iaddend. .Iadd.59. The method of claim 23, wherein the CNP variant is selected from the group consisting of TABLE-US-00075 (SEQ ID NO: 145) PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Pro-Gly-CNP37); (SEQ ID NO: 160) LQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-38); (SEQ ID NO: 75) GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Gly-CNP37) (SEQ ID NO: 159) LLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-39); and (SEQ ID NO: 60) QEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-37). .Iaddend. .Iadd.60. The method of claim 23, wherein the CNP variant is TABLE-US-00076 (SEQ ID NO: 160) LQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-38). .Iaddend. .Iadd.61. The method of claim 60, wherein the synthetic polymeric group comprises a hydrophilic polymeric moiety. .Iaddend. .Iadd.62. The method of claim 61, wherein the hydrophilic polymeric moiety comprises polyethylene glycol (PEG). .Iaddend. .Iadd.63. The method of claim 23, wherein the CNP variant is selected from the group consisting of TABLE-US-00077 (SEQ ID NO: 75) GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Gly-CNP37) and (SEQ ID NO: 160) LQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-38). .Iaddend. .Iadd.64. The method of claim 63, wherein the synthetic polymeric group comprises a hydrophilic polymeric moiety. .Iaddend. .Iadd.65. The method of claim 64, wherein the hydrophilic polymeric moiety comprises polyethylene glycol (PEG). .Iaddend. .Iadd.66. The method of claim 23, wherein the CNP variant comprises an amino acid sequence at least 95% identical to TABLE-US-00078 (SEQ ID NO: 75) GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Gly-CNP37). .Iaddend. .Iadd.67. The method of claim 23, wherein the CNP variant comprises an amino acid sequence at least 95% identical to TABLE-US-00079 (SEQ ID NO: 60) QEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-37). .Iaddend. .Iadd.68. The method of claim 27, wherein the CNP variant is selected from the group consisting of TABLE-US-00080 (SEQ ID NO: 145) PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Pro-Gly-CNP37); (SEQ ID NO: 160) LQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-38); (SEQ ID NO: 75) GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Gly-CNP37) (SEQ ID NO: 159) LLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-39); and (SEQ ID NO: 60) QEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-37). .Iaddend. .Iadd.69. The method of claim 27, wherein the CNP variant is TABLE-US-00081 (SEQ ID NO: 160) LQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-38). .Iaddend. .Iadd.70. The method of claim 69, wherein the synthetic polymeric group comprises a hydrophilic polymeric moiety. .Iaddend. .Iadd.71. The method of claim 70, wherein the hydrophilic polymeric moiety comprises polyethylene glycol (PEG). .Iaddend. .Iadd.72. The method of claim 27, wherein the CNP variant is selected from the group consisting of TABLE-US-00082 (SEQ ID NO: 75) GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Gly-CNP37) and (SEQ ID NO: 160) LQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-38). .Iaddend. .Iadd.73. The method of claim 72, wherein the synthetic polymeric group comprises a hydrophilic polymeric moiety. .Iaddend. .Iadd.74. The method of claim 73, wherein the hydrophilic polymeric moiety comprises polyethylene glycol (PEG). .Iaddend. .Iadd.75. The method of claim 27, wherein the CNP variant comprises an amino acid sequence at least 95% identical to TABLE-US-00083 (SEQ ID NO: 75) GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (Gly-CNP37). .Iaddend. .Iadd.76. The method of claim 27, wherein the CNP variant comprises an amino acid sequence at least 95% identical to TABLE-US-00084 (SEQ ID NO: 60) QEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC (CNP-37). .Iaddend.