CNP Therapy

1 . A method of treating a subject having a bone-related disorder, skeletal dysplasia or short stature and receiving C-type natriuretic peptide (CNP) therapy, comprising

i) administering CNP therapy to the subject;

ii) obtaining a sample from the subject;

iii) measuring levels of NTproCNP and/or N terminal fragment of collagen X (CXM) in a sample collected from the subject in (ii); and

iv) altering or changing the dose of CNP to bring NTproCNP levels within +/−2 SDS of mean NTproCNP for the population.

2 . The method of claim 1 , wherein CNP therapy dose level or frequency increases if the level of NTproCNP increases, or CNP therapy dose level decreases if the level of NTproCNP decreases.

3 . A method of treating a subject having a bone-related disorder, skeletal dysplasia or short stature and receiving C-type natriuretic peptide (CNP) therapy, comprising

i) administering CNP therapy to the subject;

ii) obtaining a sample from the subject;

iii) measuring levels of N terminal fragment of collagen X (CXM) in a sample collected from the subject in (ii); and

iv) increasing CNP therapy dose level or frequency if the level of collagen X decreases.

4 . The method of any one of claims 1-3 , wherein increasing the CNP therapy dose increases the average growth velocity (AGV) in the subject.

5 . The method of claim 4 , wherein the average growth velocity (AGV) in the subject increases over 6 months, over 1 year or over 2 years, or more.

6 . The method of any one of claims 1 to 5 , wherein increasing CNP therapy dose comprises increasing dose frequency and/or increasing dose amount.

7 . The method of any one of claims 1 to 6 , wherein an increase in CNP therapy dose level and decrease in NTproCNP level correlate with improved Annualized Growth Velocity (AGV) in subjects.

8 . The method of any one of claims 1 to 7 , wherein an increase in CNP therapy dose level and decrease in NTproCNP level extends the duration of growth plate activity in the subject.

9 . The method of any one of claims 1 to 8 , wherein the levels of NTproCNP are maintained between +/−2 SDS of the mean NTproCNP for that population.

10 . The method of any one of claims 1 to 8 , wherein the CNP therapy is titrated toward zero NTproCNP SDS if the NTproCNP SDS is below the mean.

11 . The method of claim 10 , wherein the zero NTproCNP SDS predicts optimal effect size.

12 . The method of any one of claims 1 to 11 , wherein the sample is blood, urine, plasma, saliva, or tissue.

13 . The method of any one of claims 1 to 12 , wherein the subject is suffering from bone-related disorder, skeletal dysplasia or short stature selected from the group consisting of achondroplasia, osteoarthritis, hypophosphatemic rickets, hypochondroplasia, short stature, dwarfism, osteochondrodysplasias, thanatophoric dysplasia, osteogenesis imperfecta, achondrogenesis, chondrodysplasia punctata , homozygous achondroplasia, camptomelic dysplasia, congenital lethal hypophosphatasia, perinatal lethal type of osteogenesis imperfecta, short-rib polydactyly syndromes, rhizomelic type of chondrodysplasia punctata , Jansen-type metaphyseal dysplasia, spondyloepiphyseal dysplasia congenita, atelosteogenesis, diastrophic dysplasia, congenital short femur, Langer-type mesomelic dysplasia, Nievergelt-type mesomelic dysplasia, Robinow syndrome, Reinhardt syndrome, acrodysostosis, peripheral dysostosis, Kniest dysplasia, fibrochondrogenesis, Roberts syndrome, acromesomelic dysplasia, micromelia, Morquio syndrome, Kniest syndrome, metatrophic dysplasia, spondyloepimetaphyseal dysplasia, disorders related to NPR2 mutation, SHOX mutation (Turner's syndrome/Leri Weill), PTPN11 mutations (Noonan's syndrome) and IGF1R mutation.

14 . The method of any one of claims 1 to 13 , wherein the CNP is a CNP variant selected from the group consisting of

(Pro-Gly-CNP37) 

(SEQ ID NO: 1)

PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(Gly-CNP-37)

(SEQ ID NO: 2)

GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(Gly-CNP53)

(SEQ ID NO: 3)

GDLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSM

SGLGC;

(Pro-CNP53)

(SEQ ID NO: 4)

PDLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSM

SGLGC;

(Met-CNP53)

(SEQ ID NO: 5)

MDLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSM

SGLGC;

[CNP-53(M48N)]

(SEQ ID NO: 6)

DLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSNS

GLGC;

(CNP-52)

(SEQ ID NO: 7)

LRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSG

LGC;

(CNP-51)

(SEQ ID NO: 8)

RVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGL

GC;

(CNP-50)

(SEQ ID NO: 9)

VDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLG

C;

(CNP-49)

(SEQ ID NO: 10)

DTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLG

C;

(CNP-48)

(SEQ ID NO: 11)

TKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-47)

(SEQ ID NO: 12)

KSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-46)

(SEQ ID NO: 13)

SRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-45)

(SEQ ID NO: 14)

RAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-44)

(SEQ ID NO: 15)

AAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-43)

(SEQ ID NO: 16)

AWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-42)

(SEQ ID NO: 17)

WARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-41)

(SEQ ID NO: 18)

ARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-40)

(SEQ ID NO: 19)

RLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-39)

(SEQ ID NO: 20)

LLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-38)

(SEQ ID NO: 21)

LQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-37)

(SEQ ID NO: 22)

QEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-36)

(SEQ ID NO: 23)

EHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-35)

(SEQ ID NO: 24)

HPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-34)

(SEQ ID NO: 25)

PNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-33)

(SEQ ID NO: 26)

NARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-32)

(SEQ ID NO: 27)

ARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-31)

(SEQ ID NO: 28)

RKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-30)

(SEQ ID NO: 29)

KYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-29)

(SEQ ID NO: 30)

YKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-28)

(SEQ ID NO: 31)

KGANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-27)

(SEQ ID NO: 32)

GANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-26)

(SEQ ID NO: 33)

ANKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-25)

(SEQ ID NO: 34)

NKKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-24)

(SEQ ID NO: 35)

KKGLSKGCFGLKLDRIGSMSGLGC;

(CNP-23)

(SEQ ID NO: 36)

KGLSKGCFGLKLDRIGSMSGLGC;

(CNP-21)

(SEQ ID NO: 37)

LSKGCFGLKLDRIGSMSGLGC;

(CNP-20)

(SEQ ID NO: 38)

SKGCFGLKLDRIGSMSGLGC;

(CNP-19)

(SEQ ID NO: 39)

KGCFGLKLDRIGSMSGLGC;

(CNP-18)

(SEQ ID NO: 40)

GCFGLKLDRIGSMSGLGC;

[CNP-37(M32N)]

(SEQ ID NO: 41)

QEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC;

(Pro-CNP-37)

(SEQ ID NO: 42)

PQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(Met-CNP-37)

(SEQ ID NO: 43)

MQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

[Gly-CNP-37(M32N)]

(SEQ ID NO: 44)

GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSNSGLGC;

(Met-Gly-CNP-37)

(SEQ ID NO: 45)

MGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(SEQ ID NO: 46)

PGQEHPQARRYRGAQRRGLSRGCFGLKLDRIGSMSGLGC;

(SEQ ID NO: 47)

PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(SEQ ID NO: 48)

PGQEHPNARRYRGANRRGLSRGCFGLKLDRIGSMSGLGC;

and

(SEQ ID NO: 49)

PGQEHPQARKYKGAQKKGLSKGCFGLKLDRIGSMSGLGC.

15 . The method of claim 14 , wherein the CNP variant is

(Pro-Gly-CNP37)

(SEQ ID NO: 1)

PGQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

(Gly-CNP-37)

(SEQ ID NO: 2)

GQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC;

or

(CNP-38)

(SEQ ID NO: 21)

LQEHPNARKYKGANKKGLSKGCFGLKLDRIGSMSGLGC.

16 . The method of any one of claims 1 to 15 , wherein levels of NTproCNP or CXM are measured in a plasma sample.

17 . The method of any one of claims 1 to 16 , wherein the subject is receiving between 7.5 μg/kg and 30 μg/kg CNP therapy.

18 . The method of any one of claims 1 to 17 , wherein the dose of CNP is increased to 30 μg/kg.

19 . The method of any one of claims 1 to 18 , wherein the NTproCNP and/or CXM is measured at least 4 hours after administration.

20 . The method of any one of claims 1 to 19 , wherein the level of NTproCNP and/or CXM is measured at least 6 months after start of CNP therapy.

21 . The method of any one of claims 1 to 20 , wherein the level of NTproCNP in a sample is compared to a baseline measurement taken prior to start of CNP therapy.

22 . The method of any one of claims 1 to 21 , wherein CNP therapy dose or frequency is increased when a decrease in NTproCNP indicates an increase in AGV in the subject.

23 . The method of any one of claims 1 to 18 , wherein the level of CXM in a sample is compared to a baseline measurement taken prior to start of CNP therapy.

24 . The method of any one of claim 1-5, 12-20, or 23 , wherein the CXM increase indicates increased bone growth, and wherein the dose of CNP frequency or level is increased when there is CXM increase that enhances AGV.

25 . The method of any one of claims 1 to 24 , wherein the subject is a pediatric subject with open growth plates and received a dose of 15 or 30 μg/kg daily.

26 . A method of selecting initiation of CNP therapy in a subject comprising

i) measuring NTproCNP in the subject at multiple timepoints to establish a baseline NTproCNP level;

ii) determining if the NTproCNP levels indicate an SDS of zero, below or above zero; and

iii) starting treatment with CNP therapy when the subject has NTproCNP levels +/−2 SDS.

27 . A method of selecting initiation of CNP therapy in a subject having achondroplasia comprising

i) measuring NTproCNP in the subject at multiple timepoints to establish a baseline NTproCNP level;

ii) determining if the NTproCNP levels indicate an SDS of zero or above zero; and

iii) starting treatment with CNP therapy when the subject has NTproCNP levels above SDS zero.

28 . The method of claim 27 , wherein NTproCNP is measured at 2 weeks, one month, 3 months, and 6 months to establish a baseline NTproCNP level.

29 . The method of any one of claims 1 to 28 , wherein NTproCNP is measured by radioimmunoassay.

30 . A method of treating a subject having a bone-related disorder, skeletal dysplasia or short stature comprising,

[i) identifying whether a subject has a Loss of Function (LoF) or Gain of Function (GoF) variant of a gene related to a bone-related disorder, skeletal dysplasia or short stature;

ii) calculating a polygenic risk score (PRS) for height of the subject;

iii) determining if the subject has a LoF variant and a PRS in the bottom 20%; and

iv) treating the subject with a CNP variant if the subject has a LoF variant and a PRS in the bottom 20%.

31 . The method of claim 30 , wherein the gene related to a bone-related disorder, skeletal dysplasia or short stature is selected from the group consisting of NPR2, SHOX, PTPN11, COL2A1, COL11A1, COL9A2, COL10), aggrecan (ACAN), indian hedgehog (IHH), NPPC, FGFR3, IGF1R, DTL, and pregnancy-associated plasma protein A2 (PAPPA2) or combinations thereof.

32 . The method of claim 30 or 31 , wherein the gene related to a bone-related disorder, skeletal dysplasia or short stature is NPR2.

33 . A method for increasing facial volume, facial sinus volume, and foramen magnum area in a subject 6 months old or less having a bone-related disorder, skeletal dysplasia or short stature comprising administering a CNP variant at a dose of at least 30 μg/kg.

34 . A method of decreasing the incidence of sudden infant death, sleep disordered breathing, and neurosurgical decompression of the foramen magnum in a subject 6 months old or less having a bone-related disorder, skeletal dysplasia or short stature comprising administering CNP variant at a dose of at least 30 μg/kg.

35 . The method of claim 33 or 34 wherein the increase in facial volume, facial sinus volume, and foramen magnum area are measured by magnetic resonance imaging (MRI).

36 . The method of claim 35 , wherein the change in facial volume, facial sinus volume, and foramen magnum area are compared to baseline levels, healthy control subjects or untreated control subjects.

37 . The method of any one of claims 33 to 36 , wherein the CNP variant is administered subcutaneously.

38 . The method of any one of claims 33 to 37 , wherein CNP variant is administered daily, weekly, every 2 weeks, monthly, or less.

39 . The method of any one of claims 33 to 38 , wherein the CNP variant is administered at a dose of 30 μg/kg for 3 months, 6 months, 1 year or more.

40 . The method of any one of claims 33 to 39 , wherein the dose of CNP variant is decreased to 15 μg/kg when the subject is about 2 years old.