Methods of treating melanocortin 4 receptor pathway-associated disorders

Abstract

To provide methods for treating melanocortin 4 receptor pathway-associated disorders.SOLUTION: The disclosure is based, at least in part, on the discovery that the use of an MC4R agonist as replacement therapy targeting defects in the POMC-MC4R pathway, e.g., targeting defects upstream of MC4R, led to significant weight loss, decrease in hunger, and / or increase in energy expenditure in obese subjects. The disclosure relates to a method for treating disorders such as Prader Willi Syndrome (PWS), obesity or hyperphagia using a melanocortin 4 receptor (MC4R)-agonist. Also disclosed are a method for treating a subject having a deficiency in pro-opiomelanocortin (POMC)-MC4R pathway, for example, a POMC-null or PCSK-null subject, using an MC4R agonist.SELECTED DRAWING: Figure 1A

Description

[Background technology]

[0001] Melanocortin 4 receptor (MC4R) activates adenylate cyclase It is a heterotrimeric G protein-coupled receptor that transmits signals more efficiently. It is expressed in neurons and other neuronal and non-neuronal tissues and regulates feeding behavior and energy homeostasis. MC4R, which is involved in the α-melanocyte-stimulating hormone (α-MSH)-mediated jaw stimulation, Nist (appetite suppressant) signaling and agouti-related peptide (AGPR) Integrates antagonist (appetitive) signals.

[0002] MC4R is involved in the regulation of leptin, leptin receptor, and proopiomelanocortin (P OMC), prohormone convertases including PCSK1, and several other enzymes such as α-MSH. Part of the leptin-melanocortin pathway or the POMC-MC4R pathway, including Binding of AGPR to MC4R inhibits MC4R activity, and binding of α-MSH inhibits MC4 activity. Stimulating R. Inhibition of receptor activity generates appetite-stimulating signals, while stimulation of receptor activity The signal from MC4R generates an appetite-suppressing signal. Regulates feeding behavior through receptors.

[0003] In humans, the hypothalamic POMC-MC4R pathway is involved in the appetite and body weight control network. It has been described that a single gene defect in this pathway leads to severe, early-onset obesity. For example, patients with POMC loss-of-function mutations suffer from severe, early-onset obesity, hyperphagia, and These patients also have hypopigmented skin. Prader-Willi syndrome (PWS) is a condition caused by a mutation in human chromosome 15, specifically and 1 or more genes in the POMC-MC4R pathway at 15q11-q13. It is thought to be caused by a defect in the function of several genes. PWS and POMC null obese individuals suffer from severe hyperphagia, which can lead to severe obesity and other complications. Which is approved for obesity and hyperphagia associated with POMC-MC4R pathway gene deficiency disorders? There is currently no effective treatment. Deficiency of POMC-MC4R is associated with early-onset obesity in these disorders, which are associated with defects in the POMC-MC4R pathway. It is involved in obesity and hyperphagia. There is a need for therapies such as MSH replacement therapy that effectively treat binge eating and bulimia and have few safety issues. It has been done. Summary of the Invention [Means for solving the problem]

[0004] In one aspect, the present invention relates to a method for treating Prader-Willi syndrome (PWS) in a subject in need thereof. A method for doing this, comprising: Approximately 0.1 mg (e.g., 0.1 mg + / - 5%) to approximately 10 mg (e.g., 10 mg + / - 5%) % daily dose of a melanocortin 4 receptor (MC4R) agonist. Including, The agonist is an MC4R agonist as described herein, for example, the agonist is (R 2 R 3 )-A 1 -c(A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A9 )-A 10 -R 1 (I) where: A 1 Acc, HN-(CH2) m -C(O), L-amino acid or D-amino acid , or deletion, A 2 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp , or Glu, A 3 is Gly, Ala, β-Ala, Gaba, Aib, D-amino acids, or deletions and A 4 is His, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-T hi, or (X 1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe, A 5 are D-Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal, D -(X 1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe, L-Phe, or D-(Et)Tyr can be, A 6 is Arg, hArg, Dab, Dap, Lys, Orn, or HN-CH(( CH2) n -N(R 4 R 5 ))-C(O), A 7 are Trp, 1-Nal, 2-Nal, Bal, BiP, D-Trp, D-2-Nal al, D-Bal, or D-Bip, A 8is Gly, D-Ala, Acc, Ala, 13-Ala, Gaba, Apn, A hx, Aha, HN-(CH2) s -C(O), or deletion, A 9 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Dab , Dap, Orn, or Lys; A 10 Acc, HN-(CH2) t -C(O), L-amino acid or D-amino acid acid, or lack thereof, R 1 is OH or NH2, R 2 and R 3 Each of these is independently calculated for each case as H,(C1-C 30 ) alkyl, (C 1-C 30 ) heteroalkyl, (C1-C 30 ) Acyl, (C2-C 30 ) alkenyl, (C2-C 30 ) alkynyl, aryl (C1-C 30 ) Alkyl, aryl (C1-C 30 ) acyl, substituted (C1-C 30 ) alkyl, substituted (C1-C 30 ) heteroalkyl, Substitution (C1-C 30 ) Acyl, Substituted (C2-C 30 ) alkenyl, substituted (C2-C 30 ) Alkynyl, substituted aryl (C1-C 30 ) alkyl, and substituted aryl (C1-C 30 ) acyl; R 4 and R 5 Each of these is independently calculated for each case as H,(C1-C 40 ) alkyl, (C 1-C 40 ) heteroalkyl, (C1-C 40) Acyl, (C2-C 40 ) alkenyl, (C2-C 40 ) alkynyl, aryl (C1-C 40 ) Alkyl, aryl (C1-C 40 ) acyl, substituted (C1-C 40 ) alkyl, substituted (C1-C 40 ) heteroalkyl, Substitution (C1-C 40 ) Acyl, Substituted (C2-C 40 ) alkenyl, substituted (C2-C 40 ) Alkynyl, substituted aryl (C1-C 40 ) alkyl, substituted aryl (C1-C 40 )a Sill, (C1-C 40 ) alkylsulfonyl, or —C(NH)—NH2; m is, independently in each instance, 1, 2, 3, 4, 5, 6, or 7; n is independently in each instance 1, 2, 3, 4, or 5; s is, independently in each instance, 1, 2, 3, 4, 5, 6, or 7; t is, independently in each instance, 1, 2, 3, 4, 5, 6, or 7; X', X 2 , X 3 , X 4 , and X 8 are H, F, Cl, and B, respectively, independently in each case. r,I,(C 1-10 ) alkyl, substituted (C 1-10 ) alkyl, (C 2-10 )Arche Nil, substitution (C 2-10 ) alkenyl, (C 2-10 ) alkynyl, substituted (C 2-10 ) alkynyl, aryl, substituted aryl, OH, NH2, NO2, or CN; Methods for treating PWS are thereby provided herein.

[0005] In some embodiments, the subject has a loss-of-function mutation in the 15q11-q13 region of chromosome 15. having or identified as having.

[0006] In some embodiments, the subject has a mutation (e.g., a loss-of-function mutation) in the MAGEL2 gene. Identified as having or having.

[0007] In some embodiments, the daily dosage is 0.1 mg to 10 mg. In various embodiments, the daily dose is from about 0.1 mg to about 7.5 mg. In various embodiments, the daily dose is from about 0.1 mg to about 2 mg. In various embodiments, the daily dose is from about 0.1 mg to about 2 mg. In embodiments, the daily dose is from about 0.1 mg to about 1 mg. The daily dose is from about 0.2 mg to about 10 mg. In various embodiments, the daily dose is from about 0. In various embodiments, the daily dose is from about 0.2 mg to about 5 mg. In various embodiments, the daily dose is from about 0.2 mg to about 2.5 mg. In embodiments, the daily dose is from about 0.2 mg to about 2 mg. The daily dose is about 0.2 mg to about 1.5 mg. In various embodiments, the daily dose is about In various embodiments, the daily dose is from about 0.3 mg to about 10 mg. In various embodiments, the daily dose is from about 0.3 mg to about 7.5 mg. In embodiments, the daily dose is from about 0.3 mg to about 5 mg. The daily dose is about 0.3 mg to about 2.5 mg. In various embodiments, the daily dose is about In various embodiments, the daily dose is from about 0.3 mg to about 1. In various embodiments, the daily dose is about 0.3 mg to about 1 mg. In an embodiment, the daily dose is about 0.25 mg (e.g., 0.25 mg) to about 0.5 mg (e.g., 0.5 mg). In some embodiments, the daily dose is about 0.5 mg (e.g., 0.5 mg). In various embodiments, the daily dose is between about 0.5 mg and about 0.75 mg (e.g., 0.75 mg). The dosage is about 0.25 mg (e.g., 0.25 mg). In some embodiments, the daily dose is In some embodiments, the daily dose is about 0.5 mg (e.g., 0.5 mg). 0.75 mg (e.g., 0.75 mg) to about 1.25 mg (e.g., 1.25 mg). In some embodiments, the daily dose is about 1 mg (e.g., 1 mg). The dosage is about 1.25 mg (for example, 1.25 mg) to about 2 mg (for example, 2 mg). In embodiments, the daily dose is about 1.5 mg (e.g., 1.5 mg). In this case, the daily dose is about 2 mg (for example, 2 mg).

[0008] In embodiments, the method comprises administering the agonist in a unit dose suitable for injection, e.g., subcutaneous injection. This includes administering to a subject a dose.

[0009] In embodiments, the unit dose is about 0.1, 0.2, 0.3, 0.4, 0.5, 0 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6 , containing 1.7, 1.8, 1.9, or 2 mg of agonist.

[0010] In embodiments, the unit dose is dispensed into a delivery device, e.g., a syringe (e.g., prefilled). dildo syringes), implantable devices, needleless hypodermic injection devices, infusion pumps (e.g., implantable infusion pump), or osmotic delivery system.

[0011] In embodiments, the agonist is administered subcutaneously, for example, by subcutaneous injection.

[0012] In embodiments, the agonist is administered for at least 3 weeks, e.g., at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 3 3, 34, 35, 36, 37, 38, 39, or 40 weeks or more, or at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months or more or less Both are given daily for periods of 1, 2, 3, 4 or more years.

[0013] In embodiments, the subject is obese, eg, severely obese.

[0014] In embodiments, the subject has early-onset severe obesity.

[0015] In embodiments, the subject has an excess of appetite.

[0016] In embodiments, the subject is monitored prior to administration of the agonist, e.g., at the time the agonist was prescribed. 25 kg / m at the time of administration, or at the time of the first administration 2 Over (e.g., ≥ 25, 30, 31, 3 2, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45 , 46, 47, 48, 49, 50 kg / m 2 Body Mass Index (BMI) of 18.5 or higher It has.

[0017] In embodiments, the subject is monitored prior to administration of the agonist, e.g., at the time the agonist was prescribed. 35 kg / m at the time of administration, or at the time of the first administration 2 Over (e.g., ≥ 36, 37, 38, 3 9, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50kg / m 2 , or higher).

[0018] In embodiments, the subject is monitored prior to administration of the agonist, e.g., at the time the agonist was prescribed. 40 kg / m at the time of administration, or at the time of the first administration 2 Over (e.g., ≥ 41, 42, 43, 4 4, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55kg / m 2 , or higher).

[0019] In some embodiments, the agonist is administered prior to administration, e.g., at the time the agonist is prescribed, or or at the time of the first dose, 45 kg / m 2 Over (e.g., ≥ 46, 47, 48, 49, 50 , 51, 52, 53, 54, 55 kg / m 2 Body Mass Index (BMI) of 18.5 or higher It has.

[0020] In embodiments, the subject is monitored prior to administration of the agonist, e.g., at the time the agonist was prescribed. have a BMI higher than the 85th to 95th percentile at the time of administration, or at the time of the first administration.

[0021] In embodiments, the subject is monitored prior to administration of the agonist, e.g., at the time the agonist was prescribed. At the time of administration, or at the time of the first administration, one or more previous therapies, such as exercise therapy, diet therapy, or have had a history of failed behavioral therapy.

[0022] In embodiments, the subject weighs less after administration of the agonist than before administration of the agonist. It has.

[0023] In various embodiments, administration of the agonist increases the subject's body weight by comparing the subject's body weight before treatment. Approximately 1kg to 3kg after one week of treatment, or approximately 1kg to 6kg after two weeks of treatment, Approximately 2kg to 12kg after 4 weeks of treatment, or approximately 4kg to 24kg after 8 weeks of treatment, Or a weight loss of approximately 8kg to 48kg after 16 weeks of treatment.

[0024] In various embodiments, administration of the agonist may be continued for 1-2 weeks or more of treatment, for example, 2-4 weeks treatment for 4 to 8 weeks or more treatment for 8 to 16 weeks or more treatment for 16 to 32 weeks or more treatment or for a period of 32 to 64 weeks or more, about 1 to 2 kg / week, e.g., about 2 kg / week reduces the target's weight by a percentage.

[0025] In various embodiments, administration of the agonist may be continued for 1-2 weeks or more of treatment, for example, 2-4 weeks or more than 4 to 8 weeks of treatment, or more than 8 to 16 weeks of treatment, The level of hunger is reduced compared to the subject's hunger level before treatment (e.g., Likert hunger response). Decrease the score on the scale, e.g., decrease the score by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 point decrease), e.g., disappearance of hunger in the subject (e.g., Lik ert hunger scale).

[0026] In various embodiments, the administration of the agonist is for example 24 hours, 1 week, or 30 days. Over the above period, the subjects' resting energy expenditure (REE) was measured, e.g., control REE ( For example, the REE of a subject before treatment, or, for example, a subject with a similar pre-treatment BMI, e.g., fat-free Detectable compared to the given REE when expressed as REE per kg of fat mass Does not significantly decrease

[0027] In various embodiments, the administration of the agonist is for example 24 hours, 1 week, or 30 days. Over the above period, the subjects' resting energy expenditure (REE) was compared, e.g., with the control REE. In comparison (e.g., compared to the subject's REE before treatment, or, e.g., compared to a similar pre-treatment BMI) of subjects, for example, 1 kg of lean body mass after a similar level of weight loss is achieved by fasting. increase (compared to a given REE when expressed as REE per unit of energy).

[0028] In some embodiments, administration of the agonist may be used to control (e.g., treat) food intake by the subject. The food intake is reduced compared to the food intake of the subject before the administration, e.g., the food intake is reduced to the daily food intake or or food intake over a 24-hour period or over a week.

[0029] In embodiments, administration of the agonist may be performed by comparing food intake with a control (e.g., a control of the subjects' food intake before treatment). at least 100 kcal compared to your food intake or a given food intake level, For example, at least 100, 125, 150, 175, 200, 225, 250, 275 , 300, 325, 350, 375, 400, 425, 450, 475, 500, 525 , 550, 575, 600, 1000 kcal or more reduction, e.g. Food intake is the amount of food consumed in a day or over a 24-hour period or a week .

[0030] In embodiments, administration of the agonist increases food intake by at least 5 kcal / kg / day, e.g., 5, 10, 20, 30, 40, 50, 60, 70, 80, or 90k cal / kg / day or more. In some embodiments, the reduction in food intake. is relative to baseline food intake. The dietary intake of a child should be at least 100 kcal / kg / day, for example, for a child approximately 1 year old. In various embodiments, the baseline food intake is measured, e.g., in late adolescent pediatric subjects. For example, at least 40 kcal / kg / day.

[0031] In some embodiments, administration of the agonist occurs 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, Subjects' waist circumferences measured after 8, 9, 10, or more weeks were compared with controls (e.g., pretreatment). The waist circumference of the subject is reduced compared to the

[0032] In some embodiments, administration of the agonist occurs 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, Subjects' waist circumferences measured after 8, 9, 10, or more weeks were compared with controls (e.g., pretreatment). at least 2 cm (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10 cm or more).

[0033] In some embodiments, administration of the agonist occurs 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, The subject's blood pressure (e.g., diastolic blood pressure and and / or systolic blood pressure) compared to the subject's blood pressure before treatment.

[0034] In some embodiments, administration of the agonist occurs 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, The subject's blood pressure (e.g., diastolic blood pressure and and / or systolic blood pressure) compared to the subject's blood pressure before treatment.

[0035] In some embodiments, administration of the agonist occurs 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, The subjects' systolic blood pressure measured after 8, 9, 10, or more weeks was compared to the subjects' blood pressure before treatment. at least 3 mmHg (e.g., at least 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7 mmHg, or more).

[0036] In some embodiments, administration of the agonist occurs 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, Diastolic blood pressure of subjects measured 8, 9, 10 weeks or more later compared to subjects before treatment at least 4 mmHg (e.g., at least 4, 7, 7.5, 8, 8. 5, 9, 9.5, 10 mmHg, or more).

[0037] In embodiments, the subject is a mammal, for example a human.

[0038] In embodiments, the agonist is Ac-Arg-c (Cys-D-Ala-His -D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO: 140).

[0039] In embodiments, the method further comprises obtaining knowledge of the subject's genotype, e.g., Obtaining knowledge of the genotype of the chromosome 15q11-q13 region or the MAGEL2 gene It further includes:

[0040] In some embodiments, the agonist is a target of the 15q11-q13 region of chromosome 15 or M It is administered in response to the detection of a predetermined sequence, eg, a mutation, in the AGEL2 gene.

[0041] In various embodiments, the knowledge can be obtained, for example, from a sample (e.g., blood, serum, urine, or obtained directly from tissue (e.g., biopsy sample).

[0042] In some embodiments, the predetermined sequence, e.g., the mutation, is detected by a nucleic acid hybridization assay. Amplification-based assays, PCR-RFLP assays, real-time PCR, and sequencing , screening analysis, FISH, spectral karyotyping or MFISH, comparative genomic hybridization hybridization, in situ hybridization, SSP, HPLC, or and mass spectrometry genotyping. .

[0043] In embodiments, a predetermined sequence, eg, a mutation, is detected in a subject.

[0044] In embodiments, the predetermined sequence, e.g., mutation, is detected in a nucleic acid molecule or It is detected in the polypeptide.

[0045] In various embodiments, the sample is blood, serum, urine, or tissue (e.g., a biopsy) from a subject. ) containing cells from

[0046] In embodiments, the knowledge is obtained from another party, for example, this party has knowledge of the subject, caregivers, physicians, endocrinologists, hospitals, clinics, third-party payers, insurance companies, or government agencies It is Seki.

[0047] In embodiments, the method comprises: Upon determining the presence or absence of a given sequence, e.g., a mutation, in a subject, (1) Identifying a subject as having Prader-Willi syndrome (PWS) or Selecting and / or (2) Identifying or determining subjects as likely or unlikely to respond to an agonist Making a choice Contains one or more of the following:

[0048] In some embodiments, the presence of a predetermined sequence, e.g., a mutation, is detected in a subject and the determination is made. Depending on the determination, the method identifies the subject as having Prader-Willi syndrome (PWS). This includes identifying.

[0049] In some embodiments, the presence of a predetermined sequence, e.g., a mutation, is detected in a subject and the determination is made. Depending on the determination, the method may identify the subject as likely to respond to the agonist. Includes:

[0050] In some embodiments, the subject has or is identified as having PWS.

[0051] In one aspect, there is provided a method of treating a disorder in a subject in need thereof, comprising: Approximately 0.1 mg (e.g., 0.1 mg + / - 5%) to approximately 10 mg (e.g., 10 mg + / - 5%) % daily dose of a melanocortin 4 receptor (MC4R) agonist. Including, The disorder is (i) Prader-Willi syndrome (PWS), (ii) characterized by one or more mutations (e.g., loss-of-function mutations) in the POMC gene; hindrance, (iii) characterized by one or more mutations (e.g., loss-of-function mutations) in the PCSK1 gene; Disability, (iv) characterized by one or more mutations (e.g., loss-of-function mutations) in the MAGEL2 gene; Disability, (v) characterized by one or more mutations (e.g., loss-of-function mutations) in the leptin receptor gene; Disability, (vi) characterized by one or more mutations (e.g., loss-of-function mutations) in the leptin gene; hindrance, (vii) one or more mutations in the 5-HT2c receptor gene (e.g., loss-of-function mutations) a disorder characterized by (viii) Nescient Helix-Loop-Helix 2 (NhHL2) Gene a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in the offspring; (ix) one or more mutations in a prohormone convertase gene (e.g., loss-of-function mutations) a disorder characterized by (x) one or more mutations in the carboxypeptidase E (CPE) gene (e.g., Disorders characterized by functionally deficient mutations, (xi) one or more mutations in the single-minded 1 (SIM1) gene disorders characterized by (e.g., loss-of-function mutations), (xii) Hypermethylated POMC gene (e.g., hypermethylated POMC intron) methylated, e.g., one or more methylated cytosines, e.g., 5' methylcytosine hypermethylated in the CpG island of the POMC gene, a disorder characterized by (xiii) A disorder characterized by a defect in the POMC-MC4R pathway, (a) characterized by the presence of one functional and one non-functional POMC allele; Heterozygous POMC mutations, (b) characterized by the presence of one functional leptin allele and one non-functional leptin allele heterozygous leptin mutations, (c) a melanocortin 4 receptor (MC4R) mutation (e.g., a loss-of-function mutation), or (d) Prohormone convertase mutations (e.g., loss-of-function mutations) is selected from The agonist is an MC4R agonist as described herein, for example, the agonist is (R 2 R 3 )-A 1 -c(A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 )-A 10 -R 1 (I) where: A 1 Acc, HN-(CH2) m -C(O), L-amino acid or D-amino acid , or deletion, A 2 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp , or Glu, A 3 is Gly, Ala, β-Ala, Gaba, Aib, D-amino acids, or deletions and A 4 is His, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-T hi, or (X 1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe, A 5 are D-Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal, D -(X 1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe, L-Phe, or D-(Et)Tyr can be, A 6is Arg, hArg, Dab, Dap, Lys, Orn, or HN-CH(( CH2) n -N(R 4 R 5 ))-C(O), A 7 are Trp, 1-Nal, 2-Nal, Bal, BiP, D-Trp, D-2-Nal al, D-Bal, or D-Bip, A 8 is Gly, D-Ala, Acc, Ala, 13-Ala, Gaba, Apn, A hx, Aha, HN-(CH2) s -C(O), or deletion, A 9 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Dab , Dap, Orn, or Lys; A 10 Acc, HN-(CH2) t -C(O), L-amino acid or D-amino acid acid, or lack thereof, R 1 is OH or NH2, R 2 and R 3 Each of these is independently calculated for each case as H,(C1-C 30 ) alkyl, (C 1-C 30 ) heteroalkyl, (C1-C 30 ) Acyl, (C2-C 30 ) alkenyl, (C2-C 30 ) alkynyl, aryl (C1-C 30 ) Alkyl, aryl (C1-C 30 ) acyl, substituted (C1-C 30 ) alkyl, substituted (C1-C 30 ) heteroalkyl, Substitution (C1-C 30 ) Acyl, Substituted (C2-C 30 ) alkenyl, substituted (C2-C 30 ) Alkynyl, substituted aryl (C1-C 30 ) alkyl, and substituted aryl (C1-C 30 ) acyl; R 4 and R 5 Each of these is independently calculated for each case as H,(C1-C 40 ) alkyl, (C 1-C 40 ) heteroalkyl, (C1-C 40 ) Acyl, (C2-C 40 ) alkenyl, (C2-C 40 ) alkynyl, aryl (C1-C 40 ) Alkyl, aryl (C1-C 40 ) acyl, substituted (C1-C 40 ) alkyl, substituted (C1-C 40 ) heteroalkyl, Substitution (C1-C 40 ) Acyl, Substituted (C2-C 40 ) alkenyl, substituted (C2-C 40 ) Alkynyl, substituted aryl (C1-C 40 ) alkyl, substituted aryl (C1-C 40 )a Sill, (C1-C 40 ) alkylsulfonyl, or —C(NH)—NH2; m is, independently in each instance, 1, 2, 3, 4, 5, 6, or 7; n is independently in each instance 1, 2, 3, 4, or 5; s is, independently in each instance, 1, 2, 3, 4, 5, 6, or 7; t is, independently in each instance, 1, 2, 3, 4, 5, 6, or 7; X', X 2 , X 3 , X 4 , and X 8 are H, F, Cl, and B, respectively, independently in each case. r,I,(C 1-10 ) alkyl, substituted (C 1-10 ) alkyl, (C 2-10)Arche Nil, substitution (C 2-10 ) alkenyl, (C 2-10 ) alkynyl, substituted (C 2-10 ) alkynyl, aryl, substituted aryl, OH, NH2, NO2, or CN , provided herein.

[0052] In embodiments, the subject has a gene encoding one or more of the genes described herein, e.g., Including the above mutations.

[0053] In some embodiments, the disorder is Prader-Willi syndrome (PWS).

[0054] In some embodiments, the subject has a paternal allele of the 15q11-q13 region of chromosome 15. have or be identified as having a loss-of-function mutation.

[0055] In some embodiments, the subject has a mutation, e.g., a loss-of-function mutation, in the MAGEL2 gene. or identified as having.

[0056] In embodiments, the disorder is caused by one or more mutations (e.g., functional mutations) in the POMC gene. It is characterized by a deletion mutation.

[0057] In embodiments, a subject may have, for example, one functional POMC allele and one non-functional POMC allele. are heterozygous carriers of the mutation(s) with a POMC allele; or It is identified as being

[0058] In various embodiments, the subject has, for example, two different non-functional POMC alleles. , e.g., compound heterozygous carriers of the mutation(s), having a POMC null genotype is or is identified as being.

[0059] In various embodiments, the subject has a mutation, e.g., a homozygous POMC null genotype. be, or be identified as, a homozygous carrier of the mutation(s).

[0060] In embodiments, the disorder is caused by one or more mutations (e.g., mutations in the PCSK1 gene) in the PCSK1 gene. It is characterized by a gene mutation (a loss of activity).

[0061] In various embodiments, a subject may have, for example, one functional and one non-functional PCSK1 allele. are heterozygous carriers of the mutation(s) with a potential PCSK1 allele, and is identified as being so.

[0062] In various embodiments, the subject has, for example, two non-functional PCSK1 alleles, e.g., For example, compound heterozygous carriers of the mutation(s) who have a PCSK1 null genotype Being or identified as being.

[0063] In various embodiments, the subject has, for example, a homozygous PCSK1 null genotype. be, or be identified as, a homozygous carrier of the mutation(s).

[0064] In embodiments, the disorder is caused by a mutation in the MAGEL2 gene (e.g. It is characterized by loss-of-function mutations.

[0065] In some embodiments, a subject may have, for example, one functional MAGEL2 allele and one non-functional MAGEL2 allele. Possess a functional MAGEL2 allele, with the remaining functional allele silenced by maternal imprinting and wherein the subject is a functional MAGEL2 null patient. are, or are identified as, heterozygous carriers of

[0066] In various embodiments, the subject has, for example, two mutant, non-functional MAGEL2 alleles. compound heterozygosity for the mutation(s), e.g., having a MAGEL2 null genotype Being or being identified as a carrier.

[0067] In embodiments, the subject has a mutation (multiple mutations), e.g., a MAGEL2 null genotype. A person is, or is identified as, a homozygous carrier of one or more of the following:

[0068] In embodiments, the disorder is caused by a mutation in the leptin receptor gene (e.g., These are characterized by mutations in the gene encoding the gene that cause loss of function (e.g., loss-of-function mutations).

[0069] In various embodiments, a subject may have, for example, one functional leptin receptor allele and one are heterozygous carriers of a mutation(s) with a non-functional leptin receptor allele or identified as being so.

[0070] In various embodiments, the subject has, for example, two non-functional leptin receptor alleles. , e.g., compound heterozygous mutation(s) having a leptin receptor null genotype. is or is identified as being a carrier.

[0071] In some embodiments, the subject has a mutation ( A person is, or is identified as, a homozygous carrier of one or more of the following:

[0072] In embodiments, the disorder is a mutation (e.g., a functional mutation) in the leptin gene. It is characterized by a deletion mutation.

[0073] In embodiments, a subject may have, for example, one functional leptin allele and one non-functional leptin allele. are heterozygous carriers of the mutation(s) with the male leptin allele, or It is identified as being

[0074] In various embodiments, the subject has, for example, two non-functional leptin alleles, e.g., For example, a compound heterozygous carrier of the mutation(s) has a leptin null genotype. or identified as being so.

[0075] In embodiments, the subject has a mutation(s), e.g., a leptin null genotype. ) or be identified as being a homozygous carrier of

[0076] In embodiments, the disorder is caused by one or more mutations in the 5-HT2c receptor gene ( These are characterized by mutations such as loss of function.

[0077] In various embodiments, the subject may have, for example, one functional 5-HT2c receptor allele and one Heterozygous carriers of the mutation(s) with two non-functional 5-HT2c receptor alleles is or is identified as being a

[0078] In various embodiments, the subject may have, for example, two non-functional 5-HT2c receptor alleles. a compound heterozygote for one or more mutations, e.g., a 5-HT2c receptor null genotype be or be identified as a zygotic carrier.

[0079] In various embodiments, the subject is a mutant, e.g., having a 5-HT2c receptor null genotype. be, or be identified as, a homozygous carrier of the mutation(s).

[0080] In some embodiments, the disorder is a nescient helix-loop-helix 2 It is characterized by one or mutations (e.g., loss-of-function mutations) in the (NhHL2) gene.

[0081] In various embodiments, a subject may have, for example, one functional NhHL2 allele and one non-functional NhHL2 allele. Are heterozygous carriers of the mutation(s) with a potential NhHL2 receptor allele? , or identified as being so.

[0082] In various embodiments, the subject has, for example, two non-functional NhHL2 alleles, e.g., For example, compound heterozygous carriers of the mutation(s) who have an NhHL2 null genotype Being or identified as being.

[0083] In embodiments, the subject has a mutation(s), e.g., an NhHL2 null genotype. are or are identified as homozygous carriers of (possibly identifiable)

[0084] In embodiments, the disorder is a mutation in a prohormone convertase gene. (e.g., loss-of-function mutations).

[0085] In various embodiments, the subject has, for example, one functional prohormone convertase allele and Heterozygous for mutation(s) with one non-functional prohormone convertase allele is or is identified as being a carrier.

[0086] In various embodiments, the subject may have, for example, two non-functional prohormone convertase alleles. having a combination of mutation(s), e.g., having a prohormone convertase null genotype Be or be identified as a heterozygous carrier.

[0087] In various embodiments, the subject has, for example, a prohormone convertase null genotype. be, or be identified as, a homozygous carrier of the mutation(s).

[0088] In embodiments, the disorder is a mutation in the carboxypeptidase E (CPE) gene characterized by one or mutations (e.g., loss-of-function mutations).

[0089] In embodiments, a subject may have, for example, one functional CPE allele and one non-functional CPE allele. have a CPE allele, are heterozygous carriers of the mutation(s), or are not It is identified as something.

[0090] In embodiments, the subject has, for example, two non-functional CPE alleles, e.g., , are compound heterozygous carriers of the mutation(s), have a CPE null genotype, or Or identified as being so.

[0091] In embodiments, the subject has a mutation(s), e.g., a CPE null genotype. are, or are identified as, homozygous carriers of

[0092] In embodiments, the disorder is a mutation in the single-minded 1 (SIM1) gene The gene is characterized by one or a mutation (e.g., a loss-of-function mutation) in

[0093] In embodiments, a subject may have, for example, one functional SIM1 allele and one non-functional SIM1 allele. are heterozygous carriers of the mutation(s) with a single SIM1 allele, or It is identified as being

[0094] In embodiments, the subject has, for example, two non-functional SIM1 alleles, e.g., For example, a compound heterozygous carrier of the mutation(s) has a SIM1 null genotype. or identified as being so.

[0095] In embodiments, the subject has a mutation(s), e.g., a SIM1 null genotype. ) or be identified as being a homozygous carrier of

[0096] In embodiments, the disorder is characterized by a hypermethylated POMC gene (e.g., a POMC gene). hypermethylated in cytosines, e.g., methylated cytosines, e.g., 5' methylated Hypermethylation in the CpG island of the POMC gene, for example, containing cytosine It is characterized by the following:

[0097] In embodiments, the disorder is: (a) characterized by the presence of one functional and one non-functional POMC allele; Heterozygous POMC mutations (b) characterized by the presence of one functional leptin allele and one non-functional leptin allele; heterozygous leptin mutations, (c) characterized by the presence of one functional and one non-functional MC4R allele; heterozygous melanocortin 4 receptor (MC4R) mutations associated with (d) POMC-MC4R, other than prohormone convertase mutations (e.g., loss-of-function mutations) It is characterized by a defect in the pathway.

[0098] In some embodiments, the daily dosage is 0.1 mg to 10 mg. In various embodiments, the daily dose is from about 0.1 mg to about 7.5 mg. In various embodiments, the daily dose is from about 0.1 mg to about 2 mg. In various embodiments, the daily dose is from about 0.1 mg to about 2 mg. In embodiments, the daily dose is from about 0.1 mg to about 1 mg. The daily dose is from about 0.2 mg to about 10 mg. In various embodiments, the daily dose is from about 0. In various embodiments, the daily dose is from about 0.2 mg to about 5 mg. In various embodiments, the daily dose is from about 0.2 mg to about 2.5 mg. In embodiments, the daily dose is from about 0.2 mg to about 2 mg. The daily dose is about 0.2 mg to about 1.5 mg. In various embodiments, the daily dose is about In various embodiments, the daily dose is from about 0.3 mg to about 10 mg. In various embodiments, the daily dose is from about 0.3 mg to about 7.5 mg. In embodiments, the daily dose is from about 0.3 mg to about 5 mg. The daily dose is about 0.3 mg to about 2.5 mg. In various embodiments, the daily dose is about In various embodiments, the daily dose is from about 0.3 mg to about 1. In various embodiments, the daily dose is about 0.3 mg to about 1 mg. In an embodiment, the daily dose is about 0.25 mg (e.g., 0.25 mg) to about 0.5 mg (e.g., 0.5 mg). In some embodiments, the daily dose is about 0.5 mg (e.g., 0.5 mg). In various embodiments, the daily dose is between about 0.5 mg and about 0.75 mg (e.g., 0.75 mg). The dosage is about 0.25 mg (e.g., 0.25 mg). In some embodiments, the daily dose is In some embodiments, the daily dose is about 0.5 mg (e.g., 0.5 mg). 0.75 mg (e.g., 0.75 mg) to about 1.25 mg (e.g., 1.25 mg). In some embodiments, the daily dose is about 1 mg (e.g., 1 mg). The dosage is about 1.25 mg (for example, 1.25 mg) to about 2 mg (for example, 2 mg). In embodiments, the daily dose is about 1.5 mg (e.g., 1.5 mg). In this case, the daily dose is about 2 mg (for example, 2 mg).

[0099] In embodiments, the method comprises administering the agonist in a unit dose suitable for injection, e.g., subcutaneous injection. This includes administering to a subject a dose.

[0100] In embodiments, the unit dose is about 0.1, 0.2, 0.3, 0.4, 0.5, 0 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6 , containing 1.7, 1.8, 1.9, or 2 mg of agonist.

[0101] In embodiments, the unit dose is dispensed into a delivery device, e.g., a syringe (e.g., prefilled). dildo syringes), implantable devices, needleless hypodermic injection devices, infusion pumps (e.g., implantable infusion pump), or osmotic delivery system.

[0102] In embodiments, the agonist is administered subcutaneously, for example, by subcutaneous injection.

[0103] In embodiments, the agonist is administered for at least 3 weeks, e.g., at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 3 3, 34, 35, 36, 37, 38, 39, or 40 weeks or more, or at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months or more or less Both are given daily for periods of 1, 2, 3, 4 or more years.

[0104] In embodiments, the subject is obese, eg, severely obese.

[0105] In embodiments, the subject has early-onset severe obesity.

[0106] In embodiments, the subject has an excess of appetite.

[0107] In embodiments, the subject is monitored prior to administration of the agonist, e.g., at the time the agonist was prescribed. 25 kg / m at the time of administration, or at the time of the first administration 2 Over (e.g., ≥ 25, 30, 31, 3 2, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45 , 46, 47, 48, 49, 50 kg / m 2 Body Mass Index (BMI) of 18.5 or higher It has.

[0108] In embodiments, the subject is monitored prior to administration of the agonist, e.g., at the time the agonist was prescribed. 35 kg / m at the time of administration, or at the time of the first administration 2 Over (e.g., ≥ 36, 37, 38, 3 9, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50kg / m 2 , or higher).

[0109] In embodiments, the subject is monitored prior to administration of the agonist, e.g., at the time the agonist was prescribed. 40 kg / m at the time of administration, or at the time of the first administration 2 Over (e.g., ≥ 41, 42, 43, 4 4, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55kg / m 2 , or higher).

[0110] In embodiments, the subject is monitored prior to administration of the agonist, e.g., at the time the agonist was prescribed. 45 kg / m at the time of administration, or at the time of the first dose 2 Over (e.g., ≥ 46, 47, 48, 4 9, 50, 51, 52, 53, 54, 55kg / m 2 , or higher) body mass index ( BMI).

[0111] In embodiments, the subject is monitored prior to administration of the agonist, e.g., at the time the agonist was prescribed. have a BMI higher than the 85th to 95th percentile at the time of administration, or at the time of the first administration.

[0112] In embodiments, the subject is monitored prior to administration of the agonist, e.g., at the time the agonist was prescribed. At the time of administration, or at the time of the first administration, one or more previous therapies, such as exercise therapy, diet therapy, or have had a history of failed behavioral therapy.

[0113] In embodiments, the subject weighs less after administration of the agonist than before administration of the agonist. It has.

[0114] In various embodiments, administration of the agonist increases the subject's body weight by comparing the subject's body weight before treatment. Approximately 1kg to 3kg after one week of treatment, or approximately 1kg to 6kg after two weeks of treatment, Approximately 2kg to 12kg after 4 weeks of treatment, or approximately 4kg to 24kg after 8 weeks of treatment, Or a weight loss of approximately 8kg to 48kg after 16 weeks of treatment.

[0115] In various embodiments, administration of the agonist may be continued for 1-2 weeks or more of treatment, for example, 2-4 weeks treatment for 4 to 8 weeks or more treatment for 8 to 16 weeks or more treatment for 16 to 32 weeks or more treatment or for a period of 32 to 64 weeks or more, about 1 to 2 kg / week, e.g., about 2 kg / week reduces the target's weight by a percentage.

[0116] In various embodiments, administration of the agonist may be continued for 1-2 weeks or more of treatment, for example, 2-4 weeks or more than 4 to 8 weeks of treatment, or more than 8 to 16 weeks of treatment, The level of hunger is reduced compared to the subject's hunger level before treatment (e.g., Likert hunger response). Decrease the score on the scale, e.g., decrease the score by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 point decrease), e.g., disappearance of hunger in the subject (e.g., Lik ert hunger scale).

[0117] In various embodiments, the administration of the agonist is for example 24 hours, 1 week, or 30 days. Over the above period, the subjects' resting energy expenditure (REE) was measured, e.g., control REE ( For example, the REE of a subject before treatment, or, for example, a subject with a similar pre-treatment BMI, e.g., fat-free Detectable compared to the given REE when expressed as REE per kg of fat mass Does not significantly decrease

[0118] In various embodiments, the administration of the agonist is for example 24 hours, 1 week, or 30 days. Over the above period, the subjects' resting energy expenditure (REE) was compared, e.g., with the control REE. In comparison (e.g., compared to the subject's REE before treatment, or, e.g., compared to a similar pre-treatment BMI) of subjects, for example, 1 kg of lean body mass after a similar level of weight loss is achieved by fasting. increase (compared to a given REE when expressed as REE per unit of energy).

[0119] In some embodiments, administration of the agonist may be used to control (e.g., treat) food intake by the subject. The food intake is reduced compared to the food intake of the subject before the administration, e.g., the food intake is reduced to the daily food intake or or food intake over a 24-hour period or over a week.

[0120] In embodiments, administration of the agonist may be performed by comparing food intake with a control (e.g., a control of the subjects' food intake before treatment). at least 100 kcal compared to your food intake or a given food intake level, For example, at least 100, 125, 150, 175, 200, 225, 250, 275 , 300, 325, 350, 375, 400, 425, 450, 475, 500, 525 , 550, 575, 600, 1000 kcal or more reduction, e.g. Food intake is the amount of food consumed in a day or over a 24-hour period or a week .

[0121] In embodiments, administration of the agonist increases food intake by at least 5 kcal / kg / day, e.g., 5, 10, 20, 30, 40, 50, 60, 70, 80, or 90k cal / kg / day or more. In some embodiments, the reduction in food intake. is relative to baseline food intake. The dietary intake of a child should be at least 100 kcal / kg / day, for example, for a child approximately 1 year old. In various embodiments, the baseline food intake is measured, e.g., in late adolescent pediatric subjects. For example, at least 40 kcal / kg / day.

[0122] In some embodiments, administration of the agonist occurs 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, Subjects' waist circumferences measured after 8, 9, 10, or more weeks were compared with controls (e.g., pretreatment). The waist circumference of the subject is reduced compared to the

[0123] In some embodiments, administration of the agonist occurs 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, Subjects' waist circumferences measured after 8, 9, 10, or more weeks were compared with controls (e.g., pretreatment). at least 2 cm (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10 cm or more).

[0124] In some embodiments, administration of the agonist occurs 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, The subject's blood pressure (e.g., diastolic blood pressure and and / or systolic blood pressure) compared to the subject's blood pressure before treatment.

[0125] In some embodiments, administration of the agonist occurs 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, The subject's blood pressure (e.g., diastolic blood pressure and and / or systolic blood pressure) compared to the subject's blood pressure before treatment.

[0126] In some embodiments, administration of the agonist occurs 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, The subjects' systolic blood pressure measured after 8, 9, 10, or more weeks was compared to the subjects' blood pressure before treatment. at least 3 mmHg (e.g., at least 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7 mmHg, or more).

[0127] In some embodiments, administration of the agonist occurs 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, Diastolic blood pressure of subjects measured 8, 9, 10 weeks or more later compared to subjects before treatment at least 4 mmHg (e.g., at least 4, 7, 7.5, 8, 8. 5, 9, 9.5, 10 mmHg, or more).

[0128] In embodiments, the subject is a mammal, for example a human.

[0129] In embodiments, the agonist is Ac-Arg-c (Cys-D-Ala-His -D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO: 140).

[0130] In embodiments, the method further comprises obtaining knowledge of the subject's genotype, e.g. do, POMC gene, PCSK1 gene, MAGEL2 gene, leptin receptor gene, Leptin gene, 5-HT2c receptor gene, Nescient Helix-Loop-Helix 2 (NhHL2) gene, Prohormone convertase genes, Carboxypeptidase E (CPE) gene, single-minded 1 (SIM1) gene, or This involves obtaining knowledge of the genotype of mutations in POMC-MC4R pathway genes.

[0131] In embodiments, the agonist is a target of a predetermined sequence in a gene described herein, e.g., For example, it is administered in response to detection of a mutation.

[0132] In embodiments, the method involves detecting a gene encoding a POMC gene (e.g., a POMC intron). hypermethylated, e.g., methylated cytosine, e.g., 5' methylcytosine hypermethylated in the CpG island of the POMC gene, ) and obtaining knowledge of the methylation status of the gene.

[0133] In embodiments, the agonist is administered in response to detection of hypermethylation.

[0134] In various embodiments, the knowledge can be obtained, for example, from a sample (e.g., blood, serum, urine, or obtained directly from tissue (e.g., biopsy sample).

[0135] In some embodiments, the predetermined sequence, e.g., the mutation, is detected by a nucleic acid hybridization assay. Amplification-based assays, PCR-RFLP assays, real-time PCR, and sequencing , screening analysis, FISH, spectral karyotyping or MFISH, comparative genomic hybridization hybridization, in situ hybridization, SSP, HPLC, or and mass spectrometry genotyping. .

[0136] In embodiments, a predetermined sequence, eg, a mutation, is detected in a subject.

[0137] In embodiments, the predetermined sequence, e.g., mutation, is detected in a nucleic acid molecule or It is detected in the polypeptide.

[0138] In some embodiments, the state of methylation, e.g., hypermethylation, e.g., methylated cytosine. The results were analyzed by mass spectrometry, methylation-specific PCR, sequencing of bisulfite-treated DNA, and ligation. HpaII small fragment enrichment by ligation-mediated PCR assay, ChIP-on-chip assay Assay, restriction enzyme landmark genome scanning, methylated DNA immunoprecipitation, DNA Molecular cleavage photoassay of adenine methyltransferase activity, methyl-sensitive Southern blot detection by one or more of the following methods: will be done.

[0139] In embodiments, hypermethylation, e.g., methylated cytosine, is detected in a subject. can be.

[0140] In embodiments, hypermethylation, e.g., methylated cytosine, is determined by determining whether the methylation is in a sample from a subject. It is detected in a nucleic acid molecule.

[0141] In various embodiments, the sample is blood, serum, urine, or tissue (e.g., a biopsy) from a subject. ) containing cells from

[0142] In embodiments, the knowledge is obtained from another party, for example, this party has knowledge of the subject, caregivers, physicians, endocrinologists, hospitals, clinics, third-party payers, insurance companies, or government agencies It is Seki.

[0143] In embodiments, the detection of the predetermined sequence results from a collaboration with another party.

[0144] In embodiments, the method comprises: the presence of (a) a predetermined sequence, e.g., a mutation, and / or (b) hypermethylation in a subject or depending on the determination of non-existence, (1) Identifying a subject as having Prader-Willi syndrome (PWS) or To choose, (2) a disorder characterized by one or more mutations in the POMC gene, e.g., POMC deficiency Identifying or selecting a subject as having an impairment; (3) a disorder characterized by one or more mutations in the PCSK1 gene, e.g., PCSK Identifying or selecting a subject as having a deficiency; (4) disorders characterized by one or more mutations in the MAGEL2 gene, e.g., MAG Identifying or selecting a subject as having an EL2 deficiency; (5) Disorders characterized by one or more mutations in the leptin receptor gene, e.g., leptin identifying or selecting a subject as having a tin receptor deficiency; (6) Disorders characterized by one or more mutations in the leptin gene, e.g., leptin deficiency Identifying or selecting a subject as having an impairment; (7) Disorders characterized by one or more mutations in the 5-HT2c receptor gene, e.g. Identifying or selecting a subject as having a 5-HT2c receptor deficiency; (8) Disorders characterized by one or more mutations in the NhHL2 gene, e.g., NhHL Identifying or selecting a subject as having 2 deficiency; (9) Disorders characterized by one or more mutations in prohormone convertase genes, e.g. identifying or selecting a subject as having, for example, a prohormone convertase deficiency; (10) A disorder characterized by one or more mutations in the CPE gene, e.g., CPE deficiency Identifying or selecting a subject as having a disorder; (11) Disorders characterized by one or more mutations in the SIM1 gene, e.g., SIM1 Identifying or selecting a subject as having a deficiency; (12) Disorders characterized by hypermethylation of the POMC gene, such as POMC deficiency Identifying or selecting a subject as a (13) a disorder characterized by one or more mutations in the POMC-MC4R pathway genes; For example, identifying or selecting a subject as having a POMC-MC4R pathway defect and / or (14) Identifying or determining whether a subject is likely or unlikely to respond to an agonist is to choose Contains one or more of the following:

[0145] In some embodiments, a given sequence, e.g., a mutation (e.g., a mutation of MAGEL2 and / or or a mutation in the paternal allele of the 15q11-q13 region of chromosome 15) in the subjects and determining, in response to the determination, that the individual has Prader-Willi syndrome (PWS). This includes identifying the object as something.

[0146] In some embodiments, the presence of a predetermined sequence, e.g., a mutation (e.g., a mutation in the POMC gene) The presence of a gene encoding a POMC gene is detected in the subject, and in response to the determination, the method comprises: Identifying the subject as having a disorder characterized by the above mutations, e.g., POMC deficiency This includes:

[0147] In some embodiments, the sequence of interest, e.g., a mutation (e.g., a mutation in the PCSK1 gene), The presence of a gene encoding a nucleotide sequence in the PCSK1 gene is detected in the subject, and in response to the determination, the method comprises: Identifying a subject as having a disorder characterized by one or more mutations, e.g., PCSK1 deficiency This includes determining

[0148] In some embodiments, a predetermined sequence, e.g., a mutation (e.g., a mutation in the leptin receptor gene) ) is detected in the subject, and in response to the determination, the method comprises: and disorders characterized by one or more mutations in the This includes identifying the target.

[0149] In some embodiments, the presence of a predetermined sequence, e.g., a mutation (e.g., a mutation in the leptin gene) The presence of a gene encoding a leptin gene is detected in the subject, and in response to the determination, the method comprises: Identifying the subject as having a disorder characterized by the above mutations, e.g., leptin deficiency. This includes:

[0150] In some embodiments, a predetermined sequence, e.g., a mutation (e.g., a mutation in the 5-HT2c receptor gene) The presence of a 5-HT2c receptor agonist (mutation) is detected in the subject, and in response to the determination, the method comprises: Disorders characterized by one or more mutations in the 5-HT2c receptor gene, e.g., 5-HT2c receptor deficiency This includes identifying an object as having something.

[0151] In some embodiments, a given sequence, e.g., a mutation (e.g., a mutation in the NhHL2 gene) The presence of a gene encoding a nucleotide sequence in the NhHL2 gene is detected in the subject, and in response to the determination, the method comprises: Identifying a subject as having a disorder characterized by one or more mutations, e.g., NhHL2 deficiency This includes determining

[0152] In some embodiments, a predetermined sequence, e.g., a mutation (e.g., a prohormone convertase gene) The presence of a mutation in a prohormone gene is detected in the subject, and responsive to the determination, the method comprises administering a prohormone transfection vector to the subject. Disorders characterized by one or more mutations in convertase genes, e.g., prohormone convertase deficiency This includes identifying the subject as having the impairment.

[0153] In some embodiments, the presence of a predetermined sequence, e.g., a mutation (e.g., a mutation in the CPE gene) is detected in the subject, and responsive to the determination, the method comprises detecting one or more mutations in the CPE gene. and identifying a subject as having a disorder characterized by a mutation in include.

[0154] In some embodiments, the presence of a predetermined sequence, e.g., a mutation (e.g., a mutation in the SIM1 gene) The presence of a gene encoding a nucleotide sequence in the SIM1 gene is detected in the subject, and in response to the determination, the method comprises: Identifying the subject as having a disorder characterized by the above mutations, e.g., SIM1 deficiency. This includes:

[0155] In some embodiments, a predetermined sequence, e.g., a mutation (e.g., a mutation in a gene described herein) The presence of a mutation (anomaly) is detected in the subject, and in response to the determination, the method comprises: Disorders characterized by one or more mutations in pathway genes, e.g., POMC-MC4R pathway defects This includes identifying the subject as having the impairment.

[0156] In some embodiments, the presence of hypermethylation in the POMC gene is detected in the subject. and, depending on the determination, the method provides for the determination of a disorder characterized by a hypermethylated POMC gene, e.g. For example, identifying a subject as having a POMC deficiency.

[0157] In some embodiments, the presence of a predetermined sequence, e.g., a mutation, or hypermethylation, is detected in a subject. and depending on the determination, the method determines whether the subject is likely to respond to an agonist. This includes identifying the target.

[0158] In some embodiments, the subject has PWS, or POMC, PCSK1, MAGEL2 , leptin receptor, leptin, 5-HT2c receptor, NhHL2, prohormone convertase , CPE, SIM1, or one or more mutations in other POMC-MC4R pathway genes or have a disorder characterized by a POMC-MC4R pathway defect, e.g., a POMC-MC4R pathway defect. It is identified as.

[0159] In one aspect, there is provided a method of treating a disorder in a subject in need thereof, the disorder being , (i) characterized by one or more mutations (e.g., loss-of-function mutations) in the PCSK1 gene; hindrance, (ii) characterized by one or more mutations (e.g., loss-of-function mutations) in the MAGEL2 gene; Disability, (iii) Identifying one or more mutations (e.g., loss-of-function mutations) in the leptin receptor gene. Symptoms of disability, (iv) one or more mutations (e.g., loss-of-function mutations) in the 5-HT2c receptor gene Disorders characterized by (v) Nescient Helix-Loop-Helix 2 (NhHL2) gene a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in (vi) one or more mutations in the carboxypeptidase E (CPE) gene (e.g., Disorders characterized by loss-of-function mutations, (vii) one or more mutations in the single-minded 1 (SIM1) gene disorders characterized by mutations (e.g., loss-of-function mutations), (viii) hypermethylated POMC gene (e.g., hypermethylated in the POMC intron) Methylated, e.g., methylated cytosine, e.g., 5' methylcytosine (e.g., hypermethylated in the CpG island of the POMC gene) Symptoms of disability, (ix) A disorder characterized by a defect in the POMC-MC4R pathway, (a) POMC mutations, e.g., one functional POMC allele and one non-functional POMC allele Heterozygous POMC mutations, characterized by the presence of the MC allele, (b) leptin mutations, e.g., one functional leptin allele and one non-functional leptin allele; heterozygous leptin mutations characterized by the presence of the tin allele, (c) melanocortin 4 receptor (MC4R) mutation, or (d) characterized by defects in the POMC-MC4R pathway other than prohormone convertase mutations Disability, (x) characterized by a homozygous POMC mutation (e.g., a loss-of-function mutation), e.g., POM Disorders characterized by the C null genotype, (xi) characterized by compound heterozygous POMC mutations (e.g., two non-functional alleles) a disorder characterized by the presence of, for example, a POMC null genotype; (xii) characterized by a homozygous leptin mutation (e.g., a loss-of-function mutation), e.g., Disorders characterized by a putin null genotype, (xiii) characterized by compound heterozygous leptin mutations (e.g., two non-functional alleles) a disorder characterized by the presence of a leptin null genotype, e.g., a disorder characterized by a leptin null genotype, and the method comprises administering an agonist of the melanocortin 4 receptor (MC4R). This includes: The agonist is an MC4R agonist as described herein, e.g., the agonist but, (R 2 R 3 )-A 1 -c(A 2 -A 3 -A 4-A 5 -A 6 -A 7 -A 8 -A 9 )-A 10 -R 1 (I) where: A 1 Acc, HN-(CH2) m -C(O), L-amino acid or D-amino acid , or deletion, A 2 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp , or Glu, A 3 is Gly, Ala, β-Ala, Gaba, Aib, D-amino acids, or deletions and A 4 is His, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-T hi, or (X 1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe, A 5 are D-Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal, D -(X 1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe, L-Phe, or D-(Et)Tyr can be, A 6 is Arg, hArg, Dab, Dap, Lys, Orn, or HN-CH(( CH2) n -N(R 4 R 5 ))-C(O), A 7 are Trp, 1-Nal, 2-Nal, Bal, BiP, D-Trp, D-2-Nal al, D-Bal, or D-Bip, A 8 is Gly, D-Ala, Acc, Ala, 13-Ala, Gaba, Apn, A hx, Aha, HN-(CH2) s -C(O), or deletion, A 9 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Dab , Dap, Orn, or Lys; A 10 Acc, HN-(CH2) t -C(O), L-amino acid or D-amino acid acid, or lack thereof, R 1 is OH or NH2, R 2 and R 3 Each of these is independently calculated for each case as H,(C1-C 30 ) alkyl, (C 1-C 30 ) heteroalkyl, (C1-C 30 ) Acyl, (C2-C 30 ) alkenyl, (C2-C 30 ) alkynyl, aryl (C1-C 30 ) Alkyl, aryl (C1-C 30 ) acyl, substituted (C1-C 30 ) alkyl, substituted (C1-C 30 ) heteroalkyl, Substitution (C1-C 30 ) Acyl, Substituted (C2-C 30 ) alkenyl, substituted (C2-C 30 ) Alkynyl, substituted aryl (C1-C 30 ) alkyl, and substituted aryl (C1-C 30 ) acyl; R 4 and R 5 Each of these is independently calculated for each case as H,(C1-C 40 ) alkyl, (C 1-C 40 ) heteroalkyl, (C1-C 40 ) Acyl, (C2-C 40 ) alkenyl, (C2-C 40 ) alkynyl, aryl (C1-C 40 ) Alkyl, aryl (C1-C 40 ) acyl, substituted (C1-C 40 ) alkyl, substituted (C1-C 40 ) heteroalkyl, Substitution (C1-C 40 ) Acyl, Substituted (C2-C 40 ) alkenyl, substituted (C2-C 40 ) Alkynyl, substituted aryl (C1-C 40 ) alkyl, substituted aryl (C1-C 40 )a Sill, (C1-C 40 ) alkylsulfonyl, or —C(NH)—NH2; m is, independently in each instance, 1, 2, 3, 4, 5, 6, or 7; n is independently in each instance 1, 2, 3, 4, or 5; s is, independently in each instance, 1, 2, 3, 4, 5, 6, or 7; t is, independently in each instance, 1, 2, 3, 4, 5, 6, or 7; X', X 2 , X 3 , X 4 , and X 8 are H, F, Cl, and B, respectively, independently in each case. r,I,(C 1-10 ) alkyl, substituted (C 1-10 ) alkyl, (C 2-10 )Arche Nil, substitution (C 2-10 ) alkenyl, (C 2-10 ) alkynyl, substituted (C 2-10 ) alkynyl, aryl, substituted aryl, OH, NH2, NO2, or CN , provided herein.

[0160] In some embodiments, the disorder is characterized by a homozygous POMC mutation (e.g., loss of mutation). It is characterized by, for example, a POMC null genotype.

[0161] In embodiments, the disorder is characterized by a compound heterozygous POMC mutation (e.g., , characterized by the presence of two non-functional alleles), e.g., characterized by a POMC null genotype do.

[0162] In embodiments, the mutation is a mutation described herein, e.g., p.Lys51Ter m g.A6851>T and p.Arg145ProfsX12 g.7134delG is.

[0163] In embodiments, the disorder is caused by one or more mutations (e.g., mutations in the PCSK1 gene) in the PCSK1 gene. It is characterized by a gene mutation (a loss of activity).

[0164] In various embodiments, a subject may have, for example, one functional and one non-functional PCSK1 allele. are heterozygous carriers of the mutation(s) with a potential PCSK1 allele, and is identified as being so.

[0165] In various embodiments, the subject has, for example, two non-functional PCSK1 alleles, e.g., For example, compound heterozygous carriers of the mutation(s) who have a PCSK1 null genotype Being or identified as being.

[0166] In embodiments, the subject has a mutation(s), e.g., a PCSK1 null genotype. are or are identified as homozygous carriers of (possibly identifiable)

[0167] In embodiments, the disorder is caused by a mutation in the MAGEL2 gene (e.g. It is characterized by loss-of-function mutations.

[0168] In some embodiments, a subject may have, for example, one functional MAGEL2 allele and one non-functional MAGEL2 allele. are heterozygous carriers of the mutation(s) and have a functional MAGEL2 allele; Or identified as being so.

[0169] In embodiments, the subject has, for example, two non-functional MAGEL2 alleles. For example, compound heterozygous carriers of the mutation(s) have a MAGEL2 null genotype. is or is identified as being a

[0170] In embodiments, the subject has a mutation (multiple mutations), e.g., a MAGEL2 null genotype. A person is, or is identified as, a homozygous carrier of one or more of the following:

[0171] In embodiments, the disorder is caused by a mutation in the leptin receptor gene (e.g., These are characterized by mutations in the gene encoding the gene that cause loss of function (e.g., loss-of-function mutations).

[0172] In various embodiments, a subject may have, for example, one functional leptin receptor allele and one are heterozygous carriers of a mutation(s) with a non-functional leptin receptor allele or identified as being so.

[0173] In various embodiments, the subject has, for example, two non-functional leptin receptor alleles. , e.g., compound heterozygous mutation(s) having a leptin receptor null genotype. is or is identified as being a carrier.

[0174] In some embodiments, the subject has a mutation ( A person is, or is identified as, a homozygous carrier of one or more of the following:

[0175] In embodiments, the disorder is characterized by a homozygous leptin mutation (e.g., loss of mutation). It is characterized by, for example, a null leptin genotype.

[0176] In embodiments, the disorder is characterized by a compound heterozygous leptin mutation (e.g., , characterized by the presence of two non-functional alleles), e.g., characterized by a leptin null genotype do.

[0177] In embodiments, the disorder is caused by one or more mutations in the 5-HT2c receptor gene ( These are characterized by mutations such as loss of function.

[0178] In various embodiments, the subject may have, for example, one functional 5-HT2c receptor allele and one Heterozygous carriers of the mutation(s) with two non-functional 5-HT2c receptor alleles is or is identified as being a

[0179] In various embodiments, the subject may have, for example, two non-functional 5-HT2c receptor alleles. a compound heterozygote for one or more mutations, e.g., a 5-HT2c receptor null genotype be or be identified as a zygotic carrier.

[0180] In various embodiments, the subject is a mutant, e.g., having a 5-HT2c receptor null genotype. be, or be identified as, a homozygous carrier of the mutation(s).

[0181] In some embodiments, the disorder is a nescient helix-loop-helix 2 It is characterized by one or mutations (e.g., loss-of-function mutations) in the (NhHL2) gene.

[0182] In various embodiments, a subject may have, for example, one functional NhHL2 allele and one non-functional NhHL2 allele. Are heterozygous carriers of the mutation(s) with a potential NhHL2 receptor allele? , or identified as being so.

[0183] In various embodiments, the subject has, for example, two non-functional NhHL2 alleles, e.g., For example, compound heterozygous carriers of the mutation(s) who have an NhHL2 null genotype Being or identified as being.

[0184] In embodiments, the subject has a mutation(s), e.g., an NhHL2 null genotype. are or are identified as homozygous carriers of (possibly identifiable)

[0185] In embodiments, the disorder is a mutation in the carboxypeptidase E (CPE) gene characterized by one or mutations (e.g., loss-of-function mutations).

[0186] In embodiments, a subject may have, for example, one functional CPE allele and one non-functional CPE allele. have a CPE allele, are heterozygous carriers of the mutation(s), or are not It is identified as something.

[0187] In embodiments, the subject has, for example, two non-functional CPE alleles, e.g., , are compound heterozygous carriers of the mutation(s), have a CPE null genotype, or Or identified as being so.

[0188] In embodiments, the subject has a mutation(s), e.g., a CPE null genotype. are, or are identified as, homozygous carriers of

[0189] In embodiments, the disorder is a mutation in the single-minded 1 (SIM1) gene The gene is characterized by one or a mutation (e.g., a loss-of-function mutation) in

[0190] In embodiments, a subject may have, for example, one functional SIM1 allele and one non-functional SIM1 allele. are heterozygous carriers of the mutation(s) with a single SIM1 allele, or It is identified as being

[0191] In embodiments, the subject has, for example, two non-functional SIM1 alleles, e.g., For example, a compound heterozygous carrier of the mutation(s) has a SIM1 null genotype. or identified as being so.

[0192] In embodiments, the subject has a mutation(s), e.g., a SIM1 null genotype. ) or be identified as being a homozygous carrier of

[0193] In embodiments, the disorder is characterized by a hypermethylated POMC gene (e.g., a POMC gene). hypermethylated in cytosines, e.g., methylated cytosines, e.g., 5' methylated Hypermethylation in the CpG island of the POMC gene, for example, containing cytosine It is characterized by the following:

[0194] In embodiments, the subject has a mutation in, for example, the intron 2-exon 3 boundary of the POMC gene. In the present invention, a patient having or having a hypermethylated CpG island in the POMC gene It is identified as.

[0195] In embodiments, the disorder is a POMC mutation, e.g., one functional POMC allele. and heterozygous POMC mutations characterized by the presence of one non-functional POMC allele. , characterized by defects in the POMC-MC4R pathway.

[0196] In embodiments, the disorder is a leptin mutation, e.g., one functional leptin allele. and heterozygous leptin mutations characterized by the presence of one non-functional leptin allele. , characterized by defects in the POMC-MC4R pathway.

[0197] In embodiments, the disorder is characterized by an MC4R mutation, e.g., one functional MC4R allele. Heterozygous melanocortin 4 receptors characterized by the presence of one non-functional MC4R allele and one It is characterized by defects in the POMC-MC4R pathway, other than MC4R mutations.

[0198] In embodiments, the disorder is a POMC-MC4 disorder other than a prohormone convertase mutation. It is characterized by defects in the R pathway.

[0199] In embodiments, the method comprises administering the agonist in a unit dose suitable for injection, e.g., subcutaneous injection. This includes administering to a subject a dose.

[0200] In embodiments, the unit dose is about 0.1, 0.2, 0.3, 0.4, 0.5, 0 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6 , containing 1.7, 1.8, 1.9, or 2 mg of agonist.

[0201] In embodiments, the unit dose is dispensed into a delivery device, e.g., a syringe (e.g., prefilled). dildo syringes), implantable devices, needleless hypodermic injection devices, infusion pumps (e.g., implantable infusion pump), or osmotic delivery system.

[0202] In embodiments, the agonist is administered subcutaneously, for example, by subcutaneous injection.

[0203] In embodiments, the agonist is administered for at least 3 weeks, e.g., at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 3 3, 34, 35, 36, 37, 38, 39, or 40 weeks or more, or at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months or more or less Both are given daily for periods of 1, 2, 3, 4 or more years.

[0204] In embodiments, the subject is obese, eg, severely obese.

[0205] In embodiments, the subject has early-onset severe obesity.

[0206] In embodiments, the subject has an excess of appetite.

[0207] In embodiments, the subject is monitored prior to administration of the agonist, e.g., at the time the agonist was prescribed. 25 kg / m at the time of administration, or at the time of the first administration 2 Over (e.g., ≥ 25, 30, 31, 3 2, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45 , 46, 47, 48, 49, 50 kg / m 2 Body Mass Index (BMI) of 18.5 or higher It has.

[0208] In embodiments, the subject is monitored prior to administration of the agonist, e.g., at the time the agonist was prescribed. 35 kg / m at the time of administration, or at the time of the first administration 2 Over (e.g., ≥ 36, 37, 38, 3 9, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50kg / m 2 , or higher).

[0209] In embodiments, the subject is monitored prior to administration of the agonist, e.g., at the time the agonist was prescribed. 40 kg / m at the time of administration, or at the time of the first administration 2 Over (e.g., ≥ 41, 42, 43, 4 4, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55kg / m 2 , or higher).

[0210] In some embodiments, the agonist is administered prior to administration, e.g., at the time the agonist is prescribed, or or at the time of the first dose, 45 kg / m 2 Over (e.g., ≥ 46, 47, 48, 49, 50 , 51, 52, 53, 54, 55 kg / m 2 Body Mass Index (BMI) of 18.5 or higher It has.

[0211] In embodiments, the subject is monitored prior to administration of the agonist, e.g., at the time the agonist was prescribed. have a BMI higher than the 85th to 95th percentile at the time of administration, or at the time of the first administration.

[0212] In embodiments, the subject is monitored prior to administration of the agonist, e.g., at the time the agonist was prescribed. At the time of administration, or at the time of the first administration, one or more previous therapies, such as exercise therapy, diet therapy, or have had a history of failed behavioral therapy.

[0213] In embodiments, the subject weighs less after administration of the agonist than before administration of the agonist. It has.

[0214] In various embodiments, administration of the agonist increases the subject's body weight by comparing the subject's body weight before treatment. Approximately 1kg to 3kg after one week of treatment, or approximately 1kg to 6kg after two weeks of treatment, Approximately 2kg to 12kg after 4 weeks of treatment, or approximately 4kg to 24kg after 8 weeks of treatment, Or a weight loss of approximately 8kg to 48kg after 16 weeks of treatment.

[0215] In various embodiments, administration of the agonist may be continued for 1-2 weeks or more of treatment, for example, 2-4 weeks treatment for 4 to 8 weeks or more treatment for 8 to 16 weeks or more treatment for 16 to 32 weeks or more treatment or for a period of 32 to 64 weeks or more, about 1 to 2 kg / week, e.g., about 2 kg / week reduces the target's weight by a percentage.

[0216] In various embodiments, administration of the agonist may be continued for 1-2 weeks or more of treatment, for example, 2-4 weeks or more than 4 to 8 weeks of treatment, or more than 8 to 16 weeks of treatment, The level of hunger is reduced compared to the subject's hunger level before treatment (e.g., Likert hunger response). Decrease the score on the scale, e.g., decrease the score by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 point decrease), e.g., disappearance of hunger in the subject (e.g., Lik ert hunger scale).

[0217] In various embodiments, the administration of the agonist is for example 24 hours, 1 week, or 30 days. Over the above period, the subjects' resting energy expenditure (REE) was measured, e.g., control REE ( For example, the REE of a subject before treatment, or, for example, a subject with a similar pre-treatment BMI, e.g., fat-free Detectable compared to the given REE when expressed as REE per kg of fat mass Does not significantly decrease

[0218] In various embodiments, the administration of the agonist is for example 24 hours, 1 week, or 30 days. Over the above period, the subjects' resting energy expenditure (REE) was compared, e.g., with the control REE. In comparison (e.g., compared to the subject's REE before treatment, or, e.g., compared to a similar pre-treatment BMI) of subjects, for example, 1 kg of lean body mass after a similar level of weight loss is achieved by fasting. increase (compared to a given REE when expressed as REE per unit of energy).

[0219] In some embodiments, administration of the agonist may be used to control (e.g., treat) food intake by the subject. The food intake is reduced compared to the food intake of the subject before the administration, e.g., the food intake is reduced to the daily food intake or or food intake over a 24-hour period or over a week.

[0220] In embodiments, administration of the agonist may be performed by comparing food intake with a control (e.g., a control of the subjects' food intake before treatment). at least 100 kcal compared to your food intake or a given food intake level, For example, at least 100, 125, 150, 175, 200, 225, 250, 275 , 300, 325, 350, 375, 400, 425, 450, 475, 500, 525 , 550, 575, 600, 1000 kcal or more reduction, e.g. Food intake is the amount of food consumed in a day or over a 24-hour period or a week .

[0221] In embodiments, administration of the agonist increases food intake by at least 5 kcal / kg / day, e.g., 5, 10, 20, 30, 40, 50, 60, 70, 80, or 90k cal / kg / day or more. In some embodiments, the reduction in food intake. is relative to baseline food intake. The dietary intake of a child should be at least 100 kcal / kg / day, for example, for a child approximately 1 year old. In various embodiments, the baseline food intake is measured, e.g., in late adolescent pediatric subjects. For example, at least 40 kcal / kg / day.

[0222] In some embodiments, administration of the agonist occurs 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, Subjects' waist circumferences measured after 8, 9, 10, or more weeks were compared with controls (e.g., pretreatment). The waist circumference of the subject is reduced compared to the

[0223] In some embodiments, administration of the agonist occurs 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, Subjects' waist circumferences measured after 8, 9, 10, or more weeks were compared with controls (e.g., pretreatment). at least 2 cm (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10 cm or more).

[0224] In some embodiments, administration of the agonist occurs 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, The subject's blood pressure (e.g., diastolic blood pressure and and / or systolic blood pressure) compared to the subject's blood pressure before treatment.

[0225] In some embodiments, administration of the agonist occurs 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, The subject's blood pressure (e.g., diastolic blood pressure and and / or systolic blood pressure) compared to the subject's blood pressure before treatment.

[0226] In some embodiments, administration of the agonist occurs 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, The subjects' systolic blood pressure measured after 8, 9, 10, or more weeks was compared to the subjects' blood pressure before treatment. at least 3 mmHg (e.g., at least 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7 mmHg, or more).

[0227] In some embodiments, administration of the agonist occurs 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, Diastolic blood pressure of subjects measured 8, 9, 10 weeks or more later compared to subjects before treatment at least 4 mmHg (e.g., at least 4, 7, 7.5, 8, 8. 5, 9, 9.5, 10 mmHg, or more).

[0228] In embodiments, the subject is a mammal, for example a human.

[0229] In embodiments, the agonist is Ac-Arg-c (Cys-D-Ala-His -D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO: 140).

[0230] In embodiments, the method further comprises obtaining knowledge of the subject's genotype, e.g. do, POMC gene, PCSK1 gene, MAGEL2 gene, leptin receptor gene, Leptin gene, 5-HT2c receptor gene, Nescient Helix-Loop-Helix 2 (NhHL2) gene, the carboxypeptidase E (CPE) gene, or To obtain knowledge of the genotype of mutations in the single-minded 1 (SIM1) gene This includes:

[0231] In embodiments, the agonist is a target of a predetermined sequence in a gene described herein, e.g., For example, it is administered in response to detection of a mutation.

[0232] In embodiments, the method involves detecting a gene encoding a POMC gene (e.g., a POMC intron). hypermethylated, e.g., methylated cytosine, e.g., 5' methylcytosine hypermethylated in the CpG island of the POMC gene, ) and obtaining knowledge of the methylation status of the gene.

[0233] In embodiments, the agonist is administered in response to detection of hypermethylation.

[0234] In various embodiments, the knowledge can be obtained, for example, from a sample (e.g., blood, serum, urine, or obtained directly from tissue (e.g., biopsy sample).

[0235] In some embodiments, the predetermined sequence, e.g., the mutation, is detected by a nucleic acid hybridization assay. Amplification-based assays, PCR-RFLP assays, real-time PCR, and sequencing , screening analysis, FISH, spectral karyotyping or MFISH, comparative genomic hybridization hybridization, in situ hybridization, SSP, HPLC, or and mass spectrometry genotyping. .

[0236] In embodiments, a predetermined sequence, eg, a mutation, is detected in a subject.

[0237] In embodiments, the predetermined sequence, e.g., mutation, is detected in a nucleic acid molecule or It is detected in the polypeptide.

[0238] In some embodiments, the state of methylation, e.g., hypermethylation, e.g., methylated cytosine. The results were analyzed by mass spectrometry, methylation-specific PCR, sequencing of bisulfite-treated DNA, and ligation. HpaII small fragment enrichment by ligation-mediated PCR assay, ChIP-on-chip assay Assay, restriction enzyme landmark genome scanning, methylated DNA immunoprecipitation, DNA Molecular cleavage photoassay of adenine methyltransferase activity, methyl-sensitive Southern blot detection by one or more of the following methods: will be done.

[0239] In embodiments, hypermethylation, e.g., methylated cytosine, is detected in a subject. can be.

[0240] In embodiments, hypermethylation, e.g., methylated cytosine, is determined by determining whether the methylation is in a sample from a subject. It is detected in a nucleic acid molecule.

[0241] In various embodiments, the sample is blood, serum, urine, or tissue (e.g., a biopsy) from a subject. ) containing cells from

[0242] In embodiments, the knowledge is obtained from another party, for example, this party has knowledge of the subject, caregivers, physicians, endocrinologists, hospitals, clinics, third-party payers, insurance companies, or government agencies It is Seki.

[0243] In embodiments, the detection of the predetermined sequence results from a collaboration with another party.

[0244] In embodiments, the detection of hypermethylation results from a collaboration with another party.

[0245] In embodiments, the method comprises: the presence of (a) a predetermined sequence, e.g., a mutation, and / or (b) hypermethylation in a subject or depending on the determination of non-existence, (1) a disorder characterized by one or more mutations in the PCSK1 gene, e.g., PCSK Identifying or selecting a subject as having a deficiency; (2) a disorder characterized by one or more mutations in the MAGEL2 gene, e.g., MAG Identifying or selecting a subject as having an EL2 deficiency; (3) disorders characterized by one or more mutations in the leptin receptor gene, e.g., leptin identifying or selecting a subject as having a tin receptor deficiency; (4) Disorders characterized by one or more mutations in the 5-HT2c receptor gene, e.g. Identifying or selecting a subject as having a 5-HT2c receptor deficiency; (5) Disorders characterized by one or more mutations in the NhHL2 gene, e.g., NhHL Identifying or selecting a subject as having 2 deficiency; (6) a disorder characterized by one or more mutations in the CPE gene, e.g., CPE deficiency Identifying or selecting a subject as having (7) Disorders characterized by one or more mutations in the SIM1 gene, e.g., SIM1 deficiency Identifying or selecting a subject as having an impairment; (8) Have a disorder characterized by hypermethylation of the POMC gene, such as POMC deficiency identifying or selecting an object as a (9) Disorders characterized by one or more mutations in POMC-MC4R pathway genes, e.g. For example, identifying or selecting a subject as having a POMC-MC4R pathway deficiency. , (10) Patients with disorders characterized by defects in the POMC-MC4R pathway other than POMC mutations Identifying or selecting a subject as a (11) Patients with disorders characterized by defects in the POMC-MC4R pathway other than leptin mutations Identifying or selecting a subject as a (12) Patients with disorders characterized by defects in the POMC-MC4R pathway other than MC4R mutations Identifying or selecting a subject as a (13) Characterized by defects in the POMC-MC4R pathway other than prohormone convertase mutations Identifying or selecting a subject as having a disability that (14) Identifying subjects as having a disorder characterized by a homozygous POMC mutation Or to select, (15) Identifying a subject as having a disorder characterized by compound heterozygous POMC mutations Identifying or selecting, (16) Identifying a subject as having a disorder characterized by a homozygous leptin mutation Or to select, (17) Identifying a subject as having a disorder characterized by compound heterozygous leptin mutations. Identifying or selecting, and / or (18) Identifying or determining whether a subject is likely or unlikely to respond to an agonist is to choose Contains one or more of the following:

[0246] In some embodiments, the presence of a given sequence, e.g., a mutation (e.g., a mutation in MAGEL2) is detected in the subject, and depending on the determination, the method comprises diagnosing Prader-Willi syndrome (PWS) This includes identifying the subject as having WS.

[0247] In some embodiments, the sequence of interest, e.g., a mutation (e.g., a mutation in the PCSK1 gene), The presence of a gene encoding a nucleotide sequence in the PCSK1 gene is detected in the subject, and in response to the determination, the method comprises: Identifying a subject as having a disorder characterized by one or more mutations, e.g., PCSK1 deficiency This includes determining

[0248] In some embodiments, a predetermined sequence, e.g., a mutation (e.g., a mutation in the leptin receptor gene) ) is detected in the subject, and in response to the determination, the method comprises: and disorders characterized by one or more mutations in the This includes identifying the target.

[0249] In some embodiments, a predetermined sequence, e.g., a mutation (e.g., a mutation in the 5-HT2c receptor gene) The presence of a 5-HT2c receptor agonist (mutation) is detected in the subject, and in response to the determination, the method comprises: Disorders characterized by one or more mutations in the 5-HT2c receptor gene, e.g., 5-HT2c receptor deficiency This includes identifying an object as having something.

[0250] In some embodiments, a given sequence, e.g., a mutation (e.g., a mutation in the NhHL2 gene) The presence of a gene encoding a nucleotide sequence in the NhHL2 gene is detected in the subject, and in response to the determination, the method comprises: Identifying a subject as having a disorder characterized by one or more mutations, e.g., NhHL2 deficiency This includes determining

[0251] In some embodiments, the presence of a predetermined sequence, e.g., a mutation (e.g., a mutation in the CPE gene) is detected in the subject, and responsive to the determination, the method comprises detecting one or more mutations in the CPE gene. and identifying a subject as having a disorder characterized by a mutation in include.

[0252] In some embodiments, the presence of a predetermined sequence, e.g., a mutation (e.g., a mutation in the SIM1 gene) The presence of a gene encoding a nucleotide sequence in the SIM1 gene is detected in the subject, and in response to the determination, the method comprises: Identifying the subject as having a disorder characterized by the above mutations, e.g., SIM1 deficiency. This includes:

[0253] In some embodiments, a predetermined sequence, e.g., a mutation (e.g., a mutation in a gene described herein) The presence of a mutation (anomaly) is detected in the subject, and in response to the determination, the method comprises: Disorders characterized by one or more mutations in pathway genes, e.g., POMC-MC4R pathway defects This includes identifying the subject as having the impairment.

[0254] In some embodiments, the presence of hypermethylation in the POMC gene is detected in the subject. and, depending on the determination, the method provides for the determination of a disorder characterized by a hypermethylated POMC gene, e.g. For example, identifying a subject as having a POMC deficiency.

[0255] In some embodiments, a given sequence, e.g., a mutation (e.g., a homozygous POMC mutation) The presence of a POMC mutation is detected in the subject, and in response to that determination, the method comprises: This includes identifying the subject as having a characteristic disorder, e.g., POMC deficiency.

[0256] In some embodiments, a given sequence, e.g., a mutation (e.g., a compound heterozygous POMC mutation), and detecting the presence of a compound heterozygous P Identifying a subject as having a disorder characterized by an OMC mutation, e.g., POMC deficiency This includes:

[0257] In some embodiments, a given sequence, e.g., a mutation (e.g., a homozygous leptin mutation) The presence of a leptin mutation is detected in the subject, and in response to that determination, the method comprises: This includes identifying the subject as having a characterized disorder, e.g., leptin deficiency.

[0258] In some embodiments, a given sequence, e.g., a mutation (e.g., a compound heterozygous leptin mutation), The presence of a compound heterozygous gene is detected in the subject, and responsive to the determination, the method comprises: Identifying a subject as having a disorder characterized by a leptin mutation, e.g., leptin deficiency This includes:

[0259] In some embodiments, the presence of a predetermined sequence, e.g., a mutation, or hypermethylation, is detected in a subject. and depending on the determination, the method determines whether the subject is likely to respond to an agonist. This includes identifying the target.

[0260] In some embodiments, the subject has a tumor that is associated with PCSK1, MAGEL2, leptin receptor, 5-HT 2c receptor, NhHL2, prohormone convertase, CPE, SIM1, or other PO Disorders characterized by one or more mutations in the MC-MC4R pathway genes, e.g., POMC- Having or identified as having an MC4R pathway defect.

[0261] In embodiments, the subject has a mutation in one or more of the POMC or leptin genes. Disorders characterized by homozygous or compound heterozygous mutations in or leptin deficiency.

[0262] In one aspect, a unit dose of an agonist described herein, the unit dose being 0 .1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1 , 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2 mg Unit dosages containing the agonist are provided herein.

[0263] In embodiments, the unit dose comprises 0.5 mg of the agonist.

[0264] In embodiments, the unit dose comprises 1.0 mg of the agonist.

[0265] In embodiments, the unit dose comprises 1.5 mg of the agonist.

[0266] In embodiments, the unit dosage is suitable for injection, for example subcutaneous injection.

[0267] In embodiments, the unit dose is administered in a delivery device suitable for injection, e.g., subcutaneous injection. will be distributed.

[0268] In embodiments, the unit dose is delivered in a syringe or pen suitable for injection, e.g., subcutaneous injection. It is placed in a syringe.

[0269] In embodiments, the agonist is Ac-Arg-c (Cys-D-Ala-His -D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO: 140).

[0270] In one aspect, there is provided a method of evaluating a subject, comprising: A specific sequence, e.g., in the 15q11-q13 region of chromosome 15 or in the MAGEL2 gene For example, obtaining information that identifies a subject as having or not having a mutation. , Identification of a subject as having a mutation may be achieved by administering an MC4R agonist (e.g., a medicament described herein) to a subject. as more likely to have symptomatic improvement after treatment with Identify patients and identify mutations in the 15q11-q13 region of chromosome 15 or the MAGEL2 gene. Identification of a subject as not having an MC4R agonist, e.g., a MC4R agonist described herein, can be performed using a MC4R agonist. Patients as less likely to have symptomatic improvement after treatment with an MC4R agonist Methods for identification are provided herein.

[0271] In another aspect, there is provided a method of evaluating a subject, comprising: POMC gene, PCSK1 gene, MAGEL2 gene, leptin receptor gene, Leptin gene, 5-HT2c receptor gene, Nescient Helix-Loop-Helix 2 (NhHL2) gene, the carboxypeptidase E (CPE) gene, or single-minded 1 (SIM1) gene one or more of the sequences may be selected, e.g., with or without a mutation. obtaining information identifying the Identification of a subject as having a given sequence, e.g., a mutation, can be used to identify an MC4R agonist (e.g., may have symptomatic improvement after treatment with an MC4R agonist (e.g., an MC4R agonist as described herein). and identifying patients as having a higher level of a given sequence, e.g., a mutation, Identification of the MC4R agonist may be achieved by treatment with an MC4R agonist, such as an MC4R agonist described herein. Methods for identifying patients as less likely to have subsequent symptomatic improvement are described herein. Provided.

[0272] According to any of the methods described herein, in embodiments, the improvement in symptoms is determined by: (a) weight loss, (b) a decrease in waist circumference; (c) decreased hunger levels; (d) reduced levels of food intake, and / or (e) No decrease or increase in resting energy expenditure Contains one or more of the following:

[0273] In embodiments, the mutation is a loss-of-function mutation.

[0274] In embodiments, the mutation is a homozygous mutation, e.g., a homozygous loss-of-function mutation. .

[0275] In embodiments, the mutation is a heterozygous mutation.

[0276] In embodiments, the heterozygous mutation is a compound heterozygous mutation (e.g., two non- (characterized by the presence of a functional allele).

[0277] In some embodiments, the heterozygous mutation comprises one functional allele and one non-functional allele. It is characterized by the presence of Reru.

[0278] In embodiments, the method further comprises providing the report to another party, e.g. For example, these parties may include subjects, caregivers, physicians, oncologists, hospitals, clinics, third-party payers, insurance companies or government agencies.

[0279] In embodiments, the report is in electronic, web-based, or paper form.

[0280] In embodiments, the report identifies the presence or absence of a mutation in the subject, and If applicable, the identifier of the subject from whom the information was obtained.

[0281] In embodiments, the report comprises: Information about the genotype of a subject (e.g., the presence or absence of a given sequence, e.g., a mutation) , information on prognosis or proposed treatment options, e.g., MC4R agonists; Treatment options, e.g., the likelihood of efficacy of MC4R agonists, the acceptability of treatment options, if any and / or information about the strength of the recommendation for the application of the treatment option to the patient. Information or recommendations regarding the administration of treatment options (e.g., MC4R agonists) Includes:

[0282] In embodiments, the agonist is Ac-Arg-c (Cys-D-Ala-His -D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO: 140).

[0283] In one aspect, a method for selecting a subject with Prader-Willi syndrome (PWS) is provided. hand, Obtaining knowledge of a subject's genotype, e.g., chromosome 15, 15q11-q13 region obtaining knowledge of the paternal allele of the region or the genotype of the MAGEL2 gene; The step of obtaining the paternal allele or MAG determining the presence or absence of a predetermined sequence, e.g., a mutation, in the EL2 gene. , The method further comprises the steps of: Provided herein.

[0284] In one aspect, a method for selecting a subject having a POMC-MC4R pathway defect is described herein. The method includes: (i) Obtaining knowledge of the subject's genotype, e.g. POMC gene, PCSK1 gene, MAGEL2 gene, leptin receptor gene, Leptin gene, 5-HT2c receptor gene, Nescient Helix-Loop-Helix 2 (NhHL2) gene, the carboxypeptidase E (CPE) gene, or To obtain knowledge of the genotype of mutations in the single-minded 1 (SIM1) gene That is, The presence of the mutation identifies the subject as having a POMC-MC4R pathway deficiency. To gain, or (ii) POMC gene (e.g., hypermethylated in the POMC intron) containing methylated cytosine, e.g., 5' methylcytosine, e.g., POMC Knowledge of the methylation status of genes (hypermethylated in CpG islands) To acquire knowledge, The presence of hypermethylation in the POMC intron is associated with POMC-MC4R pathway deficiency. This includes identifying and acquiring an object as something to be acquired.

[0285] According to any of the methods described herein, in embodiments, the method comprises: Agonists of the mitochondrial 4 receptor (MC4R), such as those described herein, e.g., For example, the method further includes administering setmelanotide to the subject. .

[0286] In embodiments, the mutation is a loss-of-function mutation.

[0287] In embodiments, the mutation is a homozygous mutation, e.g., a homozygous loss-of-function mutation. .

[0288] In embodiments, the mutation is a heterozygous mutation.

[0289] In some embodiments, the heterozygous mutation is a compound heterozygous mutation (e.g., two heterozygous mutations). (characterized by the presence of a non-functional allele).

[0290] In some embodiments, the heterozygous mutation comprises one functional allele and one non-functional allele. It is characterized by the presence of Reru.

[0291] In embodiments, the agonist is Ac-Arg-c (Cys-D-Ala-His -D-Phe-Arg-Trp-Cys)-NH2 (SEQ ID NO: 140).

[0292] Described herein are methods for treating Prader-Willi syndrome (PWS) or for the treatment thereof. an MC4R agonist, such as an MC4R agonist described herein, in the manufacture of a medicament and the MC4R agonist is about 0.1 mg (e.g., 0.1 mg + / - 5 %) to about 10 mg (e.g., 10 mg + / - 5%) daily.

[0293] Also, an MC4R agonist in the treatment of a disorder or in the manufacture of a medicament for the treatment thereof. , for example, the use of an MC4R agonist as described herein, wherein the disorder is (i) Prader-Willi syndrome (PWS), (ii) characterized by one or more mutations (e.g., loss-of-function mutations) in the POMC gene; hindrance, (iii) characterized by one or more mutations (e.g., loss-of-function mutations) in the PCSK1 gene; Disability, (iv) characterized by one or more mutations (e.g., loss-of-function mutations) in the MAGEL2 gene; Disability, (v) characterized by one or more mutations (e.g., loss-of-function mutations) in the leptin receptor gene; Disability, (vi) characterized by one or more mutations (e.g., loss-of-function mutations) in the leptin gene; hindrance, (vii) one or more mutations in the 5-HT2c receptor gene (e.g., loss-of-function mutations) a disorder characterized by (viii) Nescient Helix-Loop-Helix 2 (NhHL2) Gene a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in the offspring; (ix) one or more mutations in a prohormone convertase gene (e.g., loss-of-function mutations) a disorder characterized by (x) one or more mutations in the carboxypeptidase E (CPE) gene (e.g., Disorders characterized by functionally deficient mutations, (xi) one or more mutations in the single-minded 1 (SIM1) gene disorders characterized by (e.g., loss-of-function mutations), (xii) Hypermethylated POMC gene (e.g., hypermethylated POMC intron) methylated, e.g., one or more methylated cytosines, e.g., 5' methylcytosine hypermethylated in the CpG island of the POMC gene, a disorder characterized by (xiii) A disorder characterized by a defect in the POMC-MC4R pathway, (a) characterized by the presence of one functional and one non-functional POMC allele; Heterozygous POMC mutations, (b) characterized by the presence of one functional leptin allele and one non-functional leptin allele heterozygous leptin mutations, (c) a melanocortin 4 receptor (MC4R) mutation (e.g., a loss-of-function mutation), or (d) Prohormone convertase mutations (e.g., loss-of-function mutations) is selected from In some cases, the agonist is administered in a dose of about 0.1 mg (e.g., 0.1 mg + / - 5%) to about 10 mg. Also provided herein are uses in which the compound is administered at a daily dose of 10 mg or less (e.g., 10 mg + / - 5%). can be.

[0294] Further embodiments according to any of the methods described herein include: can be.

[0295] In embodiments, the MC4R agonist is a compound of formula I, wherein: A 1 is A6c, Arg, D-Arg, Cha, D-Cha, hCha, Chg, D- Chg, Gaba, Ile, Leu, hLeu, Met, β-hMet, 2-Nal, D -2-Nal, Nip, Nle, Oic, Phe, D-Phe, hPhe, hPro, V al, or deletion, A 2 are Asp, Cys, D-Cys, hCys, D-hCys, Glu, Pen, or or D-Pen, A 3 are D-Abu, Aib, Ala, β-Ala, D-Ala, D-Cha, Gab a, D-Glu, Gly, D-Ile, D-Leu, D-Tle, D-Val, or It is a loss, A 4 is His or 3-Pal, A 5are D-Bal, D-1-Nal, D-2-Nal, D-Phe, D-Trp, or or D-(Et)Tyr, A 6 is Arg or hArg, A 7 are Bal, BiP, 1-Nal, 2-Nal, Trp, and D-Trp, A 8 A6c, D-Ala, Aha, Ahx, Ala, β-Ala, Apn, Gab a, Gly, or deletion, A 9 is Cys, D-Cys, hCys, D-hCys, Lys, Pen, or D- Pen, A 10 is Thr or a deletion, A 3 ~A 8 a compound of formula I, wherein at least one but not both of or a pharmaceutically acceptable salt thereof.

[0296] In some embodiments, the MC4R agonist is adrenocorticotropic hormone (ACTH). do not have.

[0297] In some embodiments, the MC4R agonist is Melanotan-II (MT-II) (Ac -Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-NH2) (SEQ ID NO: 562).

[0298] In embodiments, the MC4R agonist comprises eight or more amino acids.

[0299] In some embodiments, the MC4R agonist is Ac-Arg-c (Cys-D-Ala -His-D-Phe-Arg-Trp-Cys-NH2 (SEQ ID NO: 140) or is a pharmaceutically acceptable salt of

[0300] In embodiments, the MC4R agonist is hydantoin (C(O)-(Arg-G ly))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH 2 (SEQ ID NO: 500) or a pharmaceutically acceptable salt thereof.

[0301] In embodiments, the MC4R agonist is the tripeptide D-Phe-Arg-Tr p (SEQ ID NO: 560) or a pharmaceutical salt thereof.

[0302] In some embodiments, the MC4R agonist is D-Phe-Arg-Trp (SEQ ID NO: 560) or a pharmaceutical salt thereof.

[0303] In some embodiments, the MC4R agonist is the acetylated tripeptide Ac-D-Ph A peptide comprising e-Arg-Trp-NH2 (SEQ ID NO: 561) or a pharmaceutical salt thereof. be.

[0304] In some embodiments, the MC4R agonist is c[hydantoin (C(O)-(Glu -D-Ala)-His-D-Phe-Arg-Trp-Dap]-NH2 (SEQ ID NO: 496) or a pharmaceutically acceptable salt thereof.

[0305] In embodiments, the MC4R agonist is hydantoin (C(O)-(Nle-G ly))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH 2 (SEQ ID NO: 501) or a pharmaceutically acceptable salt thereof.

[0306] In embodiments, the MC4R agonist is a hydantoin (C(O)-(Gly-G ly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)- NH2 SEQ ID NO: 506) or a pharmaceutically acceptable salt thereof.

[0307] In some embodiments, the MC4R agonist is hydantoin (C(O)-(Ala-G ly))-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)- NH2 (SEQ ID NO: 507) or a pharmaceutically acceptable salt thereof.

[0308] In some embodiments, the MC4R agonist is hydantoin (C(O)-(D-Arg -Gly))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)- NH2 (SEQ ID NO: 515) or a pharmaceutically acceptable salt thereof.

[0309] In some embodiments, the MC4R agonist is a hydantoin (C(O)-(Gly-D -Arg))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)- NH2 (SEQ ID NO: 535) or a pharmaceutically acceptable salt thereof.

[0310] In some embodiments, the MC4R agonist is hydantoin (C(O)-(Gly-A rg))-c(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH 2 (SEQ ID NO: 531) or a pharmaceutically acceptable salt thereof.

[0311] In some embodiments, the MC4R agonist is Ac-c(Cys-Glu-His-D -2-Nal-Arg-Trp-Ala-Cys)-(Pro)2-Lys-Asp-N H2 (SEQ ID NO: 468) or a pharmaceutically acceptable salt thereof.

[0312] In some embodiments, the MC4R agonist is Ac-c(Cys-Glu-His-D -2-Nal-Arg-1-Nal-Ala-Cys)-(Pro)2-Lys-Asp -NH2 (SEQ ID NO: 470) or a pharmaceutically acceptable salt thereof.

[0313] In some embodiments, the MC4R agonist is Ac-c(Cys-Glu-His-D -2-Nal-Arg-Bal-Ala-Cys)-(Pro)2-Lys-Asp-N H2 (SEQ ID NO: 471) or a pharmaceutically acceptable salt thereof.

[0314] In some embodiments, the MC4R agonist is Ac-c(Cys-Glu-His-D -2-Nal-Arg-2-Nal-β-Ala-Cys)-(Pro)2-Lys-A sp-NH2 (SEQ ID NO: 472) or a pharmaceutically acceptable salt thereof.

[0315] In some embodiments, the MC4R agonist is Ac-c(Cys-Glu-His-D -2-Nal-Arg-2-Nal-Aib-Cys)-(Pro)2-Lys-Asp -NH2 (SEQ ID NO: 473) or a pharmaceutically acceptable salt thereof.

[0316] In some embodiments, the MC4R agonist is c[hydantoin (C(O)-(Asp -Aic))-D-2-Nal-Arg-Trp-Lys]-NH2 (SEQ ID NO: 492) or a pharmaceutically acceptable salt thereof.

[0317] In some embodiments, the MC4R agonist is c[hydantoin (C(O)-(Asp -A6c))-D-2-Nal-Arg-Trp-Lys]-NH2 (SEQ ID NO: 489) or a pharmaceutically acceptable salt thereof.

[0318] In some embodiments, the MC4R agonist is Ac-Arg-c (Cys-D-Ala -His-D-2-Nal-Arg-Trp-Cys)-NH 2( Sequence number 139) and is a pharmaceutically acceptable salt thereof.

[0319] In embodiments, the MC4R agonist is Ac-hCha-c (Asp-His- D-Phe-Arg-Trp-Gaba-Lys)-NH2 (SEQ ID NO: 36) or It is a pharmaceutically acceptable salt.

[0320] In embodiments, the MC4R agonist is D-Phe-c (Cys-His-D- Phe-Arg-Bip-β-Ala-D-Cys)-Thr-NH2 (SEQ ID NO: 81) or a pharmaceutically acceptable salt thereof.

[0321] In embodiments, the MC4R agonist is D-Phe-c (Cys-His-D- Phe-hArg-Bip-β-Ala-D-Cys)-Thr-NH2 (SEQ ID NO: 83 ) or a pharmaceutically acceptable salt thereof.

[0322] In embodiments, the MC4R agonist is D-Phe-c (Cys-His-D- (Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-NH2(sequence No. 84) or a pharmaceutically acceptable salt thereof.

[0323] In embodiments, the MC4R agonist is D-Phe-c (Cys-His-D- (Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-NH2 (sequence No. 82) or a pharmaceutically acceptable salt thereof.

[0324] In embodiments, the MC4R agonist is selected from the group consisting of those listed in US Pat. 2014 / 0329743 A1.

[0325] In embodiments, the MC4R agonist is WO2, which is incorporated herein by reference. 014 / 144260 A1.

[0326] Unless otherwise defined, all technical and scientific terms used herein refer to the It has the same meaning as commonly understood by a person skilled in the art. Methods and materials similar or equivalent to those described in the document may be used in the practice or testing of the present invention. Suitable methods and materials are described below. All publications, patent applications, patents, and other references are incorporated by reference in their entirety. Therefore, the materials, methods, and examples are illustrative only and not intended to be limiting. , subheadings, or numbered or lettered elements, e.g., (a), (b), (i), etc. are provided for ease of reading only. The use of lettered elements indicates that the steps or elements are performed in alphabetical order. or that its steps or elements are necessarily separate from one another. Other features, objects, and advantages of the present invention are set forth in the specification and drawings, as well as in the accompanying drawings. This will be clear from the claims. The present invention provides, for example, the following items. (Item 1) Methods of Treating Prader-Willi Syndrome (PWS) in a Subject in Need thereof And, Approximately 0.1 mg (e.g., 0.1 mg + / - 5%) to approximately 10 mg (e.g., 10 mg + / - 5%) % daily dose of a melanocortin 4 receptor (MC4R) agonist. Including, The agonist is an MC4R agonist as described herein, e.g., The strike, (R 2 R 3 )-A 1 -c(A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 )-A 10 -R 1 (I) where: A 1 Acc, HN-(CH2) m -C(O), L-amino acid or D-amino acid , or deletion, A 2 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp , or Glu, A 3 is Gly, Ala, β-Ala, Gaba, Aib, D-amino acids, or deletions and A 4 is His, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-T hi, or (X 1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe, A 5 are D-Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal, D -(X 1 ,X 2 ,X3 ,X 4 ,X 5 )Phe, L-Phe, or D-(Et)Tyr can be, A 6 is Arg, hArg, Dab, Dap, Lys, Orn, or HN-CH(( CH2) n -N(R 4 R 5 ))-C(O), A 7 are Trp, 1-Nal, 2-Nal, Bal, BiP, D-Trp, D-2-Nal al, D-Bal, or D-Bip, A 8 is Gly, D-Ala, Acc, Ala, 13-Ala, Gaba, Apn, A hx, Aha, HN-(CH2) s -C(O), or deletion, A 9 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Dab , Dap, Orn, or Lys; A 10 Acc, HN-(CH2) t -C(O), L-amino acid or D-amino acid acid, or lack thereof, R 1 is OH or NH2, R 2 and R 3 Each of these is independently calculated for each case as H,(C1-C 30 ) alkyl, (C 1-C 30 ) heteroalkyl, (C1-C 30 ) Acyl, (C2-C 30 ) alkenyl, (C2-C 30 ) alkynyl, aryl (C1-C 30 ) Alkyl, aryl (C1-C 30 ) acyl, substituted (C1-C 30 ) alkyl, substituted (C1-C 30) heteroalkyl, Substitution (C1-C 30 ) Acyl, Substituted (C2-C 30 ) alkenyl, substituted (C2-C 30 ) Alkynyl, substituted aryl (C1-C 30 ) alkyl, and substituted aryl (C1-C 30 ) acyl; R 4 and R 5 Each of these is independently calculated for each case as H,(C1-C 40 ) alkyl, (C 1-C 40 ) heteroalkyl, (C1-C 40 ) Acyl, (C2-C 40 ) alkenyl, (C2-C 40 ) alkynyl, aryl (C1-C 40 ) Alkyl, aryl (C1-C 40 ) acyl, substituted (C1-C 40 ) alkyl, substituted (C1-C 40 ) heteroalkyl, Substitution (C1-C 40 ) Acyl, Substituted (C2-C 40 ) alkenyl, substituted (C2-C 40 ) Alkynyl, substituted aryl (C1-C 40 ) alkyl, substituted aryl (C1-C 40 )a Sill, (C1-C 40 ) alkylsulfonyl, or —C(NH)—NH2; m is, independently in each instance, 1, 2, 3, 4, 5, 6, or 7; n is independently in each instance 1, 2, 3, 4, or 5; s is, independently in each instance, 1, 2, 3, 4, 5, 6, or 7; t is, independently in each instance, 1, 2, 3, 4, 5, 6, or 7; X', X 2 , X 3 , X 4 , and X8 are H, F, Cl, and B, respectively, independently in each case. r,I,(C 1-10 ) alkyl, substituted (C 1-10 ) alkyl, (C 2-10 )Arche Nil, substitution (C 2-10 ) alkenyl, (C 2-10 ) alkynyl, substituted (C 2-10 ) alkynyl, aryl, substituted aryl, OH, NH2, NO2, or CN; How to treat PWS. (Item 2) the subject has a loss-of-function mutation in the 15q11-q13 region of chromosome 15, or The method according to item 1, wherein the (Item 3) The subject has or has a mutation (e.g., a loss-of-function mutation) in the MAGEL2 gene. Item 2. The method according to item 2, wherein the method is identified as (Item 4) The method according to any one of items 1 to 3, wherein the daily dose is 0.1 mg to 10 mg. Law. (Item 5) 5. The method according to Item 4, wherein the daily dose is about 0.1 mg to about 7.5 mg. (Item 6) Item 5. The method according to Item 4, wherein the daily dose is about 0.1 mg to about 5 mg. (Item 7) 5. The method according to Item 4, wherein the daily dose is about 0.1 mg to about 2.5 mg. (Item 8) 5. The method according to item 4, wherein the daily dose is about 0.1 mg to about 2 mg. (Item 9) 5. The method according to item 4, wherein the daily dose is about 0.1 mg to about 1 mg. (Item 10) 4. The method according to any one of items 1 to 3, wherein the daily dose is about 0.2 mg to about 10 mg. How to do it. (Item 11) Item 11. The method according to item 10, wherein the daily dose is about 0.2 mg to about 7.5 mg. (Item 12) Item 11. The method according to Item 10, wherein the daily dose is about 0.2 mg to about 5 mg. (Item 13) Item 11. The method according to item 10, wherein the daily dose is about 0.2 mg to about 2.5 mg. (Item 14) Item 11. The method according to Item 10, wherein the daily dose is about 0.2 mg to about 2 mg. (Item 15) Item 11. The method according to Item 10, wherein the daily dose is about 0.2 mg to about 1.5 mg. (Item 16) Item 11. The method according to Item 10, wherein the daily dose is about 0.2 mg to about 1 mg. (Item 17) 4. The method according to any one of items 1 to 3, wherein the daily dose is about 0.3 mg to about 10 mg. How to do it. (Item 18) Item 18. The method according to Item 17, wherein the daily dose is about 0.3 mg to about 7.5 mg. (Item 19) Item 18. The method according to Item 17, wherein the daily dose is about 0.3 mg to about 5 mg. (Item 20) Item 18. The method according to Item 17, wherein the daily dose is about 0.3 mg to about 2.5 mg. (Item 21) Item 18. The method according to Item 17, wherein the daily dose is about 0.3 mg to about 2 mg. (Item 22) Item 18. The method according to Item 17, wherein the daily dose is about 0.3 mg to about 1.5 mg. (Item 23) Item 18. The method according to Item 17, wherein the daily dose is about 0.3 mg to about 1 mg. (Item 24) The daily dose is about 0.25 mg (e.g., 0.25 mg) to about 0.5 mg (e.g., 0. 4. The method according to any one of items 1 to 3, wherein the amount of the active ingredient is 5 mg. (Item 25) The daily dose is about 0.5 mg (for example, 0.5 mg) to about 0.75 mg (for example, 0.7 4. The method according to any one of items 1 to 3, wherein the amount of the active ingredient is 5 mg. (Item 26) Item 25. The method according to item 24, wherein the daily dose is about 0.25 mg (e.g., 0.25 mg). Law. (Item 27) Item 24 or 25, wherein the daily dose is about 0.5 mg (e.g., 0.5 mg). How to post. (Item 28) The daily dose is about 0.75 mg (for example, 0.75 mg) to about 1.25 mg (for example, 1.25 mg). 4. The method according to any one of items 1 to 3, wherein the total amount of the hydroxybenzoates is 100 mg. (Item 29) 29. The method of claim 28, wherein the daily dose is about 1 mg (e.g., 1 mg). (Item 30) The daily dose is about 1.25 mg (e.g., 1.25 mg) to about 2 mg (e.g., 2 mg). 4. The method according to any one of items 1 to 3, wherein (Item 31) 31. The method of claim 30, wherein the daily dose is about 1.5 mg (e.g., 1.5 mg). (Item 32) 31. The method of claim 30, wherein the daily dose is about 2 mg (e.g., 2 mg). (Item 33) The agonist is administered to the subject in a unit dosage suitable for injection, e.g., subcutaneous injection. 33. The method according to any one of items 1 to 32, comprising: (Item 34) The unit dose is about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8 34. The method of claim 33, comprising administering 1 mg of the agonist to a patient in need thereof. (Item 35) The unit dose is delivered via a delivery device, e.g., a syringe (e.g., a pre-filled syringe). , implantable devices, needleless hypodermic injection devices, infusion pumps (e.g., implantable infusion pumps), or 35. The method of claim 33 or 34, wherein the drug is disposed in an osmotic delivery system. (Item 36) 36. Any one of items 1 to 35, wherein the agonist is administered subcutaneously, for example by subcutaneous injection. The method described in paragraph . (Item 37) The agonist is administered for at least 3 weeks, e.g., at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 , 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 weeks or more, or at least 1, 2, 3, 4, or 5 , 6, 7, 8, 9, 10, 11, or 12 months or more, or at least 1, 2, 3, 37. The method of any one of items 1 to 36, wherein the method is administered daily for a period of 4 years or more. (Item 38) 38. The method according to any one of items 1 to 37, wherein the subject is obese, such as severely obese. . (Item 39) 39. The method of any one of items 1 to 38, wherein the subject has early-onset severe obesity. (Item 40) 40. The method according to any one of items 1 to 39, wherein the subject has an excess of appetite. (Item 41) The subject is administered the agonist prior to administration, e.g., at the time the agonist is prescribed, or or at the time of the first dose, 25 kg / m 2 Over (e.g., ≥ 25, 30, 31, 32, 33 , 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 kg / m 2 have a body mass index (BMI) of 40 or higher 41. The method according to any one of items 1 to 40. (Item 42) The subject is administered the agonist prior to administration, e.g., at the time the agonist is prescribed, or or 35 kg / m at the time of the first dose. 2 Over (e.g., ≥ 36, 37, 38, 39, 40 , 41, 42, 43, 44, 45, 46, 47, 48, 49, 50kg / m 2 , or 42. The method according to any one of items 1 to 41, wherein the subject has a body mass index (BMI) of 0.5 or higher. (Item 43) The subject is administered the agonist prior to administration, e.g., at the time the agonist is prescribed, or or at the time of the first dose, 40 kg / m 2 Over (e.g., ≥ 41, 42, 43, 44, 45 , 46, 47, 48, 49, 50, 51, 52, 53, 54, 55kg / m 2 , or 43. The method according to any one of items 1 to 42, wherein the subject has a body mass index (BMI) of 100 or more. (Item 44) The subject is administered the agonist prior to administration, e.g., at the time the agonist is prescribed, or or at the time of the first dose, 45 kg / m 2 Over (e.g., ≥ 46, 47, 48, 49, 50 , 51, 52, 53, 54, 55 kg / m 2 Body Mass Index (BMI) of 18.5 or higher 44. The method according to any one of items 1 to 43, comprising: (Item 45) The subject is administered the agonist prior to administration, e.g., at the time the agonist is prescribed, or or at the time of the first administration, one or more prior therapies, e.g., exercise therapy, diet therapy, or 45. The method according to any one of items 1 to 44, wherein the patient has had a history of failure of behavioral therapy. (Item 46) the subject has a lower body weight after administration of the agonist than before administration of the agonist. 46. ​​The method according to any one of items 1 to 45. (Item 47) administration of said agonist reduces said subject's body weight by 1 week compared to said subject's body weight before treatment Approximately 1kg to 3kg after treatment, or approximately 1kg to 6kg after 2 weeks of treatment, or approximately 1kg to 6kg after 4 weeks Approximately 2kg to 12kg after 1 week of treatment, or approximately 4kg to 24kg after 8 weeks of treatment, or approximately 1 The method according to any one of items 1 to 46, wherein the patient loses approximately 8 kg to 48 kg after 6 weeks of treatment. method. (Item 48) The administration of the agonist may be, for example, 1 to 2 weeks or more of treatment, 2 to 4 weeks or more of treatment, 4 to Treatment for 8 weeks or more, treatment for 8 to 16 weeks or more, treatment for 16 to 32 weeks or more, or treatment for 32 or more The subject receives approximately 1 to 2 kg / week, for example, approximately 2 kg / week, for a period of 64 weeks or more. 48. The method according to any one of items 1 to 47, wherein the body weight of the subject is reduced. (Item 49) The administration of the agonist may be, for example, 1 to 2 weeks or more of treatment, 2 to 4 weeks or more of treatment, 4 to Treating the subject's hunger level after 8 weeks or more of treatment, or after 8 to 16 weeks or more of treatment reduced compared to the subject's previous hunger level (e.g., on a Likert hunger scale) Decrease the score, e.g., decrease the score by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points), e.g., the subject's hunger sensation disappears (e.g., Liker t) a score of 0 on the hunger scale. . (Item 50) Administration of the agonist can be, for example, for a period of 24 hours, a week, or 30 days or more. and measuring the subject's resting energy expenditure (REE), e.g., a control REE (e.g., before treatment). or, for example, a subject with a similar pre-treatment BMI, e.g., a lean body mass of 1 Detectably / significantly reduced compared to the given REE when expressed as REE per kg 50. The method according to any one of items 1 to 49, wherein the method does not reduce the amount of the oxidized material. (Item 51) Administration of the agonist can be, for example, for a period of 24 hours, a week, or 30 days or more. and measuring the subject's resting energy expenditure (REE), e.g., compared with a control REE (e.g., For example, compared to the REE of said subject before treatment, or, for example, compared to the REE of subjects with similar pre-treatment BMI per kg of lean body mass after a similar level of weight loss is achieved by fasting. (compared to the given REE when expressed as REE) according to the method described in item 50. Law. (Item 52) Administration of the agonist reduces food intake by the subject as compared to a control (e.g., the subject before treatment). a daily food intake or Food intake over 24 hours or one week, as described in any one of items 1 to 51 How to do it. (Item 53) Administration of the agonist reduces food intake to a control (e.g., the subject's food intake before treatment or or a given food intake level), e.g., at least 100 kcal less At most 100, 125, 150, 175, 200, 225, 250, 275, 300, 3 25, 350, 375, 400, 425, 450, 475, 500, 525, 550, 5 75, 600, 1000 kcal or more reduction in food intake, e.g. Item 5: Amount of food intake per day or over a 24-hour period or a week The method described in 2. (Item 54) Administration of the agonist is continued for 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 weeks after the start of treatment. The subject's waist circumference when measured at or after a control (e.g., the subject's waist circumference before treatment) is compared to the control (e.g., the subject's waist circumference when measured at or after a control). 54. The method according to any one of items 1 to 53, wherein the total body mass index (LGR) is reduced compared to waist circumference. (Item 55) Administration of the agonist is continued for 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 weeks after the start of treatment. The subject's waist circumference when measured at or after a control (e.g., the subject's waist circumference before treatment) is compared to the control (e.g., the subject's waist circumference when measured at or after a control). at least 2 cm (e.g., at least 2, 3, 4, 5, 6, 7, 8, 55. The method of claim 54, wherein the thickness of the tissue is reduced by 9, 10 cm or more. (Item 56) Administration of the agonist is continued for 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 weeks after the start of treatment. The subject's blood pressure (e.g., diastolic and / or systolic blood pressure) when measured at or after systolic blood pressure) compared to the subject's blood pressure before treatment, 10. The method according to any one of claims 1 to 9. (Item 57) Administration of the agonist is continued for 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 weeks after the start of treatment. The subject's blood pressure (e.g., diastolic and / or systolic blood pressure) when measured at or after any one of items 1 to 56, wherein the subject's blood pressure (systolic blood pressure) is reduced compared to the subject's blood pressure before treatment. The method described in paragraph . (Item 58) Administration of the agonist is continued for 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 weeks after the start of treatment. and comparing the subject's systolic blood pressure measured after 10 minutes or more with the subject's blood pressure before treatment. Compare to at least 3 mmHg (e.g., at least 3, 3.5, 4, 4.5, 5, 5. 58. The method of claim 57, wherein the blood pressure is reduced by 5, 6, 6.5, 7 mmHg or more. (Item 59) Administration of the agonist is continued for 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 weeks after the start of treatment. and comparing the subject's diastolic blood pressure measured after 10 days or more with the subject's blood pressure before treatment. Compared to at least 4 mmHg (e.g., at least 4, 7, 7.5, 8, 8.5, 9, 9.5, 10 mmHg, or more). (Item 60) 60. The method of any one of items 1 to 59, wherein the subject is a mammal, such as a human. (Item 61) The agonist is Ac-Arg-c(Cys-D-Ala-His-D-Phe-A 61. Any one of items 1 to 60, wherein the amino acid sequence is rg-Trp-Cys-NH2 (SEQ ID NO: 140). The method described in paragraph . (Item 62) Obtaining knowledge of the subject's genotype, e.g., 15q11-q1 of chromosome 15. Items 1-61, including obtaining knowledge of the genotype of the 3 regions or the MAGEL2 gene 10. The method according to any one of claims 1 to 9. (Item 63) The agonist is a member of the 15q11-q13 region of chromosome 15 or the MAGEL2 gene 63. The method of claim 62, wherein the antibody is administered in response to detection of a predetermined sequence, e.g., a mutation, in (Item 64) 1. A method of treating a disorder in a subject in need thereof, comprising: Approximately 0.1 mg (e.g., 0.1 mg + / - 5%) to approximately 10 mg (e.g., 10 mg + / - 5%) % daily dose of a melanocortin 4 receptor (MC4R) agonist. Including, The disorder is (i) Prader-Willi syndrome (PWS), (ii) characterized by one or more mutations (e.g., loss-of-function mutations) in the POMC gene; hindrance, (iii) characterized by one or more mutations (e.g., loss-of-function mutations) in the PCSK1 gene; Disability, (iv) characterized by one or more mutations (e.g., loss-of-function mutations) in the MAGEL2 gene; Disability, (v) characterized by one or more mutations (e.g., loss-of-function mutations) in the leptin receptor gene; Disability, (vi) characterized by one or more mutations (e.g., loss-of-function mutations) in the leptin gene; hindrance, (vii) one or more mutations in the 5-HT2c receptor gene (e.g., loss-of-function mutations) a disorder characterized by (viii) Nescient Helix-Loop-Helix 2 (NhHL2) Gene a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in the offspring; (ix) one or more mutations in a prohormone convertase gene (e.g., loss-of-function mutations) a disorder characterized by (x) one or more mutations in the carboxypeptidase E (CPE) gene (e.g., Disorders characterized by functionally deficient mutations, (xi) one or more mutations in the single-minded 1 (SIM1) gene disorders characterized by (e.g., loss-of-function mutations), (xii) Hypermethylated POMC gene (e.g., hypermethylated POMC intron) methylated, e.g., one or more methylated cytosines, e.g., 5' methylcytosine hypermethylated in the CpG island of the POMC gene, a disorder characterized by (xiii) A disorder characterized by a defect in the POMC-MC4R pathway, (e) characterized by the presence of one functional POMC allele and one non-functional POMC allele. Heterozygous POMC mutations, (f) characterized by the presence of one functional leptin allele and one non-functional leptin allele. heterozygous leptin mutations, (g) melanocortin 4 receptor (MC4R) mutations (e.g., loss-of-function mutations), (h) prohormone convertase mutations (e.g., loss-of-function mutations), (i) Mutations in genes associated with Bardet-Biedl syndrome (e.g., BBS1–BBS2) 0 mutation), or (j) POMC-MC4R mutations other than those associated with Alström syndrome Disorders characterized by tract defects is selected from The agonist is an MC4R agonist as described herein, e.g., The strike, (R 2 R 3 )-A 1 -c(A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 )-A 10 -R 1 (I) where: A 1 Acc, HN-(CH2) m -C(O), L-amino acid or D-amino acid , or deletion, A 2is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp , or Glu, A 3 is Gly, Ala, β-Ala, Gaba, Aib, D-amino acids, or deletions and A 4 is His, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-T hi, or (X 1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe, A 5 are D-Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal, D -(X 1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe, L-Phe, or D-(Et)Tyr can be, A 6 is Arg, hArg, Dab, Dap, Lys, Orn, or HN-CH(( CH2) n -N(R 4 R 5 ))-C(O), A 7 are Trp, 1-Nal, 2-Nal, Bal, BiP, D-Trp, D-2-Nal al, D-Bal, or D-Bip, A 8 is Gly, D-Ala, Acc, Ala, 13-Ala, Gaba, Apn, A hx, Aha, HN-(CH2) s -C(O), or deletion, A 9 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Dab , Dap, Orn, or Lys; A 10 Acc, HN-(CH2)t -C(O), L-amino acid or D-amino acid acid, or lack thereof, R 1 is OH or NH2, R 2 and R 3 Each of these is independently calculated for each case as H,(C1-C 30 ) alkyl, (C 1-C 30 ) heteroalkyl, (C1-C 30 ) Acyl, (C2-C 30 ) alkenyl, (C2-C 30 ) alkynyl, aryl (C1-C 30 ) Alkyl, aryl (C1-C 30 ) acyl, substituted (C1-C 30 ) alkyl, substituted (C1-C 30 ) heteroalkyl, Substitution (C1-C 30 ) Acyl, Substituted (C2-C 30 ) alkenyl, substituted (C2-C 30 ) Alkynyl, substituted aryl (C1-C 30 ) alkyl, and substituted aryl (C1-C 30 ) acyl; R 4 and R 5 Each of these is independently calculated for each case as H,(C1-C 40 ) alkyl, (C 1-C 40 ) heteroalkyl, (C1-C 40 ) Acyl, (C2-C 40 ) alkenyl, (C2-C 40 ) alkynyl, aryl (C1-C 40 ) Alkyl, aryl (C1-C 40 ) acyl, substituted (C1-C 40 ) alkyl, substituted (C1-C 40 ) heteroalkyl, Substitution (C1-C 40 ) Acyl, Substituted (C2-C40 ) alkenyl, substituted (C2-C 40 ) Alkynyl, substituted aryl (C1-C 40 ) alkyl, substituted aryl (C1-C 40 )a Sill, (C1-C 40 ) alkylsulfonyl, or —C(NH)—NH2; m is, independently in each instance, 1, 2, 3, 4, 5, 6, or 7; n is independently in each instance 1, 2, 3, 4, or 5; s is, independently in each instance, 1, 2, 3, 4, 5, 6, or 7; t is, independently in each instance, 1, 2, 3, 4, 5, 6, or 7; X', X 2 , X 3 , X 4 , and X 8 are H, F, Cl, and B, respectively, independently in each case. r,I,(C 1-10 ) alkyl, substituted (C 1-10 ) alkyl, (C 2-10 )Arche Nil, substitution (C 2-10 ) alkenyl, (C 2-10 ) alkynyl, substituted (C 2-10 ) alkynyl, aryl, substituted aryl, OH, NH2, NO2, or CN. . (Item 65) 65. The method of item 64, wherein the disorder is Prader-Willi syndrome (PWS). (Item 66) The subject has a loss-of-function mutation in the paternal allele of the 15q11-q13 region of chromosome 15. 66. The method according to item 64 or 65, characterized as having or comprising: (Item 67) The subject has or is known to have a mutation, e.g., a loss-of-function mutation, in the MAGEL2 gene. 67. The method according to item 65 or 66, wherein the method is characterized in that (Item 68) the disorder is characterized by one or more mutations (e.g., loss-of-function mutations) in the POMC gene. Item 65. The method according to Item 64. (Item 69) The subject may, for example, have one functional POMC allele and one non-functional POMC allele. are or are identified as heterozygous carriers of the mutation(s) having Item 69. The method according to Item 68, wherein (Item 70) The subject may, for example, have two different non-functional POMC alleles, e.g., POM are compound heterozygous carriers of the mutation(s) with a C null genotype, or Item 69. The method of item 68, as identified. (Item 71) The subject may be a homozygous POMC null genotype, e.g., a subject with a homozygous POMC null genotype. 69. The method of claim 68, wherein the patient is or is identified as a monozygous carrier. . (Item 72) the disorder is characterized by one or more mutations (e.g., loss-of-function mutations) in the PCSK1 gene. Item 65. The method according to Item 64, (Item 73) The subject may, for example, have one functional and one non-functional PCSK1 allele. those who have the allele and are or are heterozygous carriers of the mutation(s) Item 73. The method according to item 72, wherein the method is specified as follows: (Item 74) The subject may, for example, have two non-functional PCSK1 alleles, e.g., PCSK1 have a null genotype, are compound heterozygous carriers of the mutation(s), or Item 73. The method of item 72, wherein the method is identified as being (Item 75) The subject has, for example, a homozygous PCSK1 null genotype, 7. A person according to item 72 who is or is identified as a homozygous carrier. Law. (Item 76) The disorder is characterized by a mutation (e.g., a loss-of-function mutation) in the MAGEL2 gene. Item 64, characterized by the method of item 64. (Item 77) The subject may, for example, have one functional MAGEL2 allele and one non-functional MAGEL It has two alleles, and the remaining functional allele is silenced by maternal imprinting, resulting in A subject who is heterozygous for the mutation(s), including a subject who is a functional MAGEL2 null patient. 77. The method of claim 76, wherein the carrier is or is identified as being a carrier. (Item 78) The subject may, for example, have two mutant, non-functional MAGEL2 alleles, e.g., M Are compound heterozygous carriers of the mutation(s) with an AGEL2 null genotype? 77. The method of claim 76, wherein the method is, or is identified as being, (Item 79) The subject is homozygous for the mutation(s), e.g., has a MAGEL2 null genotype. 77. The method of claim 76, wherein the subject is or is identified as a sex carrier. (Item 80) The disorder is characterized by a mutation (e.g., a loss-of-function mutation) in the leptin receptor gene. 65. The method according to item 64, (Item 81) The subject may, for example, have one functional leptin receptor allele and one non-functional leptin receptor allele. have the receptor allele and are heterozygous carriers of the mutation(s), or 81. The method according to item 80, characterized in that (Item 82) The subject may, for example, have two non-functional leptin receptor alleles, e.g., are compound heterozygous carriers of the mutation(s) and have a leukocyte receptor null genotype, 81. The method according to item 80, or identified as being. (Item 83) The subject is homozygous for the mutation(s), e.g., has a leptin receptor null genotype. 81. The method of claim 80, wherein the carrier is or is identified as being a synthetic carrier. (Item 84) The disorder is characterized by a mutation (e.g., a loss-of-function mutation) in the leptin gene. Item 65. The method according to Item 64. (Item 85) The subject may, for example, have one functional leptin allele and one non-functional leptin allele. are or are identified as heterozygous carriers of the mutation(s) having Item 85. The method according to Item 84, wherein (Item 86) The subject may, for example, have two non-functional leptin alleles, e.g., a leptin null have the genotype, are compound heterozygous carriers of the mutation(s), or are not 85. The method according to item 84, wherein the method is specified as (Item 87) The subject may be homozygous for the mutation(s), e.g., have a leptin null genotype. Item 85. The method of item 84, wherein the carrier is or is identified as being a carrier. (Item 88) The disorder is caused by a mutation (e.g., a loss-of-function mutation) in the 5-HT2c receptor gene. Item 65. The method according to item 64, characterized in that (Item 89) The subject may, for example, have one functional 5-HT2c receptor allele and one non-functional 5-HT2c receptor allele. are heterozygous carriers of the mutation(s) with the HT2c receptor allele, and Item 89. The method according to Item 88, wherein the (Item 90) The subject may, for example, have two non-functional 5-HT2c receptor alleles, e.g., 5 - Compound heterozygous carriers of the mutation(s) with an HT2c receptor null genotype 89. The method of claim 88, wherein the method is or is identified as being. (Item 91) The subject may be a patient with a mutation(s), e.g., a 5-HT2c receptor null genotype. 89. The method of claim 88, wherein the patient is or is identified as a monozygous carrier. . (Item 92) The disorder is caused by the nescient Helix-Loop-Helix 2 (NhHL2) gene 65. The method of claim 64, characterized by one or a mutation (e.g., a loss-of-function mutation) in the offspring. . (Item 93) The subject may, for example, have one functional NhHL2 allele and one non-functional NhHL2 allele. have a causative allele, are heterozygous carriers of the mutation(s), or Item 92. The method of claim 92, wherein the method is characterized by: (Item 94) The subject has, for example, two non-functional NhHL2 alleles, e.g., NhHL2 have a null genotype, are compound heterozygous carriers of the mutation(s), or Item 92. The method of claim 92, wherein the method is characterized as follows: (Item 95) the subject is homozygous for the mutation(s), e.g., has an NhHL2 null genotype 93. The method of claim 92, wherein the carrier is or is identified as being. (Item 96) The disorder may involve a mutation (e.g., a loss-of-function mutation) in a prohormone convertase gene. Item 65. The method according to Item 64, wherein: (Item 97) The subject may, for example, have one functional prohormone convertase allele and one non-functional prohormone convertase allele. are heterozygous carriers of the mutation(s) with a steroid hormone convertase allele, Item 97. The method of item 96, or identified as being. (Item 98) The subject, for example, has two non-functional prohormone convertase alleles, e.g., Compound heterozygous carriers of the mutation(s) with a prohormone convertase null genotype 97. The method of claim 96, wherein the method is or is identified as being a (Item 99) The subject has, for example, a prohormone convertase null genotype, 97. A person according to item 96, who is or is identified as a homozygous carrier. Law. (Item 100) The disorder is caused by a mutation (e.g., a mutation in the carboxypeptidase E (CPE) gene) 65. The method of item 64, characterized by a loss-of-function mutation (e.g., a loss-of-function mutation). (Item 101) The subject may, for example, have one functional and one non-functional CPE allele. are, or have been identified as, heterozygous carriers of the mutation(s) Item 101. The method according to Item 100. (Item 102) The subject may have, for example, two non-functional CPE alleles, e.g., a CPE null allele. are or are compound heterozygous carriers of the mutation(s) with a phenotype Item 101. The method according to item 100, characterized in that (Item 103) The subject may be homozygous for the mutation(s), e.g., have a CPE null genotype. Item 101. The method of item 100, which is or is identified as being a rear. (Item 104) The disorder is caused by one or more mutations in the single-minded 1 (SIM1) gene. 65. The method of item 64, characterized by a mutation (e.g., a loss-of-function mutation). (Item 105) The subject may, for example, have one functional SIM1 allele and one non-functional SIM1 allele. are or are identified as heterozygous carriers of the mutation(s) having Item 105. The method according to Item 104, wherein (Item 106) The subject has, e.g., two non-functional SIM1 alleles, e.g., a SIM1 null. have the genotype, are compound heterozygous carriers of the mutation(s), or are not Item 105. The method of item 104, wherein the method is specified as (Item 107) The subject may be homozygous for the mutation(s), e.g., have a SIM1 null genotype. Item 105. The method of item 104, wherein the carrier is or is identified as being a carrier. (Item 108) The disorder is characterized by a hypermethylated POMC gene (e.g., hypermethylated in the POMC intron). Methylated, e.g., methylated cytosine, e.g., 5' methylcytosine (e.g., hypermethylated in the CpG island of the POMC gene) Item 64, characterized by the method of item 64. (Item 109) The disorder is (e) characterized by the presence of one functional POMC allele and one non-functional POMC allele; Heterozygous POMC mutations (f) characterized by the presence of one functional leptin allele and one non-functional leptin allele; heterozygous leptin mutations, (g) characterized by the presence of one functional MC4R allele and one non-functional MC4R allele; Heterozygous melanocortin 4 receptor (MC4R) mutations, (h) prohormone convertase mutations (e.g., loss-of-function mutations), (i) Mutations in genes associated with Bardet-Biedl syndrome (e.g., BBS1 to BBS20) mutations), or (j) POMC-MC4R pathway, other than mutations in genes associated with Alström syndrome Item 65. The method of item 64, characterized by a deficiency of (Item 110) The method according to any one of items 64 to 109, wherein the daily dose is 0.1 mg to 10 mg. How to post. (Item 111) Item 111. The method according to item 110, wherein the daily dose is about 0.1 mg to about 7.5 mg. (Item 112) Item 111. The method according to item 110, wherein the daily dose is about 0.1 mg to about 5 mg. (Item 113) Item 111. The method according to item 110, wherein the daily dose is about 0.1 mg to about 2.5 mg. (Item 114) Item 111. The method according to Item 110, wherein the daily dose is about 0.1 mg to about 2 mg. (Item 115) Item 111. The method according to item 110, wherein the daily dose is about 0.1 mg to about 1 mg. (Item 116) Any one of items 64 to 109, wherein the daily dose is about 0.2 mg to about 10 mg. The method described below. (Item 117) Item 117. The method according to item 116, wherein the daily dose is about 0.2 mg to about 7.5 mg. (Item 118) Item 117. The method according to item 116, wherein the daily dose is about 0.2 mg to about 5 mg. (Item 119) Item 117. The method according to item 116, wherein the daily dose is about 0.2 mg to about 2.5 mg. (Item 120) Item 117. The method according to item 116, wherein the daily dose is about 0.2 mg to about 2 mg. (Item 121) Item 117. The method according to item 116, wherein the daily dose is about 0.2 mg to about 1.5 mg. (Item 122) Item 117. The method according to item 116, wherein the daily dose is about 0.2 mg to about 1 mg. (Item 123) Any one of items 64 to 109, wherein the daily dose is about 0.3 mg to about 10 mg. The method described below. (Item 124) Item 124. The method according to Item 123, wherein the daily dose is about 0.3 mg to about 7.5 mg. (Item 125) Item 124. The method according to Item 123, wherein the daily dose is about 0.3 mg to about 5 mg. (Item 126) Item 124. The method according to Item 123, wherein the daily dose is about 0.3 mg to about 2.5 mg. (Item 127) Item 124. The method according to Item 123, wherein the daily dose is about 0.3 mg to about 2 mg. (Item 128) Item 124. The method according to Item 123, wherein the daily dose is about 0.3 mg to about 1.5 mg. (Item 129) Item 124. The method according to Item 123, wherein the daily dose is about 0.3 mg to about 1 mg. (Item 130) The daily dose is about 0.25 mg (e.g., 0.25 mg) to about 0.5 mg (e.g., 0. 109. The method according to any one of items 64 to 109, wherein the amount of the active ingredient is 5 mg. (Item 131) The daily dose is about 0.5 mg (for example, 0.5 mg) to about 0.75 mg (for example, 0.7 109. The method according to any one of items 64 to 109, wherein the amount of the active ingredient is 5 mg. (Item 132) Item 130, wherein the daily dose is about 0.25 mg (e.g., 0.25 mg). method. (Item 133) Item 130 or 131, wherein the daily dose is about 0.5 mg (e.g., 0.5 mg). The method described below. (Item 134) The daily dose is about 0.75 mg (for example, 0.75 mg) to about 1.25 mg (for example, 1.25 mg). 109. The method according to any one of items 64 to 109, wherein the total amount of the active ingredient is 10 mg. (Item 135) Item 135. The method of item 134, wherein the daily dose is about 1 mg (e.g., 1 mg). (Item 136) The daily dose is about 1.25 mg (e.g., 1.25 mg) to about 2 mg (e.g., 2 mg). The method according to any one of Items 64 to 109, wherein (Item 137) Item 136. The method according to item 136, wherein the daily dose is about 1.5 mg (e.g., 1.5 mg). . (Item 138) Item 137. The method of item 136, wherein the daily dose is about 2 mg (e.g., 2 mg). (Item 139) The agonist is administered to the subject in a unit dosage suitable for injection, e.g., subcutaneous injection. The method according to any one of items 64 to 138, comprising: (Item 140) The unit dose is about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8 140. The method of claim 139, comprising administering 1 mg of the agonist to a patient in need thereof. (Item 141) The unit dose is delivered via a delivery device, e.g., a syringe (e.g., a pre-filled syringe). , implantable devices, needleless hypodermic injection devices, infusion pumps (e.g., implantable infusion pumps), or 141. The method of claim 139 or 140, wherein the pharmaceutical composition is disposed in an osmotic delivery system. (Item 142) 2. Any of items 64 to 141, wherein the agonist is administered subcutaneously, for example by subcutaneous injection. 1. The method according to claim 1. (Item 143) The agonist is administered for at least 3 weeks, e.g., at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 , 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 weeks or more, or at least 1, 2, 3, 4, or 5 , 6, 7, 8, 9, 10, 11, or 12 months or more, or at least 1, 2, 3, Patients described in any one of items 64 to 142 who receive daily treatment for a period of 4 years or more Law. (Item 144) 4. The method according to any one of items 64 to 143, wherein the subject is obese, e.g., severely obese. method. (Item 145) 145. The method according to any one of items 64 to 144, wherein the subject has early-onset severe obesity. . (Item 146) 146. The method of any one of items 64 to 145, wherein the subject has an excess of appetite. (Item 147) The subject is administered the agonist prior to administration, e.g., at the time the agonist is prescribed, or or at the time of the first dose, 25 kg / m 2 Over (e.g., ≥ 25, 30, 31, 32, 33 , 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 kg / m 2 have a body mass index (BMI) of 40 or higher 147. The method according to any one of Items 64 to 146. (Item 148) The subject is administered the agonist prior to administration, e.g., at the time the agonist is prescribed, or or 35 kg / m at the time of the first dose. 2 Over (e.g., ≥ 36, 37, 38, 39, 40 , 41, 42, 43, 44, 45, 46, 47, 48, 49, 50kg / m 2 , or A patient according to any one of items 64 to 147 who has a body mass index (BMI) of 100 or more. Law. (Item 149) The subject is administered the agonist prior to administration, e.g., at the time the agonist is prescribed, or or at the time of the first dose, 40 kg / m 2 Over (e.g., ≥ 41, 42, 43, 44, 45 , 46, 47, 48, 49, 50, 51, 52, 53, 54, 55kg / m 2 , or A patient according to any one of items 64 to 148 who has a body mass index (BMI) of 100 or more. Law. (Item 150) The subject is administered the agonist prior to administration, e.g., at the time the agonist is prescribed, or or at the time of the first dose, 45 kg / m 2 Over (e.g., ≥ 46, 47, 48, 49, 50 , 51, 52, 53, 54, 55 kg / m 2 Body Mass Index (BMI) of 18.5 or higher The method according to any one of items 64 to 149, comprising: (Item 151) The subject is administered the agonist prior to administration, e.g., at the time the agonist is prescribed, or or at the time of the first administration, one or more prior therapies, e.g., exercise therapy, diet therapy, or 151. The method according to any one of items 64 to 150, wherein behavioral therapy has failed. (Item 152) the subject has a lower body weight after administration of the agonist than before administration of the agonist. 152. The method according to any one of Items 64 to 151. (Item 153) administration of said agonist reduces said subject's body weight by 1 week compared to said subject's body weight before treatment Approximately 1kg to 3kg after treatment, or approximately 1kg to 6kg after 2 weeks of treatment, or approximately 1kg to 6kg after 4 weeks Approximately 2kg to 12kg after 1 week of treatment, or approximately 4kg to 24kg after 8 weeks of treatment, or approximately 1 Lose approximately 8kg to 48kg after 6 weeks of treatment. How to post. (Item 154) The administration of the agonist may be, for example, 1 to 2 weeks or more of treatment, 2 to 4 weeks or more of treatment, 4 to Treatment for 8 weeks or more, treatment for 8 to 16 weeks or more, treatment for 16 to 32 weeks or more, or treatment for 32 or more The subject receives approximately 1 to 2 kg / week, for example, approximately 2 kg / week, for a period of 64 weeks or more. The method according to any one of items 64 to 153, wherein the body weight of the subject is reduced. (Item 155) The administration of the agonist may be, for example, 1 to 2 weeks or more of treatment, 2 to 4 weeks or more of treatment, 4 to Treating the subject's hunger level after 8 weeks or more of treatment, or after 8 to 16 weeks or more of treatment reduced compared to the subject's previous hunger level (e.g., on a Likert hunger scale) Decrease the score, e.g., decrease the score by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points), e.g., the subject's hunger sensation disappears (e.g., Liker t) a score of 0 on the hunger scale) method. (Item 156) Administration of the agonist can be, for example, for a period of 24 hours, a week, or 30 days or more. and measuring the subject's resting energy expenditure (REE), e.g., a control REE (e.g., before treatment). or, for example, a subject with a similar pre-treatment BMI, e.g., a lean body mass of 1 Detectably / significantly reduced compared to the given REE when expressed as REE per kg The method according to any one of Items 64 to 155, wherein the method does not reduce the amount of the oxidized material. (Item 157) Administration of the agonist can be, for example, for a period of 24 hours, a week, or 30 days or more. and measuring the subject's resting energy expenditure (REE), e.g., compared with a control REE (e.g., For example, compared to the REE of said subject before treatment, or, for example, compared to the REE of subjects with similar pre-treatment BMI , e.g., 1 kg of lean body mass after a similar level of weight loss is achieved by fasting. increase (compared to a given REE when expressed as REE per ton), item 156 The method described below. (Item 158) Administration of the agonist reduces food intake by the subject as compared to a control (e.g., the subject before treatment). a daily food intake or 24-hour or weekly food intake, items 64-157 The method described. (Item 159) Administration of the agonist reduces food intake to a control (e.g., the subject's food intake before treatment or or a given food intake level), e.g., at least 100 kcal less At most 100, 125, 150, 175, 200, 225, 250, 275, 300, 3 25, 350, 375, 400, 425, 450, 475, 500, 525, 550, 5 75, 600, 1000 kcal or more reduction in food intake, e.g. The amount is the daily food intake or the food intake over a 24-hour period or a week. 58. The method according to claim 58. (Item 160) Administration of the agonist is continued for 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 weeks after the start of treatment. The subject's waist circumference when measured at or after a control (e.g., the subject's waist circumference before treatment) is compared to the control (e.g., the subject's waist circumference when measured at or after a control). The method according to any one of items 64 to 159, wherein the total body mass index (LGR) is reduced compared to the total body mass index (Waist circumference). (Item 161) Administration of the agonist is continued for 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 weeks after the start of treatment. The subject's waist circumference when measured at or after a control (e.g., the subject's waist circumference before treatment) is compared to the control (e.g., the subject's waist circumference when measured at or after a control). at least 2 cm (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10 cm or more). (Item 162) Administration of the agonist is continued for 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 weeks after the start of treatment. The subject's blood pressure (e.g., diastolic and / or systolic blood pressure) when measured at or after Item 64-1 does not detectably increase the systolic blood pressure (systolic blood pressure) of the subject compared to the blood pressure of the subject before treatment. 61. The method of any one of claims 61 to 61. (Item 163) Administration of the agonist is continued for 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 weeks after the start of treatment. The subject's blood pressure (e.g., diastolic and / or systolic blood pressure) when measured at or after Any of items 64 to 162, wherein the systolic blood pressure (systolic blood pressure) of the subject is reduced compared to the blood pressure of the subject before treatment. 1. The method according to claim 1. (Item 164) Administration of the agonist is continued for 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 weeks after the start of treatment. and comparing the subject's systolic blood pressure measured after 10 minutes or more with the subject's blood pressure before treatment. Compare to at least 3 mmHg (e.g., at least 3, 3.5, 4, 4.5, 5, 5. 5, 6, 6.5, 7 mmHg or more). (Item 165) Administration of the agonist is continued for 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 weeks after the start of treatment. and comparing the subject's diastolic blood pressure measured after 10 days or more with the subject's blood pressure before treatment. Compared to at least 4 mmHg (e.g., at least 4, 7, 7.5, 8, 8.5, 9, 9.5, 10 mmHg, or more). (Item 166) 66. The method according to any one of items 64 to 165, wherein the subject is a mammal, for example a human. Law. (Item 167) The agonist is Ac-Arg-c(Cys-D-Ala-His-D-Phe-A Any of items 64 to 166, wherein the amino acid sequence is rg-Trp-Cys-NH2 (SEQ ID NO: 140). 1. The method according to claim 1. (Item 168) Obtaining knowledge of the subject's genotype, e.g., Prohormone convertase genes, including the POMC gene and PCSK1 gene, MAGEL2 gene, leptin receptor gene, Leptin gene, 5-HT2c receptor gene, Nescient Helix-Loop-Helix 2 (NhHL2) gene, Carboxypeptidase E (CPE) gene, single-minded 1 (SIM1) gene, POMC-MC4R pathway genes, BBS1~BBS20), ALMS1, BDNF, MCH1R, MCH, NTRK2, SIM1, ENPP1, COH1, CN R1, NPC1, c-MAF, PTER, FTO, TMEM18 (childhood), SDCCAG8, TNKS / MSRA, GNPDA2 (childhood), NEGr1, INSIG2, KCTD15, NROB2, and 16p11 .2 deletion Item 64, which includes obtaining knowledge of the genotype of mutations (including the SH2B1 gene) A method according to any one of claims 1 to 167. (Item 169) The agonist is selected from the group consisting of a compound selected from the group consisting of a compound having a specific structure, ... 169. The method of claim 168, wherein the administration is in response to (Item 170) 1. A method of treating a disorder in a subject in need thereof, wherein the disorder is (i) characterized by one or more mutations (e.g., loss-of-function mutations) in the PCSK1 gene; hindrance, (ii) characterized by one or more mutations (e.g., loss-of-function mutations) in the MAGEL2 gene; Disability, (iii) Identifying one or more mutations (e.g., loss-of-function mutations) in the leptin receptor gene. Symptoms of disability, (iv) one or more mutations (e.g., loss-of-function mutations) in the 5-HT2c receptor gene Disorders characterized by (v) Nescient Helix-Loop-Helix 2 (NhHL2) gene a disorder characterized by one or more mutations (e.g., loss-of-function mutations) in (vi) one or more mutations in the carboxypeptidase E (CPE) gene (e.g., Disorders characterized by loss-of-function mutations, (vii) one or more mutations in the single-minded 1 (SIM1) gene disorders characterized by mutations (e.g., loss-of-function mutations), (viii) hypermethylated POMC gene (e.g., hypermethylated in the POMC intron) Methylated, e.g., methylated cytosine, e.g., 5' methylcytosine (e.g., hypermethylated in the CpG island of the POMC gene) Symptoms of disability, (ix) A disorder characterized by a defect in the POMC-MC4R pathway, (e) POMC mutations, e.g., one functional POMC allele and one non-functional POMC allele. Heterozygous POMC mutations, characterized by the presence of the MC allele, (f) leptin mutations, e.g., one functional leptin allele and one non-functional leptin allele; heterozygous leptin mutations characterized by the presence of the tin allele, (g) melanocortin 4 receptor (MC4R) mutation, or (h) Patients characterized by defects in the POMC-MC4R pathway other than prohormone convertase mutations Disability, (x) characterized by a homozygous POMC mutation (e.g., a loss-of-function mutation), e.g., POM Disorders characterized by the C null genotype, (xi) characterized by compound heterozygous POMC mutations (e.g., two non-functional alleles) a disorder characterized by the presence of, for example, a POMC null genotype; (xii) characterized by a homozygous leptin mutation (e.g., a loss-of-function mutation), e.g., Disorders characterized by a putin null genotype, (xiii) characterized by compound heterozygous leptin mutations (e.g., two non-functional alleles) a disorder characterized by the presence of a leptin null genotype, e.g., a disorder characterized by a leptin null genotype, (xiv) Mutations in genes associated with Bardet-Biedl syndrome (e.g., BBS1 to BBS 20 mutations), or (xv) Disorders characterized by mutations in genes associated with Alström syndrome and the method comprises administering an agonist of the melanocortin 4 receptor (MC4R). This includes: The agonist is an MC4R agonist as described herein, e.g., The strike, (R 2 R 3 )-A 1 -c(A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 )-A 10 -R 1 (I) where: A 1 Acc, HN-(CH2) m -C(O), L-amino acid or D-amino acid , or deletion, A 2 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp , or Glu, A 3 is Gly, Ala, β-Ala, Gaba, Aib, D-amino acids, or deletions and A 4 is His, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-T hi, or (X1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe, A 5 are D-Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal, D -(X 1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe, L-Phe, or D-(Et)Tyr can be, A 6 is Arg, hArg, Dab, Dap, Lys, Orn, or HN-CH(( CH2) n -N(R 4 R 5 ))-C(O), A 7 are Trp, 1-Nal, 2-Nal, Bal, BiP, D-Trp, D-2-Nal al, D-Bal, or D-Bip, A 8 is Gly, D-Ala, Acc, Ala, 13-Ala, Gaba, Apn, A hx, Aha, HN-(CH2) s -C(O), or deletion, A 9 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Dab , Dap, Orn, or Lys; A 10 Acc, HN-(CH2) t -C(O), L-amino acid or D-amino acid acid, or lack thereof, R 1 is OH or NH2, R 2 and R 3 Each of these is independently calculated for each case as H,(C1-C 30 ) alkyl, (C 1-C 30 ) heteroalkyl, (C1-C30 ) Acyl, (C2-C 30 ) alkenyl, (C2-C 30 ) alkynyl, aryl (C1-C 30 ) Alkyl, aryl (C1-C 30 ) acyl, substituted (C1-C 30 ) alkyl, substituted (C1-C 30 ) heteroalkyl, Substitution (C1-C 30 ) Acyl, Substituted (C2-C 30 ) alkenyl, substituted (C2-C 30 ) Alkynyl, substituted aryl (C1-C 30 ) alkyl, and substituted aryl (C1-C 30 ) acyl; R 4 and R 5 Each of these is independently calculated for each case as H,(C1-C 40 ) alkyl, (C 1-C 40 ) heteroalkyl, (C1-C 40 ) Acyl, (C2-C 40 ) alkenyl, (C2-C 40 ) alkynyl, aryl (C1-C 40 ) Alkyl, aryl (C1-C 40 ) acyl, substituted (C1-C 40 ) alkyl, substituted (C1-C 40 ) heteroalkyl, Substitution (C1-C 40 ) Acyl, Substituted (C2-C 40 ) alkenyl, substituted (C2-C 40 ) Alkynyl, substituted aryl (C1-C 40 ) alkyl, substituted aryl (C1-C 40 )a Sill, (C1-C 40 ) alkylsulfonyl, or —C(NH)—NH2; m is, independently in each instance, 1, 2, 3, 4, 5, 6, or 7; n is independently in each instance 1, 2, 3, 4, or 5; s is, independently in each instance, 1, 2, 3, 4, 5, 6, or 7; t is, independently in each instance, 1, 2, 3, 4, 5, 6, or 7; X', X 2 , X 3 , X 4 , and X 8 are H, F, Cl, and B, respectively, independently in each case. r,I,(C 1-10 ) alkyl, substituted (C 1-10 ) alkyl, (C 2-10 )Arche Nil, substitution (C 2-10 ) alkenyl, (C 2-10 ) alkynyl, substituted (C 2-10 ) alkynyl, aryl, substituted aryl, OH, NH2, NO2, or CN. . (Item 171) The disorder is characterized by a homozygous POMC mutation (e.g., loss of mutation), e.g., 171. The method of claim 170, characterized by a POMC null genotype. (Item 172) The disorder is characterized by compound heterozygous POMC mutations (e.g., two non-functional alleles). characterized by the presence of a POMC null genotype, see item 170. The method described. (Item 173) The mutations are p.Lys51Term g.A6851>T and p.Arg145Pr Item 173. The method of item 172, wherein ofsX12 g.7134delG. (Item 174) the disorder is characterized by one or more mutations (e.g., loss-of-function mutations) in the PCSK1 gene. Item 170. The method according to Item 170, (Item 175) The subject may, for example, have one functional and one non-functional PCSK1 allele. those who have the allele and are or are heterozygous carriers of the mutation(s) Item 175. The method according to Item 174, wherein (Item 176) The subject may, for example, have two non-functional PCSK1 alleles, e.g., PCSK1 have a null genotype, are compound heterozygous carriers of the mutation(s), or Item 175. The method of item 174, wherein the method is identified as being (Item 177) The subject is homozygous for the mutation(s), e.g., has a PCSK1 null genotype. 175. The method of claim 174, which is or is identified as being a carrier. (Item 178) The disorder is characterized by a mutation (e.g., a loss-of-function mutation) in the MAGEL2 gene. Item 170, characterized by the method of item 170. (Item 179) The subject may, for example, have one functional MAGEL2 allele and one non-functional MAGEL Are or are heterozygous carriers of the mutation(s) with two alleles Item 178, characterized in that the method of item 178 is (Item 180) The subject may, for example, have two non-functional MAGEL2 alleles, e.g., MAGE are compound heterozygous carriers of the mutation(s) with an L2 null genotype, and The method according to item 178, wherein the (Item 181) The subject is homozygous for the mutation(s), e.g., has a MAGEL2 null genotype. 179. The method of claim 178, wherein the person is or is identified as being a sex carrier. (Item 182) The disorder is characterized by a mutation (e.g., a loss-of-function mutation) in the leptin receptor gene. Item 170. The method according to item 170, (Item 183) The subject may, for example, have one functional leptin receptor allele and one non-functional leptin receptor allele. have the receptor allele and are heterozygous carriers of the mutation(s), or Item 182. The method of claim 182, wherein the method is specified as being (Item 184) The subject may, for example, have two non-functional leptin receptor alleles, e.g., are compound heterozygous carriers of the mutation(s) and have a leukocyte receptor null genotype, Item 182. The method of claim 182, wherein the method is or is identified as being. (Item 185) The subject is homozygous for the mutation(s), e.g., has a leptin receptor null genotype. 183. The method of claim 182, wherein the carrier is or is identified as being a synthetic carrier. (Item 186) The disorder is characterized by a homozygous leptin mutation (e.g., loss of mutation), e.g., 171. The method of item 170, characterized by a leptin null genotype. (Item 187) The disorder is characterized by compound heterozygous leptin mutations (e.g., two non-functional characterized by the presence of a leptin null genotype, e.g., as described in item 170. The method described. (Item 188) The disorder is caused by a mutation (e.g., a loss-of-function mutation) in the 5-HT2c receptor gene. Item 170. The method according to Item 170, (Item 189) The subject may, for example, have one functional 5-HT2c receptor allele and one non-functional 5-HT2c receptor allele. are heterozygous carriers of the mutation(s) with the HT2c receptor allele, and The method according to item 188, wherein the (Item 190) The subject may, for example, have two non-functional 5-HT2c receptor alleles, e.g., 5 - Compound heterozygous carriers of the mutation(s) with an HT2c receptor null genotype Item 189. The method of item 188, which is or is identified as being. (Item 191) The subject may be a patient with a mutation(s), e.g., a 5-HT2c receptor null genotype. 188. A person according to item 188, who is or is identified as being a monozygous carrier. Law. (Item 192) The disorder is caused by the nescient Helix-Loop-Helix 2 (NhHL2) gene 170. The method according to item 170, characterized by one or a mutation (e.g., a loss-of-function mutation) in a gene Law. (Item 193) The subject may, for example, have one functional NhHL2 allele and one non-functional NhHL2 allele. have a causative allele, are heterozygous carriers of the mutation(s), or Item 192. The method of claim 192, wherein the method is characterized by: (Item 194) The subject has, for example, two non-functional NhHL2 alleles, e.g., NhHL2 have a null genotype, are compound heterozygous carriers of the mutation(s), or Item 192. The method of claim 192, wherein the method is characterized as being (Item 195) the subject is homozygous for the mutation(s), e.g., has an NhHL2 null genotype 193. The method of claim 192, which is or is identified as being a carrier. (Item 196) The disorder is caused by a mutation (e.g., a mutation in the carboxypeptidase E (CPE) gene) 171. The method of claim 170, characterized by a loss-of-function mutation. (Item 197) The subject may, for example, have one functional and one non-functional CPE allele. are, or have been identified as, heterozygous carriers of the mutation(s) Item 197. The method of item 196. (Item 198) The subject may have, for example, two non-functional CPE alleles, e.g., a CPE null allele. are or are compound heterozygous carriers of the mutation(s) with a phenotype Item 197. The method of item 196, wherein the method is characterized by (Item 199) The subject may be homozygous for the mutation(s), e.g., have a CPE null genotype. Item 197. The method of item 196, which is or is identified as being a rear. (Item 200) The disorder is caused by one or more mutations in the single-minded 1 (SIM1) gene. 171. The method of claim 170, characterized by a mutation (e.g., a loss-of-function mutation). (Item 201) The subject may, for example, have one functional SIM1 allele and one non-functional SIM1 allele. are or are identified as heterozygous carriers of the mutation(s) having The method according to Item 200, wherein (Item 202) The subject has, e.g., two non-functional SIM1 alleles, e.g., a SIM1 null. have the genotype, are compound heterozygous carriers of the mutation(s), or are not Item 201. The method of item 200, as specified. (Item 203) The subject may be homozygous for the mutation(s), e.g., have a SIM1 null genotype. Item 201. The method of item 200, wherein the carrier is or is identified as being. (Item 204) The disorder is characterized by a hypermethylated POMC gene (e.g., hypermethylated in the POMC intron). Methylated, e.g., methylated cytosine, e.g., 5' methylcytosine (e.g., hypermethylated in the CpG island of the POMC gene) Item 170, characterized by the method of item 170. (Item 205) The subject has a POM gene, for example, at the intron 2-exon 3 boundary of the POMC gene. have or have been identified as having a hypermethylated CpG island in the C gene The method according to Item 204. (Item 206) The disorder is characterized by POMC mutations, e.g., one functional POMC allele and one non-functional POMC allele. POMC-MC4, other than heterozygous POMC mutations characterized by the presence of a POMC allele 171. The method of item 170, characterized by a defect in the R pathway. (Item 207) The disorder is characterized by leptin mutations, e.g., one functional leptin allele and one non-functional leptin allele. POMC-MC4, other than heterozygous leptin mutations characterized by the presence of leptin alleles 171. The method of item 170, characterized by a defect in the R pathway. (Item 208) The disorder is characterized by MC4R mutations, e.g., one functional and one non-functional MC4R allele. Heterozygous melanocortin 4 receptor (MC4R) mutations characterized by the presence of MC4R alleles 171. The method of claim 170, characterized by a defect in the POMC-MC4R pathway other than a mutation. (Item 209) The disorder is characterized by a defect in the POMC-MC4R pathway other than a prohormone convertase mutation. Item 170. The method according to Item 170, (Item 210) The agonist is administered to the subject in a unit dosage suitable for injection, e.g., subcutaneous injection. The method according to any one of items 170 to 209, comprising: (Item 211) The unit dose is about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8 211. The method of claim 210, comprising administering 1 mg of the agonist to a patient in need thereof. (Item 212) The unit dose is delivered via a delivery device, e.g., a syringe (e.g., a pre-filled syringe). , implantable devices, needleless hypodermic injection devices, infusion pumps (e.g., implantable infusion pumps), or 212. The method of claim 210 or 211, wherein the drug is disposed in an osmotic delivery system. (Item 213) Any of items 170 to 211, wherein the agonist is administered subcutaneously, for example by subcutaneous injection. 1. The method according to claim 1. (Item 214) The agonist is administered for at least 3 weeks, e.g., at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 , 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 weeks or more, or at least 1, 2, 3, 4, or 5 , 6, 7, 8, 9, 10, 11, or 12 months or more, or at least 1, 2, 3, 214. The method according to any one of items 170 to 213, wherein the method is administered daily for a period of 4 years or more. method. (Item 215) 5. The method according to any one of items 170 to 214, wherein the subject is obese, e.g. severely obese. How to do it. (Item 216) 6. The method according to any one of items 170 to 215, wherein the subject has early-onset severe obesity. Law. (Item 217) 217. The method of any one of items 170 to 216, wherein the subject has an excess of appetite. (Item 218) The subject is administered the agonist prior to administration, e.g., at the time the agonist is prescribed, or or at the time of the first dose, 25 kg / m 2 Over (e.g., ≥ 25, 30, 31, 32, 33 , 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 kg / m 2 have a body mass index (BMI) of 40 or higher 218. The method according to any one of Items 170 to 217. (Item 219) The subject is administered the agonist prior to administration, e.g., at the time the agonist is prescribed, or or 35 kg / m at the time of the first dose. 2 Over (e.g., ≥ 36, 37, 38, 39, 40 , 41, 42, 43, 44, 45, 46, 47, 48, 49, 50kg / m 2 , or 219. The method according to any one of items 170 to 218, wherein the patient has a body mass index (BMI) of 100 or more. method. (Item 220) The subject is administered the agonist prior to administration, e.g., at the time the agonist is prescribed, or or at the time of the first dose, 40 kg / m 2 Over (e.g., ≥ 41, 42, 43, 44, 45 , 46, 47, 48, 49, 50, 51, 52, 53, 54, 55kg / m 2 , or 219. The method according to any one of items 170 to 219, wherein the patient has a body mass index (BMI) of 100 or more. method. (Item 221) The subject is administered the agonist prior to administration, e.g., at the time the agonist is prescribed, or or at the time of the first dose, 45 kg / m 2 Over (e.g., ≥ 46, 47, 48, 49, 50 , 51, 52, 53, 54, 55 kg / m 2 Body Mass Index (BMI) of 18.5 or higher The method according to any one of Items 170 to 220, comprising: (Item 222) The subject is administered the agonist prior to administration, e.g., at the time the agonist is prescribed, or or at the time of the first administration, one or more prior therapies, e.g., exercise therapy, diet therapy, or 222. The method according to any one of items 170 to 221, wherein the patient has had a history of failure of behavioral therapy. (Item 223) the subject has a lower body weight after administration of the agonist than before administration of the agonist. 223. The method according to any one of Items 170 to 222. (Item 224) administration of said agonist reduces said subject's body weight by 1 week compared to said subject's body weight before treatment Approximately 1kg to 3kg after treatment, or approximately 1kg to 6kg after 2 weeks of treatment, or approximately 1kg to 6kg after 4 weeks Approximately 2kg to 12kg after 1 week of treatment, or approximately 4kg to 24kg after 8 weeks of treatment, or approximately 1 Lose approximately 8kg to 48kg after 6 weeks of treatment. The method described. (Item 225) The administration of the agonist may be, for example, 1 to 2 weeks or more of treatment, 2 to 4 weeks or more of treatment, 4 to Treatment for 8 weeks or more, treatment for 8 to 16 weeks or more, treatment for 16 to 32 weeks or more, or treatment for 32 or more The subject receives approximately 1 to 2 kg / week, for example, approximately 2 kg / week, for a period of 64 weeks or more. The method according to any one of items 170 to 224, wherein the body weight of the subject is reduced. (Item 226) The administration of the agonist may be, for example, 1 to 2 weeks or more of treatment, 2 to 4 weeks or more of treatment, 4 to Treating the subject's hunger level after 8 weeks or more of treatment, or after 8 to 16 weeks or more of treatment reduced compared to the subject's previous hunger level (e.g., on a Likert hunger scale) Decrease the score, e.g., decrease the score by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points), e.g., the subject's hunger sensation disappears (e.g., Liker t) score of 0 on the hunger scale, described in any one of items 170-225 How to do it. (Item 227) Administration of the agonist can be, for example, for a period of 24 hours, a week, or 30 days or more. and measuring the subject's resting energy expenditure (REE), e.g., a control REE (e.g., before treatment). or, for example, a subject with a similar pre-treatment BMI, e.g., a lean body mass of 1 Detectably / significantly reduced compared to the given REE when expressed as REE per kg The method according to any one of Items 170 to 226, wherein the method does not reduce the amount of the oxidized material. (Item 228) Administration of the agonist can be, for example, for a period of 24 hours, a week, or 30 days or more. and measuring the subject's resting energy expenditure (REE), e.g., compared with a control REE (e.g., For example, compared to the REE of said subject before treatment, or, for example, compared to the REE of subjects with similar pre-treatment BMI , e.g., 1 kg of lean body mass after a similar level of weight loss is achieved by fasting. increase (compared to a given REE when expressed as REE per ton), item 227 The method described below. (Item 229) Administration of the agonist reduces food intake by the subject as compared to a control (e.g., the subject before treatment). a daily food intake or Any one of items 170-228, which is food intake over a 24-hour period or over a week The method described below. (Item 230) Administration of the agonist reduces food intake to a control (e.g., the subject's food intake before treatment or or a given food intake level), e.g., at least 100 kcal less At most 100, 125, 150, 175, 200, 225, 250, 275, 300, 3 25, 350, 375, 400, 425, 450, 475, 500, 525, 550, 5 75, 600, 1000 kcal or more reduction in food intake, e.g. Item 2: Amount of food intake per day or over a 24-hour period or a week 29. The method according to claim 29. (Item 231) Administration of the agonist is continued for 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 weeks after the start of treatment. The subject's waist circumference when measured at or after a control (e.g., the subject's waist circumference before treatment) is compared to the control (e.g., the subject's waist circumference when measured at or after a control). The method according to any one of items 170 to 230, wherein the total body mass index (LGR) is reduced compared to the waist circumference. (Item 232) Administration of the agonist is continued for 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 weeks after the start of treatment. The subject's waist circumference when measured at or after a control (e.g., the subject's waist circumference before treatment) is compared to the control (e.g., the subject's waist circumference when measured at or after a control). at least 2 cm (e.g., at least 2, 3, 4, 5, 6, 7, 8, 232. The method of claim 231, wherein the thickness of the tissue is reduced by 9, 10 cm or more. (Item 233) Administration of the agonist is continued for 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 weeks after the start of treatment. The subject's blood pressure (e.g., diastolic and / or systolic blood pressure) when measured at or after Item 170 - Systolic blood pressure (systolic blood pressure) does not detectably increase compared to the blood pressure of the subject before treatment. 232. The method of any one of claims 232. (Item 234) Administration of the agonist is continued for 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 weeks after the start of treatment. The subject's blood pressure (e.g., diastolic and / or systolic blood pressure) when measured at or after any of items 170 to 233, wherein the systolic blood pressure (systolic blood pressure) of the subject is reduced compared to the blood pressure of the subject before treatment. 1. The method according to claim 1. (Item 235) Administration of the agonist is continued for 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 weeks after the start of treatment. and comparing the subject's systolic blood pressure measured after 10 minutes or more with the subject's blood pressure before treatment. Compare to at least 3 mmHg (e.g., at least 3, 3.5, 4, 4.5, 5, 5. 5, 6, 6.5, 7 mmHg or more). (Item 236) Administration of the agonist is continued for 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 weeks after the start of treatment. and comparing the subject's diastolic blood pressure measured after 10 days or more with the subject's blood pressure before treatment. Compared to at least 4 mmHg (e.g., at least 4, 7, 7.5, 8, 8.5, 9, 9.5, 10 mmHg, or more). (Item 237) 237. The method according to any one of items 170 to 236, wherein the subject is a mammal, e.g. a human. method. (Item 238) The agonist is Ac-Arg-c(Cys-D-Ala-His-D-Phe-A Any of items 170 to 237, wherein the amino acid sequence is rg-Trp-Cys-NH2 (SEQ ID NO: 140). 1. The method according to claim 1. (Item 239) Obtaining knowledge of the subject's genotype, e.g., POMC gene, PCSK1 gene, MAGEL2 gene, leptin receptor gene, Leptin gene, 5-HT2c receptor gene, Nescient Helix-Loop-Helix 2 (NhHL2) gene, Carboxypeptidase E (CPE) gene, single-minded 1 (SIM1) gene, Any of the BBS1 to BBS20 genes ALMS1 gene, or BDNF, MCH1R, MCH, NTRK2, SIM1, ENPP1, COH1 , CNR1, NPC1, c-MAF, PTER, FTO, TMEM18 (childhood), SD CCAG8, TNKS / MSRA, GNPDA2 (childhood), NEGr1, INSIG2 , KCTD15, or NROB2 gene mutations, or 16p11.2 deletions (SH2 Any of items 170-238, including obtaining knowledge of the genotype (including the B1 gene) 1. The method according to claim 1. (Item 240) 239. The method of claim 239, wherein the agonist is selected from the group consisting of detecting a predetermined sequence, e.g., a mutation, in the gene according to item 239. 239. The method of claim 239, wherein the compound is administered in response to (Item 241) POMC gene (e.g., hypermethylated in the POMC intron, For example, a methylated cytosine, such as a 5' methylcytosine, e.g., a nucleotide sequence of the POMC gene Obtain knowledge of the methylation status of CpG islands (hypermethylated) 239. The method according to any one of items 170 to 238, comprising: (Item 242) 242. The method of claim 241, wherein the agonist is administered in response to detection of hypermethylation. . (Item 243) A unit dose of the agonist described herein, said unit dose being 0.1, 0. 2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2 mg of said agonist Unit dose, including sto. (Item 244) The unit dose according to item 243, containing 0.5 mg of agonist. (Item 245) The unit dose according to item 243 containing 1.0 mg of agonist. (Item 246) The unit dose according to item 243 containing 1.5 mg of agonist. (Item 247) 247. A unit dose according to any one of items 243 to 246, suitable for injection, e.g. subcutaneous injection. amount. (Item 248) Any of items 243 to 247 disposed in a delivery device suitable for injection, e.g., subcutaneous injection. The unit dose according to any one of claims 1 to 14. (Item 249) Any of items 243 to 248, in a syringe suitable for injection, e.g., subcutaneous injection. 1. The unit dosage as described in paragraph 1. (Item 250) The agonist is Ac-Arg-c(Cys-D-Ala-His-D-Phe-A Any of items 243 to 249, wherein the amino acid sequence is rg-Trp-Cys-NH2 (SEQ ID NO: 140). The unit dose according to any one of claims 1 to 14. (Item 251) The disorder is caused by one or a mutation (e.g., a loss of function) in the BBS1-19 or 20 gene. 65. The method of item 64, characterized in that the mutation is a deletion mutation. (Item 252) The subject may, for example, have one functional BBS1-19 or 20 allele and one non-functional BBS1-19 or 20 allele. Heterozygous carriers of the mutation(s) with the BBS1-19 or 20 allele 97. The method of claim 96, wherein the method is or is identified as being. (Item 253) The subject may, for example, have two non-functional BBS1-19 or 20 alleles, e.g., For example, compound heterozygotes for the mutation(s) have a BBS1-19 or 20 null genotype. 97. The method of claim 96, wherein the subject is or is identified as a sex carrier. (Item 254) The subject may have, for example, a BBS1-19 or 20 null genotype, 96. Being or being identified as a homozygous carrier of How to do it. (Item 255) The disorder is characterized by a mutation (e.g., a loss-of-function mutation) in the ALMS1 gene. Item 65. The method according to Item 64, (Item 256) The subject may, for example, have one functional and one non-functional ALMS1 allele. are or are considered to be heterozygous carriers of the mutation(s) 256. The method of claim 255, wherein (Item 257) The subject has, for example, two non-functional ALMS1 alleles, e.g., ALMS1 have a null genotype, are compound heterozygous carriers of the mutation(s), or Item 256. The method of item 256, wherein the method is identified as being (Item 258) the subject is homozygous for the mutation(s), e.g., has an ALMS1 null genotype 257. The method of claim 256, which is or is identified as being a carrier. (Item 259) The disorder is characterized by the inclusion of BDNF, MCH1R, MCH, NTRK2, SIM1, ENPP1, C OH1, CNR1, NPC1, c-MAF, PTER, FTO, TMEM18 (childhood) , SDCCAG8, TNKS / MSRA, GNPDA2 (childhood), NEGr1, INS One or more mutations (e.g., functional) in the IG2, KCTD15, or NROB2 genes deletion mutation), or 16p11.2 deletion (including the SH2B1 gene), 64. The method described in claim 64. (Item 260) The subject is, for example, BDNF, MCH1R, MCH, NTRK2, SIM1, ENP P1, COH1, CNR1, NPC1, c-MAF, PTER, FTO, TMEM18( Childhood), SDCCAG8, TNKS / MSRA, GNPDA2 (childhood), NEGr1 , INSIG2, KCTD15, or NROB2 genes, or 16p11.2 deletions (including the SH2B1 gene) are, or have been identified as, heterozygous carriers of the mutation(s) Item 250, the method of claim 250. (Item 261) The subject has, for example, two non-functional alleles of, e.g., BDNF, MCH1R , MCH, NTRK2, SIM1, ENPP1, COH1, CNR1, NPC1, cM AF, PTER, FTO, TMEM18 (childhood), SDCCAG8, TNKS / MSR A, GNPDA2 (childhood), NEGr1, INSIG2, KCTD15, or NR Null genotype for OB2 gene or 16p11.2 deletion (including SH2B1 gene) have, are, or are compound heterozygous carriers of the mutation(s) 251. The method according to item 250, as specified. [Brief explanation of the drawings]

[0327] The following detailed description of the preferred embodiments of the present invention will be better understood when read in conjunction with the accompanying drawings. It will be understood that for purposes of illustrating the invention, presently preferred embodiments are shown in the drawings. However, the present invention does not necessarily have to be limited to the precise construction and means of the embodiment shown in the drawings. It should be understood that the present invention is not limited to the above.

[0328] [Figure 1A] 1A and 1B are graphs showing the effect on suppression of cumulative food intake after treatment with setomelanotide (RM-493 at 0.1 mg / kg (mpk)) compared to vehicle in Magel2 null (Magel2) and wild-type (WT) mice. Figure 1A is an expanded version of the inset in Figure 1B, showing cumulative food intake over a 3-hour period after dosing. Figure 1B shows cumulative food intake overnight. [Figure 1B] 1A and 1B are graphs showing the effect on suppression of cumulative food intake after treatment with setomelanotide (RM-493 at 0.1 mg / kg (mpk)) compared to vehicle in Magel2 null (Magel2) and wild-type (WT) mice. Figure 1A is an expanded version of the inset in Figure 1B, showing cumulative food intake over a 3-hour period after dosing. Figure 1B shows cumulative food intake overnight. [Figure 2] FIG. 1 is a set of graphs showing the change in body weight in wild-type obese humans after 2 or 4 weeks of treatment with setomelanotide. [Figure 3A] 1 shows food intake over time for wild-type and db / db mice administered vehicle or setomelanotide.FIG. 1 is a graph showing food intake as a function of time for wild-type and db / db mice at various setomelanotide concentrations. [Figure 3B] 1 shows food intake over time in wild-type and db / db mice treated with vehicle or setomelanotide. [Figure 3C] 1 shows food intake over time in wild-type and db / db mice treated with vehicle or setomelanotide. [Figure 3D] 1 shows food intake over time for wild-type and db / db mice administered vehicle or setomelanotide.FIG. 1 is a graph showing food intake as a function of time for wild-type and db / db mice at various setomelanotide concentrations. [Figure 3E] FIG. 1 is a graph showing food intake as a function of time in wild-type and db / db mice at various concentrations of setomelanotide. [Figure 3F] FIG. 1 is a graph showing food intake as a function of time in wild-type and db / db mice at various concentrations of setomelanotide. DETAILED DESCRIPTION OF THE INVENTION

[0329] The present disclosure provides a method for the treatment of POMC-MC4 by using an MC4R agonist as a replacement therapy. Targeting defects in the R pathway, e.g., upstream of MC4R, can result in significant weight loss. leading to decreased hunger and / or increased energy expenditure in obese subjects. The present disclosure is based, at least in part, on the discovery that POMC-MC4 have a defect in one or more genes upstream of MC4R in the R pathway (e.g., a gene defect); obese subjects have a greater risk of developing a deficiency in MC4R agonists than obese subjects without such a deficiency. A significantly greater response (e.g., weight and / or hunger reduction and / or energy This is based in part on the finding that consumers are more likely to experience adverse health effects (increased consumption). As described herein, a subject having a non-functional Magel2 gene (e.g., Magel 2 null obesity) responsiveness (e.g., reduced food intake) following exposure to an MC4R agonist is significantly higher than obese subjects without such genetic disorders (e.g., wild-type obese subjects). There are cases where this happens.

[0330] Also, as described herein, a subject having a non-functional POMC gene (e.g., POMC null obesity is a type of obesity that does not have such a genetic disorder and is sensitive to MC4R agonists. significantly greater response (e.g., weight and / or Decreased hunger and / or increased energy expenditure. Nist resulted in a weight loss of approximately 2 to 2.5 kg per week (26 weeks) over the course of treatment. After 6 weeks, this resulted in a total weight loss of approximately 36 kg (equivalent to approximately 23% of the initial weight). This weight loss in C-deficient subjects was significantly greater than that in wild-type obese subjects (2–4 weeks after MC4R agonist treatment). weight loss of approximately 0.6 to 0.9 kg per week over a period of The greater weight loss seen in POMC-deficient subjects was more than double that observed in control subjects. It was long-lasting and did not appear to desensitize.

[0331] The dramatic weight loss and duration of weight loss observed in POMC-deficient subjects was due to the MC4R activity. However, the mean mean age of obese subjects treated with steroids was significantly greater than that observed for wild-type obese subjects treated with steroids. and weight loss is more significant than that seen in obese subjects treated with currently available therapeutic agents. In clinical studies, Belviq® (Lorcacelli) at prescribed doses HCl tablets), Qsymia® (phentermine and topiramate sustained-release capsules), Contrave® (naltrexone HCl and bupropion) HCl extended-release tablets), and Saxenda® (liraglutide injection) Commercially available medications produced placebo-corrected weight loss in obese subjects after one year of treatment. Once the subjects appeared to have desensitized and adapted to the effects of the therapy, the obese subjects were Weight loss in elephants is a physiological and compensatory process involving a reduction in energy expenditure associated with weight loss in subjects. It is thought that the limit is reached at about 5% due to various changes, so MC4R agonists, e.g. For example, a POMC-MC4R pathway-deficient subject (e.g., The hyperresponsiveness of POMC-deficient subjects is astounding. This limitation in the small group was observed with weight loss of well over 5% even after 13 to 26 weeks of treatment. This was not observed in subsequent POMC-deficient subjects.

[0332] Without being bound by theory, MC4R agonists such as setomelanotide may inhibit PO Genetic defects in the MC-MC4R pathway (e.g., PWS and POMC null obesity) replaces the missing MC4R signaling step in subjects with a genetic disorder Therefore, MC4R agonists such as setomelanotide may act to inhibit these in a patient population, even higher than in a patient population with typical (e.g., wild-type) obesity Therefore, the methods and compositions described herein may be effective in treating P Genetic disorders such as WS, POMC-null, and PCSK-null obesity (e.g., POMC-MC MC4R pathway function in subjects with a genetic deficiency in one or more genes of the 4R pathway to repair and thereby reduce the extreme hyperphagia and obesity seen in these subjects. The present invention provides an optimized method for detecting one or more genes in the POMC-MC4R pathway. Methods for treating subjects with genetic defects in genes, as well as methods for treating subjects with such defects and / or likely to respond to MC4R agonists (e.g., wild-type obese subjects The present invention provides a method for identifying / selecting subjects (who are more likely to respond to an MC4R agonist than to can be.

[0333] definition As used herein, "about" and "approximately" generally refer to the nature or precision of a measurement. It means the degree of error that is allowed for a given measured quantity. The accuracy is within 20 percent (%), typically within 10%, or better, of a given value or range of values. This is typically within 5%.

[0334] As used herein, "obtain" or "obtaining" refers to the or the physical entity of a nucleic acid or polypeptide, or a value, e.g., a numerical value, or knowledge (e.g., "directly" or "indirectly" acquiring information (e.g., knowledge of sequence or mutation status) It refers to taking ownership of a physical entity, value, or knowledge by "directly acquiring" it. "To obtain" means to perform a physical process to obtain a physical entity, value, or knowledge. "Indirectly obtaining" means obtaining a substance indirectly (for example, by performing a synthetic or analytical method). " refers to the direct acquisition of a physical entity, value, or knowledge by another party or source (e.g., Refers to receiving a physical entity, value, or knowledge from a third-party laboratory (a third-party laboratory certified by the FDA). Physical Entity Directly obtaining a process that involves a physical change of a physical substance, e.g., a starting material. Exemplary transformations include creating a physical entity from two or more starting materials. to produce, shear or fragment a substance, separate or purify a substance, Combining these separate entities to form a mixture, breaking covalent or non-covalent bonds, or The direct acquisition of value or knowledge involves chemical reactions, including the formation of involves performing a process that involves a physical change of a sample or another substance. Examples include , analytical processes (referred to herein as analytical methods) that involve physical changes in a substance, e.g., a sample, analyte, or reagent. (sometimes called "physical analysis"), analytical methods, such as one or more of the following: The method includes carrying out a method comprising: Separating or purifying an analyte or a fragment or other derivative from another substance; combining a derivative of with another substance, such as a buffer, solvent, or reactant; or For example, breaking or cleaving a covalent or non-covalent bond between a first atom and a second atom of the analyte. or by the formation of a covalent bond or bonds between, for example, a first atom and a second atom of a reagent. alters the structure of the reagent or its fragment or other derivative by breaking or forming non-covalent bonds The structure of the analyte or its fragment or other derivative can be altered by cleaving the analyte. and.

[0335] As used herein, the term "obesity" refers to the condition identified by the Center for or defined by the Disease Control (e.g., URL.cd c.gov / obesity / defining.html and www.cdc.gov / obesity / childhood / defining.html (last accessed August 19, 2015) or the National Institute s of Health's "Clinical Guidelines on the Identification,Evaluation,and Treatment of Overweight and Obesity in Adults A subject with a body mass index (BMI) within a defined range. BMI can be measured, for example, by Divide the subject's weight in grams (kg) by the square of the subject's height in meters (m), for example. For example, 30 kg / m 2 Adults with a BMI above 100 are considered obese. For example, 25.0 to 29.9 kg / m 2 An adult with a BMI of and 18.5 to 24.9 kg / m 2 Adults with a BMI of are in the normal or healthy weight range It is considered to have a 2 Adults with a BMI below are considered underweight For example, an adult who is 5 feet 9 inches tall and weighs 203 pounds or more is considered obese. For children and teenagers, obesity is defined as the number of children and teenagers of the same age and sex who are overweight or obese. Refers to subjects with a BMI at or above the 95th percentile.

[0336] A subject with "severe obesity" or "severe obesity" is defined as having a body mass index (BMI) of 35 kg / m 2 That's it, example For example, 40 kg / m 2 For example, a severely obese subject is a subject with a BMI of 100 or above. Being 100% over your ideal (normal, healthy) weight.

[0337] As used herein, "early onset," as in, for example, early onset obesity, refers to the onset of obesity in adulthood. before, e.g., during childhood, e.g., when the subject is under 18 years of age (e.g., 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or under 1 year of age, or during adolescence, for example, when the child is under 12 years of age, or when the child is under 6 years of age a condition (e.g., a disorder, e.g., a disorder described herein, e.g., obesity) occurring during , PWS, POMC null refers to the first occurrence of one or more symptoms of obesity).

[0338] As used herein, the term "metabolic syndrome" refers to the co-occurring A group of conditions that increase the risk of coronary artery disease, stroke, and type 2 diabetes. American Heart Association and National Heart, According to the Lung and Blood Institute, a condition also known as Syndrome X The metabolic syndrome is considered to be present when a subject has three or more of the following symptoms: do. 1) Blood pressure of 130 / 85 mmHg or higher, 2) fasting blood sugar (glucose) of 100 mg / dL or more; 3) Large waist circumference (length around the waist): - Men - 40 inches and above, - Women - 35 inches and above, 4) Low HDL cholesterol: - Men - less than 40 mg / dL, - Women - less than 50 mg / dL 5) Triglycerides greater than 150 mg / dL. Metabolic syndrome is characterized by changes in a subject's blood pressure, blood glucose levels, HDL cholesterol, cholesterol levels, LDL cholesterol levels, total cholesterol levels, and triglycerides It can be diagnosed by testing the levels.

[0339] As used herein, the term "agonist" refers to an agonist, whether naturally occurring or synthetic. Regardless, upon interacting with (e.g., binding to) its target, e.g., MC4R Any chemical compound that increases the signaling activity of MC4R above its basal level Agonists are also known as superagonists (i.e., those that inhibit the endogenous agonist at the target receptor). can produce a higher maximum response than steroids and therefore have greater than 100% efficacy compounds), full agonists (i.e., compounds that elicit a maximal response after receptor occupancy and activation) compounds), or partial agonists (i.e., compounds that can activate the receptor but do not activate the receptor) The compound may be a compound that is unable to induce the maximum response of the system.

[0340] As used herein, "treating" means achieving one or more of the following results: This includes, for example, a decrease in body weight compared to a control (e.g., pre-treatment body weight or a predetermined body weight). reduction (e.g., as measured by body mass index (BMI) and / or weight); e.g., control reduction in waist circumference compared to a control (e.g., pre-treatment waist circumference or a given waist circumference); Decreased hunger levels compared to pre-treatment hunger levels or predetermined hunger levels; e.g., control ( Resting energy expenditure (REE) compared to pre-treatment REE or prescribed REE ) increase in food intake compared to a control level (e.g., pre-treatment or a given food intake) Decreased intake; disorders described herein, e.g., obesity, PWS, POMC null obesity, e.g., I Type 1 diabetes, prediabetic state, blood hemoglobin A1C (Hb1Ac) level above 6%, Hyperinsulimenia, hyperlipidemia, insulin insensitivity Remission or improvement of clinical symptoms or indicators related to obesity or glucose intolerance; and / or slowing, inhibiting, or preventing the progression of symptoms associated with obesity; or obesity or Partially or completely delaying, inhibiting, or preventing the onset or development of obesity-related symptoms Slowing, inhibiting, or preventing the progression of obesity can include, for example, administering a steroid to a normal-weight subject. In embodiments, the control includes delaying, inhibiting, or preventing the progression of a disease. Parameter values ​​measured before treatment with an MC4R agonist as described in The term "treating" includes treating coronary artery disease associated with metabolic syndrome. Partially or completely reducing the risk of heart disease, stroke, and type 2 diabetes, as well as Clinical symptoms associated with metabolic syndrome or signs of metabolic syndrome, e.g. For example, remission or improvement of one or more of the five indicators listed above is more likely. For example, the term "treating" includes treating insulin resistance, glucose tolerance, metabolic parameters, including clearance, and cardiovascular disease parameters, including heart rate and blood pressure. This includes slowing, inhibiting, or preventing the progression of parameters associated with the syndrome.

[0341] As used herein, "inhibition" or "inhibiting" refers to the ability of a subject to undergo any of the above-described procedures. For example, the inhibition of a parameter, e.g., activity, may be at least 5%, 10%, 20%, 30%, 40%, or more, The term is included in the definition of inhibition, therefore, inhibition does not have to be 100%.

[0342] "Prophylactic treatment" means a treatment prior to the onset of obesity to prevent, inhibit, or reduce the occurrence of obesity. Refers to the procedure.

[0343] As used herein, the term "subject" refers to a mammal, e.g., a human. Elephants are used for animals requiring veterinary treatment, such as companion animals (e.g., dogs, cats, etc.); Livestock (e.g., cattle, sheep, pigs, horses, etc.) and laboratory animals (e.g., rats, mice, etc.) It can also refer to animals such as cats, guinea pigs, etc.

[0344] As used herein, the term "mutation" refers to a mutation that is a mutation of the wild-type sequence of a gene or a fragment thereof. For example, a mutation may be a point mutation, a frame shift mutation, or a These mutations may include nucleotide mutations, missense mutations, inversions, deletions, insertions, truncations, and chromosomal translocations. In this form, a mutation results in a gene or a fragment thereof being a non-functional protein, with reduced activity. Proteins (or partially functional proteins), or proteins with altered activity For example, a "loss-of-function" mutation can result in a gene or fragment thereof encoding , encoding a non-functional protein having substantially reduced activity compared to its wild-type counterpart. refers to a mutation that results in the non-functionality of a protein (e.g., a non-functional protein is a mutation that results in the non-functionality of its wild-type counterpart) Less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or more For example, a "partial loss of function" mutation occurs when a gene or a fragment of it is expressed in the wild-type Encodes a partially functional protein with reduced activity compared to its wild-type counterpart refers to a mutation that results in a partially functional protein being different from its wild-type counterpart (e.g., (having less than 50% and more than 10% of the activity of the original).

[0345] As used herein, "heterozygosity" refers to the heterozygous mutation for a given gene in a subject. This refers to the existence of two different alleles (having different nucleic acid sequences) that represent a gene. In this context, a "heterozygous mutation" refers to the presence of a mutation in one allele of a given gene in a subject. the presence of a mutation in the other allele of the same gene (e.g., one allele for a given gene) In other embodiments, the term "variant" may refer to a "mutant allele" or "mutant alleles" (one mutant allele and one wild-type allele). A "compound heterozygous" mutation may be a "compound heterozygous" mutation, which is a mutation occurring in one allele of a given gene. Mutations (e.g., loss-of-function or partial loss-of-function mutations) in alleles of the same gene The presence of a different (e.g., loss-of-function or partial loss-of-function) mutation in the other allele and (e.g., two different alleles that are both mutated, e.g., non-functional or partial In some embodiments, a compound heterozygous mutation refers to two non-functional alleles. If the gene comprises a gene encoding a gene encoding a nucleotide sequence, the genotype may be a null genotype or a functionally deficient genotype.

[0346] As used herein, "homozygous" means a group of two identical individuals for a given gene. In some embodiments, a "homozygous mutation" refers to the presence of an allele in a given gene. This means that there are two mutant alleles for a gene, and these two mutant alleles are identical. .

[0347] As used herein, a "null genotype" refers to a gene that has two non-functional loci in a subject. This refers to the presence of a potential allele.

[0348] As used herein, "unit dosage" refers to a unit dose for a subject to be treated. Each unit is a suitable physically discrete unit, in association with the required pharmaceutical carrier. It contains a predetermined quantity of active compound calculated to produce a desired therapeutic effect.

[0349] As used herein, "dosage" refers to a quantity or amount of a therapeutic agent. In this embodiment, the dosage is a single administration, e.g., a single injection of one or more unit doses, a single infusion In some embodiments, the dose is administered to a subject in a single dose. multiple injections, multiple infusions, or multiple administrations of one or more unit doses In other embodiments, the dosage is the amount administered to an elephant over a specific period of time, e.g., per day. In such instances, the dose may refer to the total amount administered to a subject. is referred to as the "daily dose" or dose in terms of portions per day.

[0350] As used herein, "hunger" or "hunger level" refers to a subject's appetite, food cravings, and appetite. In some embodiments, the subject's hunger sensation may be related to a desire to consume or a perception of the need for food. Alternatively, hunger levels can be quantified by using a scale to obtain a hunger score. In embodiments, the hunger scale may be scaled to indicate more unbearable hunger. Assign higher scores to subjects who feel it more frequently (e.g., often or always) and less intolerable. by subjects who experience hunger less frequently (e.g., occasionally or never) Assign a low score. For example, Sibilia.Psychologicol To See pics 19(2010),2,341-354. For example, 0-10 points Likert hunger scale (0 = no hunger, 10 = severe hunger) Another example is the Likert scale, which assigns a score of 1 to 4 points. A sensitivity scale may be used, where subjects who never experience unbearable hunger are given a 1; A score of 0 was assigned to subjects who occasionally experienced unbearable hunger, and a score of 2 was assigned to subjects who occasionally experienced unbearable hunger. Subjects who frequently experience unbearable hunger were assigned a score of 3; Subjects who consistently experience this sensation are assigned a score of 4. See Ibid.

[0351] POMC-MC4R pathway Melanocortin (MC), agouti, agouti-related protein, and their receptors The melanocortin system, including the melanocortin system, regulates energy homeostasis and regulates appetite, energy expenditure, and body metabolism. It integrates hormonal, metabolic, and neural signals to control weight. Alpha-melanocyte-stimulating hormone (α-MSH), β-MSH, γ-MSH, and A MCs containing CTH are derived from a precursor protein called proopiomelanocortin (POMC). It is a family of peptide hormones derived from proteins. Activation of C4 receptors (MC4R) increases energy expenditure and decreases food intake. See, e.g., Fan et al. Nature 1997;385:165-68. The POMC-MC4R pathway is involved in, for example, the regulation of appetite and energy expenditure. Melanocortin (MC) and MC4, which together contribute to the regulation of energy homeostasis, receptor (MC4R), POMC, proprotein convertase subtilisin / kexin type 1 ( PCSK1 (also known as PC1 / 3), MAGE-like-2 (MAGEL2), leptin receptor Receptor (leptin-R), leptin, 5-hydroxytryptamine (serotonin) receptor 2 C, G protein-coupled (5-HT2c receptor), distinct helix-loop Helix 2 (NhHL2, also known as NSCL2), prohormone convertase, carboxypeptide putidase E (CPE), and single-minded 1 (Sim1), Several proteins are involved. Other components of the MC4R and POMC-MC4R pathway include: It plays an important role in weight control. Mutations in the MC4R gene cause early-onset and severe obesity. Other gene defects in the POMC-MC4R pathway have also been reported to result in early gestation. It is believed that there is a high possibility of developing diabetes and leading to severe obesity.

[0352] MC4R hMC4R is identified by the genome sequence with GenBank accession number CH471077.2. It is a protein encoded by

[0353] Mutations in the MC4R receptor are a cause associated with severe childhood obesity. The carrier prevalence of MC4R mutations in obese populations is approximately 2.5%, with the highest prevalence being severe. 6% of obese children have been found to have MC4R mutations. The phenotype is broadly similar to that described in mice with mutations in the C4R gene. C4R-deficient patients exhibit hyperphagia, accompanied by increases in lean body mass, bone mineral density, and linear growth rate. Hyperinsulinemia and increased body fat mass are associated with increased cortisol levels, gonadotropins, and thyroid There are no changes in glandular and sex steroid levels. In contrast to MC4R deletion, Hyperphagia and hyperinsulinemia tend to subside with age. As in mice, the phenotype in heterozygous carriers is significantly higher than that in homozygous carriers. The hyperphagia observed in response to the test meal is indicative of a leptin deficiency. Less severe than those observed in people. The severity of the impairment is determined by the amount of food ingested in the test diet by subjects carrying that particular mutation. The amount of α-glucan in the α-glucan can be predicted and correlated with the onset and severity of the obesity phenotype. Different MC4R mutations are associated with obesity and lead to similar obesity phenotypes It is likely that further mutations of R will be discovered.

[0354] Examples of MC4R mutations that cause obesity in humans are described, for example, in Farooqi et al. al.,The Journal of Clinical Investigation n, July 2000, vol. 106(2), pp. 271-279 and Vaiss e et al.,The Journal of Clinical Investi gation,July 2000,vol.106(2),pp.253-262 (Related Articles 1 and 2, the relevant portions of which are incorporated herein by reference).

[0355] Additional mutations that may cause obesity in humans include those associated with Xiang et al., "Pharmacological characterization of 30 human melanocorti n-4 receptor polymorphisms with the endo endogenous proopiomelanocortin-derived agoni sts,synthetic agonists,and the endogenou s agouti-related protein antagonist.”Bio Chemistry, 2010 Jun 8;49(22):4583-600 R18H, R18L, S36Y, P48S, V50M, F51L, E61K, I69T, D90N, S94R, G98R, I121T, A154D, Y157S, W1 74C, G181D, F202L, A219V, I226T, G231S, G238D, N240S, C271R, S295P, P299L, E308K, I317V, L325 F, and 750DelGA.

[0356] Further examples of mutations that can cause obesity in humans include human genes and genetic Online Mendelian Inheritance, a database of disorders in Man (OMIM), URL http: / / omim.org / en At try / 155541, accession number 155541(MC4R) (more precisely, accession number Those listed under Nos. 155541.0001 to 155541.0023. Examples include 4-BP DEL, NT631; 4-BP INS, NT732; and TYR. 35TER;ASP37VAL;SER58CYS;ILE102SER;ASN274 SER;1-BP INS, 112A;4-BP DEL, 211CTCT;ILE12 5LYS;ALA175THR;ILE316SER;TYR287TER;ASN97 ASP; 15-BP DEL (delta 88-92 codons); and SER127LEU The relevant portions of the OMIM database are incorporated herein by reference. do.

[0357] Further exemplary mutations of MC4R are described in Lee. Annals Acad. Med. 38 .1(2009):34-44.

[0358] In an exemplary embodiment, the MC4R mutation results in retention of MC4R signaling activity. .

[0359] Mutations in the genomic sequence encoding MC4R can be detected by methods known to those skilled in the art. For example, nucleotide primers, e.g., Farooqi et al. ,The Journal of Clinical Investigation,J uly 2000,vol.106(2),pp.271-279 and Vaisse e t al.,The Journal of Clinical Investigat ion, July 2000, vol. 106(2), pp. 253-262 The genome sequence is cloned using primers and other tools, and then sequenced using commercially available sequencing equipment and software. The cloned sequences may be analyzed using a

[0360] The activity of MC4R can be measured by methods known to those skilled in the art. The cloned MC4R DNA was transiently transfected into cells, and the transfection The cells are exposed to an agonist of MC4R (e.g., α-MSH) to induce secondary metastasis of MC4R. The intracellular levels of the receptor cAMP were measured, for example, as described by Roubert et al. Journal of Endocrinology(2010)207,pp.177 MC4R signaling may be measured by electrochemiluminescence assay as described in -183. The reduction in cAMP produced by wild-type MC4R in response to a given agonist is MC4R mutants. can be done.

[0361] POMC POMC is a component of the POMC-MC4R pathway, acting upstream of MC4R. C is cleaved by prohormone convertases to produce multiple peptide hormones (e.g., alpha- before producing β-MSH, ACTH, beta-endorphin, and enkephalins The convertases that process the POMC polypeptide include protease 1, protease 2, and protease 3. Prohormone convertase 1 (PC1, also known as PC1 / 3 or PCSK1), a prohormone converting enzyme Enzyme 2 (PC2), carboxypeptidase E (CPE), peptidyl α-amidated mono Oxygenase (PAM), N-acetyltransferase (N-AT), and proline Examples include ribosomal carboxypeptidase (PRCP).

[0362] The POMC gene is located on human chromosome 2p23.3, and the gene sequence is incorporated herein by reference. The DNA sequence of the human genomic DNA is provided in GenBank accession number NG_008997.1, which is incorporated herein by reference. An exemplary nucleic acid sequence for POMC mRNA transcript variant X1 is incorporated herein by reference. The sequence of the present invention is provided in GenBank accession number XM_011532917.1, which is incorporated by reference. An exemplary amino acid sequence of human POMC isoform X1 is incorporated herein by reference. The human PO An exemplary nucleic acid sequence for MC mRNA transcript variant 1 is incorporated herein by reference. The human PO An exemplary amino acid sequence of the MC pre-proprotein is shown in GenBank accession number NP_0 01030333.1. Human POMC mRNA transcript variant 2 An exemplary nucleic acid sequence is shown in GenBank Accession No. NM_0, which is incorporated herein by reference. 00939.2. Exemplary amino acids of human POMC pre-proproteins are provided in The sequence is provided in GenBank accession number NP_000930.1.

[0363] POMC-expressing POMC neurons are POMC neurons from POMC neurons. The secretion of POMC peptides leads to an appetite suppressant effect that reduces body weight and food intake. Loss-of-function mutations in the gene have been reported to result in obesity, red hair, and adrenal insufficiency. For example, defects in POMC (e.g., loss-of-function mutation(s) or hypermethylation) can lead to fertility problems. It has been associated with hypertension and ACTH deficiency. l.Intl.J.Ped.Endocrinol.2011:5 and Kuehnen et al.PLoS Genetics.8.3(2012):e1002543 See POMC for homozygous codon 231 cytosine to adenosine (c The .231C>A) mutation results in a premature stop codon, causing excessive weight gain and congenital adrenal insufficiency. , and has been reported to cause a functional defect of POMC associated with hypoglycemia. For example, Mendiratta et al. Intl. J. Ped. Endocrin ol.2011:5. In embodiments, exemplary mutations of POMC are: Lee. Annals Acad. Med. 38.1 (2009): 34-44 It is being done.

[0364] In various embodiments, exemplary mutations of POMC are set forth in Table 1 below. In embodiments, the homozygous and / or heterozygous (e.g., compound heterozygous) variants of Table 1 are Sexual (sexual) mutations are expected. [Table 1]

[0365] In certain embodiments, for example, the POMC amino acid sequences referenced in Table 1 are copied below: Takahashi, et al. 1981 Febs Letters 135 (1) 97 (the 26 amino acid signal peptide is underlined) ). [ka]

[0366] In certain embodiments, for example, the POMC gene nucleotide sequence referenced in Table 1 is For example, the Tak gene provided in GenBank accession number V01510.1 and copied below: ahashi et al.Nucl Acids Res.1983,11(19)6 847. [ka] [ka] [ka]

[0367] In some embodiments, examples of POMC that lead to, for example, homozygous POMC deficiency include: Suitable mutations are described, for example, in the references in Table 2, each of which is incorporated herein by reference. It is incorporated into the detailed text. [Table 2-1] [Table 2-2]

[0368] Furthermore, hypermethylation of the POMC gene has been associated with childhood obesity. , Kuehnen et al.PLoS Genetics.8.3(2012):e See 1002543. Cp at the intron 2-exon 3 boundary of the POMC gene Hypermethylated variants in the G island were significantly associated with obesity compared with normal-weight children Exon 3 of POMC binds to the transcriptional enhancer P300. It is thought that hypermethylation of exon 3 reduces the expression of POMC transcripts. See above.

[0369] In yet other embodiments, exemplary mutations of POMC include any one or more of the following: Aslan, Int J Obes (Lond). 20 14 Jan;38(1):148-51, Krude, Nature 1998;19 ;155-157, Krude, J clin Res Metab 2003,88( 10);4633-4640, Samuels,J Clin Endocrin Me tab,2013;98(2);736-742, Clement,J Clin En docrin Metab.,2008;93(12);4955-4962,Cree mers,J Clin Endocr Metab,2008,93(11);449 4-4499,Cirillo,British Assoc Derm,2012,1 67;1390-1400, ESPE poster Barcelona 2015, R Marina et al., Farooqi, Diabetes 2006;55 ;2549-2553,Mendiratta,Int J Pediatr Endo crinol.2011;2011:5, A Meloni,et al.,ESPE Poster Barcelona 2015, Hinney,J Clin Endo crin Metab,1998,10;3737-3741, Lee,Cell Me tabol.,2006;3;135-140(PLOF), Dubern,Pedia tric Res.2008;63(2);211-216, Philippe et al. al.Int.J.Obes.39.2.(2015):295-302, Bieber man,2006;3;141-146, or Buono,Clin Chem,20 05;51(8);1358-1364, Challis,Hum.Mol.Genet .11(17):1997, Hum.Mol.Genet.11(17):1998(each (The document is incorporated herein by reference in its entirety).

[0370] PCSK1 Proprotein convertase subtilisin / kexin type 1 (PCSK1, also known as PC1 / 3) by processing (cleaving) prohormones such as POMC into their mature forms. It is an enzyme that acts upstream of MC4R in the POMC-MC4R pathway.

[0371] PCSK1, encoding a truncated propeptide in fewer than 2 of 14 exons A heterozygous nonsense variant (p.Arg80*) in α-glucanase is associated with obesity in humans. For example, Philippe et al. Intl. J. See Obesity 39.2(2015):295-302.

[0372] The PCSK1 gene is located at cytogenetic location 5q15-q21 in humans. The PCSK1 gene sequence is identified in GenBank Accession No. N00001111, which is incorporated herein by reference. G_021161.1. An exemplary human PCSK1 transcript variant 1 The nucleic acid sequence is identified in GenBank Accession No. NM_00043, which is incorporated herein by reference. 9.4 (e.g., Hsiao et al. Gene 533(1), 32-37 (2014). An exemplary human PCSK1 isoform 1 The amino acid sequence is set forth in GenBank Accession No. NP_000, which is incorporated herein by reference. An exemplary nucleic acid sequence for human PCSK1 transcript variant 2 is provided at: , GenBank accession number NM_001177875, which is incorporated herein by reference. 1. An exemplary amino acid sequence of human PCSK isoform 2 is provided in reference provided in GenBank accession number NP_001171346.1, which is incorporated herein by reference. It has been done.

[0373] In some embodiments, the expression of PCSK1, e.g., leading to homozygous PCSK1 deficiency, Exemplary mutations are described, for example, in the references in Table 3, each of which is incorporated by reference. The present application is incorporated by reference. [Table 3-1] [Table 3-2]

[0374] In some embodiments, for example, a PCSK1 gene that leads to a heterozygous PCSK1 deficiency. Exemplary mutations are described, for example, in the references in Table 4, each of which is incorporated by reference. and is incorporated herein by reference. [Table 4-1] [Table 4-2]

[0375] In yet other embodiments, exemplary mutations of PCSK1 include any one or more of the following: These include one or more mutations that may be associated with: Martin, Gastroenterology 145:138-48,2013、Creemers, Diabetes 61:383 ,2012, Jackson,Nature Gen.:July 16,1997,p .303, Martin, Gastroenterology 145:138-48, 2013, Blanco et al. Endrocrinology 156:362 5-37, 2015, Jackson, J. Clin. Investigation 1 12:1550-51,2003, Benzinou, Nat. Genetics 8: 943,2008,Yourshaw,Gastroenterology 57(6) :759,2013, Faroqi, J. Clin. Endocrinol. and M. etab.92:3369-73,2007,Pickett,PLoS One 8: e55065,2013, Bohours-Nouet,EXPE Poster at Barcelona 2015 PWS meeting, Graeme et al. .,Mol.Gen.Metabol.110:191-94,2013,Blanco et al. Endrocrinology 155:3434-47, 2014, W ilschansky PLoS ONE 9:108878,2014, Frank, Mol.Gen Metabol.2013, and Harter J.Pediatr. Gastroentrol Nutr. 2015 (each of which is incorporated herein by reference in its entirety). (This is cited in the book.)

[0376] MAGEL2 MAGEL2 (Melanoma antigen (MAGE) family L2, or MAGE-like protein) Protein 2) is a ubiquitin ligase of zinc finger-containing E3 ubiquitin protein ligase. It is thought to be involved in the regulation of enzyme activity and possibly the circadian clock. 2 is involved in pathways regulating protein degradation, protein modification, transcription, and cytoskeletal rearrangement. It is a member of the MAGE family of proteins that mediates mitochondrial function. For example, Mercer et al. See al.PLoS Genetics 9.1(2013):e1003207 I want to be.

[0377] In mice, MAGEL2 is expressed in the hypothalamus, including the arcuate nucleus, which regulates energy homeostasis. MAGEL2 is expressed in the nucleus of the thymus and rectum. MAGEL2 is expressed in the thymus and rectum of the thymus and rectum. ) has been reported to initially show poor weight gain, followed by increased body fat accumulation and weight gain. For example, Mercer et al. PLoS Genetics 9.1 (20 13):e1003207. Adult mice lacking MAGEL2 (M AGEL2 null mice exhibit impaired appetite suppression response to leptin and P response to leptin. It has been reported that OMC neurons exhibit a lack of response. See i et al. Hum. Mol. Genet. 2015, 1-8. MA Mice lacking GEL2 (MAGEL2 null mice) also show increased expression of GEL2 in the paraventricular nucleus of the hypothalamus. In some embodiments, the alpha-MSH levels were significantly lower in the control group. Common MAGEL2 mutations, e.g., loss-of-function MAGEL2 mutations, have been reported by Schaaf et al. Nat Genet.2013 Nov;45(11):1405-8.doi:10 .1038 / ng.2776.Epub 2013 Sep 29, and Soden e t al.Sci Transl Med.2014 Dec 3;6(265):26 5ra168, each of which is incorporated herein by reference.

[0378] MAGEL2 is inactivated in several cases of Prader-Willi syndrome (PWS). Inactivating mutations in MAGEL2 are characteristic of PWS. It has been found in children. See above. A heterozygous c.1652delT (p.Val551fs) mutation was reported in a 13-year-old human subject. For example, Schaaf et al. Nat. Genet. 45.11 (20 13):1405-09. Heterozygous c.1802delC (p.Pr The o601fs mutation was also reported in an 8-year-old human subject. See Ibid. Also, heterozygous c. The 3181_3182delAT (p.Ile1061fs) mutation was reported in a 5-year-old human subject See above. In a 19-year-old human subject, c.3124C>T (p.Gln1024*) Mutations have also been reported. See Id. PWS is discussed in more detail below.

[0379] The human MAGEL2 gene sequence is NG_016776, which is incorporated herein by reference. .1. An exemplary nucleic acid sequence of the human MAGEL2 transcript is incorporated herein by reference. An exemplary amino acid sequence of human MAGEL2 is NM_019066.4. NP_061939.3, which is incorporated herein by reference.

[0380] Leptin and leptin-R Leptin regulates energy homeostasis - food intake, body weight, and glucose homeostasis It is a hormone produced by fat cells that acts to inhibit hunger in order to Leptin binds to the leptin receptor (leptin-R, also known as LEP-R, OB-R, or CD29 5), acting upstream of MC4R in the POMC-MC4 pathway. POMC neurons mediate leptin activity in the brain, and leptin binds to leptin-R. One of the effects of combining these proteins is the stimulation of POMC expression. l.EMBO Reports 13.12(2012):1079-86 Deletion of leptin-R in POMC neurons resulted in the development of these leptin-R null mice. In humans, this leads to obesity, an effect that can be partially rescued by overexpression of leptin-R. See above. Leptin mutation (Lep ob / ob) or leptin-R mutation (Lep db / db) has been associated with impaired glucose homeostasis and increased body weight in mice. It has been reported that fa / fa rats are leptin-R deficient. For example, Cettour-Rose et al. logy:2002;143(6);2277-2283.

[0381] Examples of mutant (e.g., non-functional) versions of leptin in humans are associated with obesity. It has been described that the guanine nucleotide at codon 133 of the leptin gene Homozygous frameshift mutations with deletion of tid have been shown to cause severe obesity in some severely obese children. Related. For example, Montague et al. Nature 387.66 36(1997):903-8. The sequence (c.298G→T) is a mismatch between the aspartate at amino acid position 100 (p.D100Y) and the nucleotide sequence (c.298G→T). This leads to the conversion of glutamic acid to tyrosine and has been associated with early-onset extreme obesity (e.g. , Wabitsch et al.N.Engl.J.Med.372.1(2015) :47-54). Homozygous Gln223Arg in leptin-R and The homozygous Lys656Asn mutation has been associated with obesity in humans. asuo et al.Hypertens.Res.31.6(2008):1093 -100. Additional exemplary mutations of leptin / leptin-R are described in Lee. Annals Acad.Med.38.1(2009):34-44 .

[0382] In some embodiments, a leptin receptor deficiency may be present, e.g., a leptin receptor deficiency that leads to a homozygous leptin receptor deficiency. Exemplary mutations in the LEPR are described, for example, in the references in Table 5, and each reference The documents are incorporated herein by reference. [Table 5-1] [Table 5-2]

[0383] In some embodiments, a leptin receptor deficiency may be present, e.g., a leptin receptor deficiency that leads to a homozygous leptin receptor deficiency. Exemplary mutations of receptors are described, for example, in the references in Table 6, and each reference is incorporated herein by reference. The present application is incorporated by reference. [Table 6-1] [Table 6-2]

[0384] An exemplary nucleic acid sequence of a human leptin transcript is NM_0, which is incorporated herein by reference. 00230.2 and BC060830.1. Examples of human leptin precursors The typical amino acid sequence is set forth in NP_000221.1, AAH, which is incorporated herein by reference. 69452.1, AAH69527.1, AAH69323.1, AAH60830.1 An exemplary nucleic acid sequence for the human leptin receptor is provided in GenBank accession numbers used are U66497.1, U66496.1, and U66495. 1, U43168.1, NM_001198689.1, NM_001198688.1 , NM_001198687.1, NM_001003679.3, NM_002303 .5, NM_001003680.3. An exemplary human leptin receptor The amino acid sequence is GenBank Accession No. P48357, which is incorporated herein by reference. .2, AAB09673.1, AAC23650.1, AAB07497.1, AAB0 7496.1, AAB07495.1, AAA93015.1.

[0385] In yet other embodiments, exemplary mutations in LEPR include any one or more of the following: These include one or more of the mutations listed in: Faroqui et al., N Engl J Med 356:237-24,2007, Gill et al.,Obesit y 22:576-84,2014, Kimber et al., Endocrino l.149:6043-52,2008, Huvenne et al. J. Clin. Endo Metab.100:E757-66,2015, and Mammes et al. al., Eur.J.Clin.Inv.31:398-4004, 2015 (each reference is (which is incorporated herein by reference in its entirety).

[0386] 5HT2c receptor 5-hydroxytryptamine (serotonin) receptor 2C, G protein-coupled (5-H T2c receptors are G protein-coupled receptors (GP) that bind to the neurotransmitter serotonin. 5HT2c receptors are involved in the regulation of feeding, among other physiological functions. The 5HT2c receptor acts on the MC4R in the POMC-MC4R pathway. It acts on the bloodstream. 5-HT 2C Stimulation of the receptor leads to an increase in POMC in the anterior pituitary gland. By binding to serotonin receptors, including the 5HT2c receptor, serotonin Increases POMC activity and reduces feeding behavior. For example, Roepke et al. Am.J.Physiol.Endocrinol.Metab.302.11(201 2):E1399-406. 5HT2c receptor agonists were used in rats and It has been reported to reduce food intake in mice. See rr.Top.Med.Chem.3.8(2003):885-97. Alternative splicing of the 5-HT2C receptor leads to the snoRNA SNORD115 SNORD115 is inactivated in PWS. Although not wishing to be bound by it, the 5HT2c polymorphism is thought to be associated with obesity. There are.

[0387] The human 5-HT2c receptor gene sequence is available from GenBank, incorporated herein by reference. k accession number NG_012082.2 (e.g., Jahnsen JA et al.Eur.J.Pharmacol.684(1-3),44-50(201 2)). An exemplary nucleic acid sequence for the human 5-HT2c receptor is incorporated herein by reference. GenBank accession numbers NM_001256761.2, NM_001, which are incorporated by reference. 256760.2, NM_000868.3. Human 5-HT2c receptor An exemplary amino acid sequence of is set forth in GenBank Accession No. N P_001243690.1, NP_001243689.1, NP_000859.1 is provided to.

[0388] NhLH2 NhLH2 is a neuronal transcription factor that acts upstream of MC4R in the POMC-MC4R pathway. NhLH2 is a transcription factor that binds to the basic helix-loop-helix (b NhLH2 is a member of the POMC neuron and MC4R It is expressed in some differentiated adult neurons, including neurons. , can be controlled by food intake and leptin levels. For example, Good e t al.Trends Endocrinol.Metab.24.8(2013): See 385-90. Deletion of this gene leads to adult-onset obesity. Based on knockout mouse studies, NhLH2 mediates weight control and fertility. For example, Good et al. Nat. Genet. 15 (1997) ):397-401. In embodiments, for example, heterozygous NhLH Exemplary mutations that lead to 2 deficiency syndrome are described, for example, in Rayy et al., J. Med. Soc., 1999, 14, 1962, 1966, 1968, 1969, 1970, 1971, 1972, 1973, 1974, 1975, 1976, 1977, 1978, an et al. Gene. 2013;512(1):134-42 .

[0389] NhLH2 activates the leptin-regulated transcription factor signal transducer and activator of activator 3 (Sta t-3) and regulates PCSK1 in response to leptin or food intake. H2 knockout mice have lower levels of PCSK1 than wild-type mice. This is due to the increased levels of PCSK1-processed peptides, such as mature POMC. See, for example, Good et al. Trends Endocrinol See Metab.24.8(2013):385-90.

[0390] An exemplary nucleic acid sequence for human NhLH2 is found in GenBank, incorporated herein by reference. Accession numbers XM_006710666.2, XR_946659.1, NM_00111 1061.1, NM_005599.3 (e.g., Al Rayyan et al. Gene 512(1), 134-142(2013) An exemplary amino acid sequence of human NhLH2 is provided in GenB, incorporated herein by reference. ank Accession Numbers XP_006710729.1, NP_001104531.1, NP_ 005590.1.

[0391] Prohormone convertases Prohormone convertases process precursors of peptide hormones and neuropeptides. PCSK1 (also known as PCSK2) is a serine protease that converts prohormone to steroid hormones. 1, PC3, and PC1 / 3), PCSK2 (also known as PC2), PCSK3 (also known as Furi PCSK1 (also known as PC4), PCSK5 (also known as PC5, P C6, and PC5 / 6), PCSK6 (also known as PACE4), PCSK7 (also known as PC7, P C8), PCSK8 (also known as site 1 protease, S1P, SKI), and PCSK9 ( There are several types of prohormone convertases, including NARC-1. For example, PC1 cleaves POMC to generate alpha-MSH. ProACTH is then cleaved by PC2 to produce ACTH1-17. For example, Pritchard et al. J. Endocrinol. 17 2(2002):411-21.

[0392] Defective POMC processing is thought to lead to obesity. Patients whose children carry compound heterozygous mutations have severe childhood obesity, abnormal glucose homeostasis, and , hypocortisolism, and hypogonadotropic hypogonadotrophic hypogonadism See Id. Another obese patient was reported to have defective POMC processing. . See above.

[0393] An exemplary sequence for PCSK1 is set forth above. An exemplary nucleic acid sequence for human PCSK2 is , GenBank Accession No. NM_002594.4 (e.g., For example, van Wamelen et al.J.Neuropathol.Exp.N eurol.72(12),1126-1134(2013)), NM_ 001201529.2, NM_001201528.1. Human PCS An exemplary amino acid sequence of K2 is provided under GenBank Accession No. No. NP_001188458.1, NP_001188457.1, NP_002585 An exemplary nucleic acid sequence for human PCSK3 is provided at .2, which is incorporated herein by reference. GenBank accession numbers used are NM_001289824.1 and NM_0012898 23.1, NM_002569.3. Exemplary amino acids of human PCSK3 are provided in The sequence is GenBank Accession No. NP_001276, which is incorporated herein by reference. 753.1 (e.g., Dahms et al. ACS Chem. Biol. 9(5) ,1113-1118(2014)), NP_001276752.1, An exemplary nucleic acid sequence for human PCSK4 is provided in reference NP_002560.1. GenBank accession number NM_017573.4, which is incorporated herein by reference. (e.g., Seidah et al. J. Biol. Chem. 288(30) , 21473-21481 (2013). The amino acid sequence is GenBank Accession No. NP_0600, which is incorporated herein by reference. 43.2. The human PCSK5 gene sequence is incorporated herein by reference. The human PCSK5 gene is available under GenBank accession number NG_029445.1. Exemplary nucleic acid sequences are listed under GenBank Accession Nos. NR_ 120409.1, NM_006200.5, NM_001190482.1 (e.g., Mbikay et al. Genomics 26(1), 123- 129 (1995)). An exemplary amino acid sequence of human PCSK5 is provided in GenBank accession number NP_001177411.1, which is incorporated herein by reference. The human PCSK6 gene sequence is provided in US Pat. No. 6,219,191.2. The human PCSK6 gene sequence is incorporated herein by reference. The sequence of the present invention is provided in GenBank accession number NG_030047.3, which is incorporated herein by reference. An exemplary nucleic acid sequence for human PCSK6 is provided in GenBank Accession No. 10-140004, which is incorporated herein by reference. Input numbers NM_138325.3, NM_001291309.1, NM_138323. 2, NM_138324.2, NM_138322.3, NM_138319.3, NM _002570.4 (e.g., Tsuji et al. J. Biol. hem. 122(2), 438-452 (1997). Human PCSK7 Exemplary nucleic acid sequences are listed under GenBank Accession Nos. NM_111111, NM_111121, NM_111131, NM_111141, NM_111151, NM_111161, NM_111171, NM_111181, NM_111191, NM_111192, NM_111193, 004716.3 (see, e.g., Stickel et al. Hum. M ol. Genet. 23(14), 3883-3890(2014)). An exemplary amino acid sequence of human PCSK7 is provided in GenBalance, Inc., which is incorporated herein by reference. The human PCSK8 gene sequence is provided in the NK accession number NP_004707.2. Provided in GenBank Accession No. NG_033017.1, which is incorporated herein by reference. An exemplary nucleic acid sequence for human PCSK8 is described in G. enBank accession number NM_003791.3 (e.g., Weiss et al.J.Invest.Dermatol.134(1),168-175(2 014)). An exemplary amino acid sequence of human PCSK8 is incorporated herein by reference. The sequence of the present invention is provided in GenBank accession number NP_003782.1, which is incorporated herein by reference. The PCSK9 gene sequence is identified in GenBank Accession No. N00001111, which is incorporated herein by reference. G_009061.1. An exemplary nucleic acid sequence for human PCSK9 is provided in reference GenBank Accession No. XM_011541193.1, NR, incorporated herein by reference. _110451.1, and NM_174936.3 (e.g., Brou wers et al.Clin.Sci.126(9),679-684(2014) (See, e.g., 1999). An exemplary amino acid sequence of human PCSK9 is incorporated herein by reference. GenBank accession numbers XP_011539495.1 and NP_777596 used It is provided in .2.

[0394] In some embodiments, prohormone convertases, e.g., leading to homozygous deficiency, Exemplary mutations, e.g., of PCSK1, are described in the references in, e.g., Table 3, and each reference The documents are incorporated herein by reference.

[0395] In some embodiments, the prohormone convertases, which lead to, for example, heterozygous deficiency, Exemplary mutations of proteins, e.g., PCSK1, are described in the references in Table 4, e.g., The references are incorporated herein by reference.

[0396] CPE Carboxypeptidase E (CPE), also known as carboxypeptidase H (CPH) Convertases catalyze the release of C-terminal lysine or arginine residues from polypeptides CPE is an enzyme involved in the processing of many neuropeptides and peptide hormones. For example, CPE is a prohormone convertase that generates an intermediate peptide precursor. Downstream of the enzyme, the polypeptide is further processed to produce the mature peptide. It acts to remove terminal basic residues. For example, CPE acts to remove terminal basic residues from the POMC processing enzyme. Mutations in CPE are associated with obesity. For example, The female patient had a truncating mutation in the CPE gene (c.76_98del; p.E26RfsX6 8) have been described. For example, Alsters et al. PloS ONE. 10.6(2015):e0131417. In various embodiments, for example, Exemplary mutations in CPE that lead to homozygous CPE deficiency are described, for example, in the References in the book: Alsters et al. PloS One. 10.6 (2015) :e0131417.

[0397] Exemplary nucleic acid sequences of CPEs are listed under GenBank Accession Nos. No. NM_001873.2 (Skalka et al. Oncoge ne 32(23), 2836-2847(2013)). Exemplary amino acid sequences of CPE The columns refer to GenBank accession number NP_001864.1, which is incorporated herein by reference. is provided to.

[0398] Sim1 Single-minded 1 (Sim1) measures body weight, energy expenditure, and appetite. Sim1 is a transcription factor involved in the development of the paraventricular nucleus of the hypothalamus, which controls POMC- It acts on MC4R in the MC4R pathway. and Sim1- / - mice) are associated with susceptibility to hyperphagia, obesity, and diet-induced obesity. For example, Xi et al., PLoS One See also Sim1 in mice. Neuron ablation is associated with increased food intake and reduced energy expenditure. In various embodiments, for example, a heterozygous Sim1 deficiency Exemplary mutations in Sim1 that lead to disease are described, for example, in Bo nnefond et al.J.Clin.Invest.123.7(2013): It is described in 3037-41.

[0399] The human SIM1 gene sequence is available under GenBank accession number SN1111111, which is incorporated herein by reference. An exemplary nucleic acid sequence for human SIM1 is provided in reference NG_008230.1. GenBank Accession No. XM_011536073.1 (e.g., Ramachandrappa et al.J.Clin.Invest.123 (7), 3042-3050 (2013)), XM_011536072 .1, XM_005267100.2, NM_005068.2. An exemplary amino acid sequence of SIM1 is provided in GenBank Accession No. 10-140024, which is incorporated herein by reference. Input number XP_011534375.1, XP_011534374.1, XP_0052 67157.1, NP_005059.2.

[0400] BBS1~20 BBS1 to BBS20 are 20 genes associated with Bardet-Biedl syndrome. Mutation(s) in one or more of the BBS genes result in obesity, blindness, and hearing loss. Mice lacking the BBS1 gene in the nervous system develop obesity. For example, Guo et al. PLOS Genetics 1 2.2(2016):e1005890. Also, the BBS gene mutation Telozygous carriers have been described as having a higher propensity for obesity than control subjects. ,Gupta et al.J.Endocrinol.203(2009):327- Please refer to 36.

[0401] In embodiments of any of the methods described herein, the method further comprises: The method includes treating a subject having one or more mutations in one or more of BBS1 to BBS20. In embodiments, the methods described herein involve the use of one of the genes BBS1 to BBS20. and (iii) administering to a subject having one or more mutations in at least one of the MC4R agonists described herein. Exemplary mutations include mutations in one or more of the BBS genes, e.g., BBS2 , BBS4, and / or BBS6. SNPs in BBS6 and BBS4 have been linked to adult and childhood obesity by several reports. For example, Gupta et al. J. Endoc See rinol.203(2009):327-36.

[0402] ALMS1 Alström syndrome (ALMS) is a condition that results in the early onset of type 2 diabetes in affected individuals. This can lead to blindness, hearing loss, diabetes and obesity, hyperinsulinemia and glucosuria. ALMS is an autosomal recessive genetic disorder associated with impaired glucose metabolism. It is caused by mutations in the ALMS1 gene, which is a target gene for early-onset obesity. Progression from GI ≥ 100 to impaired fasting glucose or impaired glucose tolerance and overt diabetes is associated with weight loss. Progression of beta-cell insulin secretion without further deterioration of insulin resistance with age Sexual dysfunction is thought to be the main cause (Bettini et al. Pedia tr.Diabetes 13:59-67, 2012). AL as a ciliary protein The specificity of MS1 includes some of the observed phenotypes, including Bardet-Biedl syndrome. Describe their similarities to other ciliopathies, including cerebrospinal fluid disorders.

[0403] Nucleic acid sequences associated with Alström syndrome, variants of the nucleic acid sequences, and nucleic acid sequences and to determine whether an individual is a carrier of Alström syndrome. Screening methods for testing individuals to determine if they are resistant to HIV-1 are described, for example, in U.S. Pat. This is disclosed in US Pat. No. 6,171.

[0404] In embodiments of any of the methods described herein, the method comprises: This includes treating a subject who has one or more mutations in one or more alleles of a gene. In some embodiments, the methods described herein are useful for treating subjects with one or more mutations in this gene. The present invention includes the use of an MC4R agonist as described herein for the treatment of a rheumatoid arthritis.

[0405] Nucleic acid sequences associated with Alström syndrome, variants of the nucleic acid sequences, and nucleic acid sequences and to determine whether an individual is a carrier of Alström syndrome. Screening methods for testing individuals to determine if they are resistant to HIV-1 are described, for example, in U.S. Pat. This is disclosed in US Pat. No. 6,171.

[0406] Pseudohypoparathyroidism (GNAS1) In pseudohypoparathyroidism, the body fails to respond to parathyroid hormone It is one of the clinical conditions associated with obesity and short stature. The main symptoms are low calcium levels. Affected individuals may experience cataracts, dental problems, seizures, numbness, and high blood phosphate levels. Symptoms typically begin with It is observed in childhood. People with this disorder have low levels of thyroid-stimulating hormone and gonadotropins. Type 1A is characterized by short stature, a round face, obesity, and short hands. It is also associated with a group of conditions called Albright's hereditary osteodystrophy, including: Hypoparathyroidism type 1A is caused by mutations in the GNAS gene and is an autosomal dominant disorder. The GNAS1 gene is described, for example, in US20060147936. are.

[0407] In embodiments of any of the methods described herein, the method comprises: This includes treating a subject who has one or more mutations in one or more alleles of a gene. In some embodiments, the methods described herein are useful for treating subjects with one or more mutations in this gene. The present invention includes the use of an MC4R agonist as described herein for the treatment of a rheumatoid arthritis.

[0408] More genes Additional genes useful in the methods disclosed herein include BDNF, MCH1R , MCH, NTRK2, SIM1(J Clin Invest.2013;123(7 ):3042-3050.doi:10.1172 / JCI68016), ENPP1, COH1, CNR1, NPC1, c-MAF, PTER, FTO, TMEM18 (childhood ), SDCCAG8, TNKS / MSRA, GNPDA2 (childhood), NEGr1, IN SIG2, KCTD15, NROB2, and 16p11.2 deletions (including the SH2B1 gene) (including

[0409] In embodiments of any of the methods described herein, the method comprises: and treating a subject with one or more mutations in one or more of his or her offspring. In embodiments, the methods described herein involve targeting one or more of these genes. This includes the use of an MC4R agonist as described herein to treat a subject carrying a mutation.

[0410] hindrance According to the methods and compositions described herein, in some embodiments, an MC4R agonist MC4R agonists, such as those described herein, e.g., setomelanotide, may be used to treat metabolic disorders. , for example, to treat disorders such as obesity, bulimia, or metabolic syndrome. It is used.

[0411] In embodiments, an MC4R agonist, such as an MC4R agonist described herein, Drugs such as setomelanotide are used to treat POMC-MC4R deficiencies caused by deficiencies in one or more components of the POMC-MC4R pathway. In some embodiments, MC4 is used to treat genetic disorders caused by R agonists, such as the MC4R agonists described herein, such as setomelanotide, Treating genetic disorders such as Prader-Willi syndrome (PWS) or POMC null obesity In embodiments, an MC4R agonist, such as those described herein, is used to MC4R agonists, such as setomelanotide, inhibit the following genes: POMC, PCSK1, MAGEL2, leptin-R, leptin, 5-HT2c receptor, NhHL2, prohormones Genes associated with deficiencies of one or more of the enzymes convertase, CPE, MC4R, or Sim1 In some embodiments, MC4R agonists, such as The MC4R agonists described herein, e.g., setomelanotide, can be used in combination with, for example, POMC agonists. Used to treat genetic disorders associated with hypermethylation of the POMC gene in rhesus monkeys will be done.

[0412] In some embodiments, the genetic disorder is obesity, e.g., severe obesity, and / or hyperphagia. Related.

[0413] Prader-Willi syndrome (PWS) Prader-Willi syndrome (PWS) affects approximately 1 in 8,000 to 25 in 10,000 people in the United States. PWS is a rare genetic disorder with a prevalence of 1 in 2,000 people. Severe hyperphagia, a physiological condition that takes precedence over all else, leading to obesity and other complications Obesity is one of the biggest health threats for people with PWS. Bulimia requires costly and constant supervision to prevent binge eating, which reduces the independence of people with PWS. Without supervision, these patients may suffocate, rupture their stomachs, or risk of premature death as a result of or from complications caused by morbid obesity Currently, there are no approved treatments for obesity and binge eating associated with PWS. stomach.

[0414] Symptoms of PWS include hypotonia in infants with failure to thrive, rapid weight gain in childhood, and Symptoms of PWS include hyperphagia and hyperphagia, as well as intellectual disability, growth retardation, short stature, and hypogonadism. The diagnostic criteria are, for example, those set out in Holm et al. Pediatrics 91 (1993): 398-402.

[0415] The genetics underlying PWS include a mutation in human chromosome 15, specifically 15q11-q13. It is thought that the loss of function of several genes is involved. See et al. Nat. Genet. 45.11 (2013): 1405-09. The protein-coding genes in this region of chromosome 15 are MKRN3, MAG Includes EL2, NDN, NPAP1, and SNURF-SNRPN. See Ibid. MAGE Examples of L2 null deficiencies are described, for example, in Schaaf et al. al. and Soden et al.Sci Transl Med.2014 Dec 3;6(265):265ra168. Approximately 70% of PWS patients have a father There is a large deletion (approximately 4 Mb) in the 15q11-q13 chromosomal region. vini et al.Front.Neuroendocrinol.34(2014 Approximately 25% of individuals with PWS have maternal uniparental disomy. See Ibid. Mice lacking MAGEL2 gene expression have POMC neurons. They have the disorder and develop some of the same symptoms as people with PWS. Deletions of the MAGEL2 gene (found on chromosome 15 in humans) usually result in the downstream M Protease inhibitors are key components of the MC4 pathway, which promotes satiety by activating C4 receptors. It is thought that this may impair the function of opiomelanocortin (POMC) neurons. Dysfunction of MC4 may create a blockage in the MC4 pathway.

[0416] Without wishing to be bound by theory, the MC4R agonists described herein, For example, setomelanotide bypasses defective POMC neurons and acts as a blocker of the MC4 pathway. Activating the MC4 pathway may restore weight and appetite control in PWS subjects. For example, the melanocortin receptor agonists described herein, such as cerebrospinal fluid agonists, Tomelanotide can act as a replacement therapy for MSH.

[0417] POMC null obesity Patients with POMC null obesity, also described as POMC deficiency syndrome, are pro-opioid Homozygous deficiency of the omelanocortin (POMC) gene, which is an early-onset Patients with POMC null mutations have a BMI of over 40 and are unable to control Insatiable appetite (severe hyperphagia) begins in childhood and leads to severe obesity. This genetic disorder is It may also be associated with hormone deficiencies such as hypoadrenalism, and may be associated with red hair and fair skin. This disorder can lead to early death. POMC null obesity is an extremely rare genetic disorder. It is a genetic disorder, and there are no approved treatments for the obesity and binge eating associated with this condition. No. There are an estimated 50-500 POMC null individuals worldwide.

[0418] Bardet-Biedl syndrome (BBS) In some embodiments, the MC4R agonists described herein are used to treat Bardet-Biedl syndrome. It is used to treat BBS, a genetically heterogeneous disorder. S is a form of Laurence-Moon-Biedl syndrome and is associated with obesity, retinopathy, learning disabilities, and multiple sclerosis. It is characterized by dactyly and genital hypoplasia. gl. J. Med. 321 (1989):1002-9. Without being bound by theory, Although we do not wish to be bound by this, BBS consists of 20 genes (BBS1 to BBS20). It is believed to be characterized by one or more mutations in one or more of the following: Most of the genes encode proteins thought to be important for cilia function, formation, and stability. It encodes eight BBS proteins (BBS1, BBS2, BBS4, BBS5, BBS7, BBS8, BBS9, and BBS18) are BBSs that mediate transport to the ciliary membrane. It is thought that BBS6, BBS10, and BB form a complex called ome. S12 is thought to form a complex with type II chaperonins of the CCT / TRiC family. It is being done.

[0419] Mutation(s) in the BBS gene(s) can result in the absence of cilia, e.g., neurocilia, or ciliary defects. Ciliary dysfunction is thought to be caused by abnormalities in leptin signaling. It is believed to cause hypoleptinemia and hyperleptinemia. Energy homeostasis and obesity-related disorders The role of primary cilia and ciliary proteins in injury has been reviewed, for example, by Gupta et al. Endocrinol.203(2009):327-36, and Oh et al. Cell Metab.21.1(2015):21-31. The patients had hyperleptinemia suggesting leptin resistance, and the triglycerides and The serum BP, diastolic BP-Z, and visceral fat mass were found to be significantly higher than those of controls. For example, Feuillan et al. J. Clin. Endocrinol. See etab.96.3(2011). For example, obesity in BBS mutant mice is , thought to be caused by leptin resistance and defective leptin receptor trafficking For example, Berbari et al. Proc. Natl. Acad. Sci. US A 110.19(2013):7796-7801. BBS2, BB4 BB6 and BB6 mutant mice have been shown to be hyperleptinemic and do not respond to leptin. In response, the researchers were unable to reduce their food intake. al.Proc.Natl.Acad.Sci.USA 110.19(2013): See 7796-7801.

[0420] Alström syndrome Alström syndrome (ALMS) is a condition that results in the early onset of type 2 diabetes in affected individuals. Clinical complications include severe obesity, hyperinsulinemia, and impaired glucose metabolism, which can lead to ALMS is a symptomatic autosomal recessive disorder that is mapped to chromosome 2p13. It is caused by mutations in the ALMS1 gene, which regulates schizophrenia.

[0421] The progression from early-onset obesity to impaired fasting glucose or glucose tolerance and overt diabetes is associated with weight loss. The presence of small amounts of insulin does not result in further deterioration of insulin resistance with age. It is believed that the primary cause is a progressive failure of insulin secretion (Bettini et al. .Pediatr.Diabetes 13:59-67,2012).

[0422] Outcome In various embodiments, the methods described herein are directed to reducing weight (e.g., body weight), lowering hunger levels, and a decrease in blood pressure, a non-detectable decrease in energy expenditure (e.g., resting energy expenditure) Presence, increased energy expenditure (e.g., resting energy expenditure), 1 day / 1 week / 1 reduction in food intake over a period of 2 months, reduction in waist circumference, absence of a detectable increase in blood pressure, or e.g. and producing one or more outcomes, including a reduction in the subject's blood pressure compared to a control.

[0423] In some embodiments, the control is a control group prior to administration of (treatment with) an MC4R agonist. In some embodiments, the control is a predetermined value, e.g., an average the values ​​of the parameters in a population of obese people, e.g., a population of similar age and sex to the subject, is a point in time in the past (e.g., a past visit to a doctor, medical facility, or laboratory) is the value of the parameter of interest measured at

[0424] In embodiments, the outcome (e.g., a decrease, an increase, a detectable increase in a given parameter) can be achieved. The absence of a decrease, or the absence of a detectable increase, indicates the effectiveness of treatment with an MC4R agonist. For subjects 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks or more after starting In other embodiments, the outcome (e.g., a decrease, an increase, or a decrease in a given parameter) is measured. , absence of a detectable decrease, or absence of a detectable increase) for a period during the course of treatment. Over a period of time (e.g., 1-2 weeks, 2-4 weeks, 4-6 weeks, 6-8 weeks, 8-12 weeks, or over a period of 12 to 16 weeks) are measured in subjects.

[0425] In embodiments, the methods described herein include a control (e.g., a subject's weight before treatment, Or a predetermined value, for example, a value obtained by comparing obese people of the same age and sex as the subject who have not received a therapeutic intervention. compared to the mean weight of the population, or at a previous measurement, e.g., the subject's weight at a previous visit In some embodiments, the reduction occurs within 1 week of administration of the compound. Approximately 1kg to 3kg after treatment, approximately 1kg to 6kg after 2 weeks of treatment, approximately 2kg to 6kg after 4 weeks of treatment kg to 12 kg, approximately 4 kg to 24 kg after 8 weeks of treatment, or approximately 8 kg to 16 kg after 16 weeks of treatment In various embodiments, this reduction occurs over, for example, 1-2 weeks or more of treatment. treatment, 2-4 weeks or more of treatment, 4-8 weeks or more of treatment, 8-16 weeks of treatment, or 16+ weeks of treatment Over a 32-week treatment period, a weight loss rate of approximately 1-2 kg / week, e.g., approximately 2 kg / week, is expected. It is something that can be done.

[0426] Measurement of weight, e.g., body weight, can be performed using methods standard in the art. can.

[0427] In some embodiments, the methods described herein may be used to measure the hunger level of a control (e.g., a subject's hunger level before treatment). level, or a predetermined hunger level, e.g., a population of obese humans of similar age and sex to the subject. compared to the subject's average hunger level or previous measurements, e.g., previous visits) In some embodiments, the methods described herein comprise: Causes the subject to lose hunger.

[0428] In various embodiments, hunger is measured on a scale ranging from 0 to 10 and is expressed as a Like score as described herein. In some embodiments, the present invention is directed to a scale such as the rt hunger scale. The method described above may include a control (e.g., a subject's hunger level before treatment, or a predetermined hunger level, For example, the average hunger level of a population of obese people of similar age and sex to the subject, or a historical measurement a reduction in the subject's hunger score compared to a regular interval (e.g., the subject's hunger level at a previous visit) In embodiments, the methods described herein may be used in conjunction with a control (e.g., a control group of a subject before treatment). hunger level, or a predetermined hunger level, e.g., a population of obese people of similar age and sex to the subject the group's average hunger level, or the subject's hunger level at a previous measurement, e.g., at a previous visit) and In comparison, lowering the Likert hunger scale score, e.g., In various embodiments, the score is reduced by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 points. Therefore, the methods described herein result in a score of 0 on the Likert hunger scale after treatment. Glass.

[0429] In various embodiments, the reduction in hunger levels is observed over 1-2 weeks of treatment, 2-4 weeks or more Measured / observed after treatment, 4-8+ weeks of treatment, or 8-16+ weeks of treatment.

[0430] REE is a measure of a subject's basal metabolic rate, as described by Chen et al. J. Clin. E Indocrinol.Metab.100.4(2015):1639-45 In some embodiments, the REEs can be determined using methods such as those described in the literature. At specific time points after treatment (e.g., 3, 4, 5, 6, 7 days, or 1, 2, 3, 4 weeks, or (later) in the whole-room indirect calorimetry room. The blood pressure is determined by placing the subject in a metabolic chamber (also known as a calorimeter). In some embodiments, the REE is measured over a 30 minute measurement period, and some In this case, REE values ​​from several 30-minute periods are averaged to generate the average REE. In some embodiments, the REE is administered while the subject is awake and without psychological or physical stress. The test may be performed after a 10-12 hour fasting period at thermoneutral temperatures (e.g., about 25°C). In embodiments, REE is energy per unit time (e.g., kcal / hr or In embodiments, the REE is measured in units of kcal / day, e.g., as described in the Examples. As described, the REE is measured relative to kg lean body mass of the subject (e.g., REE / kg lean body mass). fat content).

[0431] In embodiments, the methods described herein may be administered, for example, on days 3, 4, 5, 6, 7 of treatment. , or 1, 2, 3, 4 weeks or more later, measured after 1 hour, 1 day (e.g. for a period of time, e.g., 24 hours), a week (e.g., 7 days), or a month (e.g., 30 days) The subject's energy expenditure, e.g., resting energy expenditure (REE), over a period of time is measured using a control R EE (e.g., the REE of a subject before treatment, or a predetermined REE, e.g., a subject of similar age and The mean REE of obese human populations normalized for body weight and sex, or previous measurements The subject's REE is not changed or decreased compared to the time of the visit, e.g., the subject's REE at a previous visit.

[0432] In embodiments, the methods described herein may be administered, for example, on days 3, 4, 5, 6, 7 of treatment. , or 1, 2, 3, 4 weeks or more later, measured after 1 hour, 1 day (e.g. for a period of time, e.g., 24 hours), a week (e.g., 7 days), or a month (e.g., 30 days) Energy expenditure of a subject over a period of time, e.g., resting energy expenditure per kg of lean body mass The REE is calculated as a control REE (e.g., the REE of the subject before treatment) or a predetermined REE, e.g., For example, the mean REE of a population of obese people of similar age and sex to the subject, or a previous measurement, does not detectably change or decrease compared to the subject's REE at a previous visit.

[0433] In embodiments, the methods described herein may be administered, for example, on days 3, 4, 5, 6, 7 of treatment. , or 1, 2, 3, 4 weeks or more later, measured after 1 hour, 1 day (e.g. for a period of time, e.g., 24 hours), a week (e.g., 7 days), or a month (e.g., 30 days) The subject's energy expenditure, e.g., resting energy expenditure (REE), over a period of time is measured using a control R EE (e.g., the REE of a subject before treatment, or a predetermined REE, e.g., a subject of similar age and The mean REE of obese human populations normalized for body weight and sex, or previous measurements The REE is increased relative to the subject's REE at the time of the previous visit.

[0434] In various embodiments, for example, 3, 4, 5, 6, 7 days of treatment, or 1, 2, 3, 4 The subject's REE increased by at least 20 kcal when measured weeks or more later. l / day (e.g., at least 20, 30, 40, 50, 60, 70, 80, 90, 100 , 110, 120, 130, 140, 150 kcal / day or more).

[0435] In various embodiments, for example, 3, 4, 5, 6, 7 days of treatment, or 1, 2, 3, 4 The subject's RE compared to the subject's REE before treatment when measured weeks or more later The increase in E is at least 2% (e.g., at least 2%, 3%, 4%, 5%, 6%, 7% , 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, or more) be.

[0436] In some embodiments, for example, for adult subjects, after treatment with an MC4R agonist (e.g., (e.g., 3, 4, 5, 6, 7 days or 1, 2, 3, 4 weeks or more after treatment) The REE of a subject (e.g., an adult subject) should be at least 1800 kcal / day (e.g., at least Tomo 1800, 1825, 1850, 1875, 1900, 1925, 1950, 197 5, 2000, 2025, 2050, 2100, 2150, 2200, 2250, 230 In some embodiments, for example, children For patients, after treatment with an MC4R agonist (e.g., 3, 4, 5, 6, 7 days of treatment, or 1, 2, 3, 4 weeks or more later) the REE of the subject (e.g., a pediatric subject) , at least 200 kcal / day (e.g., at least 200, 225, 250, 275 , 300, 325, 350, 375, 400, 450, 500 kcal / day, or That's all.

[0437] In embodiments, the methods described herein involve measuring food intake by a subject using a control (e.g., , the subject's food intake before treatment, or a predetermined food intake level, e.g., the average human obesity (food intake of the full population, or at a previous measurement, e.g., subject's food intake at a previous visit) and For example, food intake is reduced compared to daily food intake or 24-hour or 1 In embodiments, the reduction is measured as food intake over a period of one week. For human subjects, e.g., daily food intake, or 24-hour period, or week, or Food intake of at least 100 kcal over a 30-day or longer period Lee, for example, at least 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 1000 calories or more. In an embodiment, the average food intake is determined, for example, in a pediatric subject about 1 year old, based on the MC4R agonist activity. After treatment with, for example, setomelanotide, a baseline of approximately 100 kcal / kg / day or more From the in, approximately 90, 80, 70, 60, 50, 40, 30, 20, or 10 kcal / In embodiments, the average food intake may be reduced to 0.01 kg / day or less, e.g., during late adolescence. In pediatric subjects, approximately 40% of patients had a MC4R agonist-related vasoconstriction after treatment with MC4R agonists, such as setomelanotide. Approximately 35, 30, 20, or 10 kcal from a baseline of ≥ kcal / kg / day / kg / day or less.

[0438] Food intake can be measured, for example, by Rutishauser. Pub. Health Nutr. 8 This should be determined by the standard method described in .7A(2005):1100-07. This can be done.

[0439] In embodiments, the methods described herein are administered at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 3 The subjects' waist circumferences when measured 7, 8, 9, 10, or more weeks later were compared with the control (e.g., compared to the subject's waist circumference before treatment or at a previous measurement, e.g., the subject's waist circumference at a previous visit and reduce it.

[0440] In some embodiments, the administration of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or a control (e.g., a subject's waist circumference before treatment, or a given waist circumference) when measured at a later time waist circumference, e.g., the waist circumference of an average obese human population of similar age and sex, or at a previous measurement , e.g., a reduction in a subject's (e.g., adult subject's) waist circumference compared to a previous visit) , at least 2 cm (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10 cm, or more).

[0441] In some embodiments, waist circumference is measured using standard methods. In this context, waist circumference is the greatest circumference around the midsection of a subject, e.g., around the abdomen of a subject. In terms of morphology, waist circumference is measured around the natural waist (e.g., between the lowest rib and the top of the hip bone), around the navel, Or measured at the narrowest point in the center.

[0442] In embodiments, the methods described herein are administered at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 3 The subject's blood pressure (e.g., diastolic blood pressure) when measured 7, 8, 9, 10, or more weeks later and / or systolic blood pressure) are measured using a control blood pressure (e.g., the subject's blood pressure before treatment, or a predetermined Blood pressure, e.g., blood pressure of an average obese human population of similar age and sex, or historical measurements The blood pressure does not detectably increase compared to the time of the visit (e.g., the subject's blood pressure at a previous visit).

[0443] In embodiments, the methods described herein are administered at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 3 The subject's blood pressure (e.g., diastolic blood pressure) when measured 7, 8, 9, 10, or more weeks later and / or systolic blood pressure) control blood pressure (e.g., the subject's blood pressure before treatment, or a predetermined blood pressure , for example, the blood pressure of an average obese human population of similar age and sex, or at a previous measurement, e.g., lowering the subject's blood pressure at a previous visit).

[0444] In some embodiments, the administration of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or blood pressure, e.g., systolic blood pressure, measured 1 or more years later compared to the subject's blood pressure before treatment The pressure drop should be at least 3 mmHg (e.g., at least 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7 mmHg, or higher).

[0445] In some embodiments, the administration of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or blood pressure, e.g., diastolic blood pressure, measured 1 or more years later compared to the subject's blood pressure before treatment The pressure drop should be at least 4 mmHg (e.g., at least 4, 7, 7.5, 8, 8.5, 9, 9.5, 10 mmHg, or higher).

[0446] In embodiments, the methods described herein do not have adverse effects on heart rate or blood pressure. I don't.

[0447] subject According to any of the methods described herein, in certain embodiments, the subject is a Before administration of the agonist described herein, e.g., at the time the agonist is prescribed or In various embodiments, the subject is obese at the time of the first administration of the drug. before administration of the agonist described in At the time of the first administration of the compound, the patient is a severely obese child or adult. The animal may be administered, for example, prior to administration of an agonist described herein, e.g., at the time the agonist is prescribed. point, or hyperphagia at the time of the first administration of agonist.

[0448] In some embodiments, the subject (e.g., an adult subject) is administered a steroid hormone (e.g., steroid hormone) prior to administration of the agonist, e.g., 25 kg / m at the time of prescription or first dose of nicotine 2 or 30kg / m 2 Over (e.g., ≥ 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 3 5, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48 , 49, 50 kg / m2 have a body mass index (BMI) of 18.5 or higher.

[0449] In some embodiments, the subject (e.g., a pediatric subject) is administered a steroid hormone (e.g., steroids) prior to administration of the agonist, e.g., At the time of prescription or first dose of the drug, the blood glucose level was higher than the 85th to 95th percentile. have a high body mass index (BMI).

[0450] In embodiments, the subject is monitored for a period of time, e.g., prior to administration of the agonist, e.g., after the agonist is administered. At the time of administration, or at the time of the first administration, the patient has a body weight of at least about 5 kg, for example at least about 5kg, 10kg, 20kg, 30, 40, 50, 60, 70, 80, 90, 100, 1 10, 120, 130, 140, 145, 150, 155, 160, 165, 170, 1 75, 180, 185, 190, 200, 205, 210, 215, 220 kg, or In embodiments, the subject has a weight equal to or greater than the above, e.g., before administration of the agonist: For example, at least 20 kg at the time the agonist is prescribed or at the time of the first administration , have a body weight of at least 60 kg, or at least 100 kg.

[0451] In various embodiments, the subject is an adult, e.g., 18 years of age or older, e.g., 18, 19, 20 , 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 4 7, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60 , 61, 62, 63, 64, 65, 66, 67, 68, 69, 70 or more do.

[0452] In various embodiments, the subject is a pediatric subject, e.g., a subject under the age of 18 (e.g., 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or The child is under 1 year old.

[0453] In embodiments, the subject has a defect in one or more genes in the POMC-MC4R pathway, e.g. For example, the subject may have or be identified as having a genetic defect or mutation. In the embodiment, the subject is POMC, PCSK1, MAGEL2, leptin receptor, leptin , 5-HT2c receptor, NhHL2, prohormone convertase, CPE, MC4R, if In particular, the Sim1 gene or other genes that disrupt the function of the POMC-MC4R pathway In some embodiments, the gene has or is identified as having one or more mutations. The subject is a patient with a hypermethylated POMC gene (e.g., hypermethylated in the POMC intron). methylated cytosine, e.g., methylated cytosine, e.g., 5' methylcytosine, e.g., (e.g., hypermethylated CpG islands in the POMC gene) , or identified as having.

[0454] In some embodiments, the subject has Prader-Willi syndrome.

[0455] In various embodiments, the subject has a mutation in the 15q11-q13 region of chromosome 15, e.g., the paternal allele. The gene is identified as having or having a loss-of-function mutation in the allele.

[0456] In some embodiments, the subject has a mutation (e.g., a loss-of-function mutation) in the MAGEL2 gene. Identified as having or having.

[0457] In some embodiments, the subject is POMC null, PCSK1 null genotype, MAGEL2 Null genotype, leptin receptor null genotype, leptin null genotype, 5-HT2c receptor Null genotype, NhHL2 null genotype, prohormone convertase null genotype, CPE Have a null genotype, an MC4R null genotype, and / or a SIM1 null genotype? For example, a subject may be identified as having a POMC null, a PCSK1 null, or Obesity, MAGEL2 null obesity, leptin receptor null obesity, leptin null obesity, 5-HT2 c receptor null obesity, NhHL2 null obesity, prohormone convertase null genotype, CPE null have or have MC4R null obesity, MC4R null obesity, and / or SIM1 null obesity It is identified as such.

[0458] In embodiments, the subject has a POMC mutation described herein, such as a P mutation described in Table 1. In some embodiments, the subject has or is identified as having an OMC mutation. Cys28Phe, Leu37Phe, His143Glu, Phe144Leu, Tyr221Cys, Pro231Leu, Arg236Gly, or Glu244X or has a mutation in the POMC amino acid sequence selected from one or more of: The numbering of this amino acid sequence is based on the same method as that used by Takahashi, et al. 981 Febs Letters 135(1)97 (and SEQ ID NO: 563), which corresponds to the numbering of the protein including the signal peptide, and X , indicating early termination.

[0459] In some embodiments, the subject has a POMC mutation (e.g., a homozygous POMC mutation) listed in the references in Table 2. In some embodiments, the patient has or is identified as having a POMC mutation. Subjects must have a POMC mutation listed in the references in Table 1 (e.g., a heterozygous POMC mutation ) or be identified as having.

[0460] In some embodiments, the POMC mutation is a homozygous mutation. The POMC mutation is a heterozygous mutation (e.g., a compound heterozygous mutation). In some embodiments, the POMC mutation is a loss-of-function mutation. is a partial loss-of-function mutation.

[0461] In embodiments, the subject has hypermethylation in the POMC gene, e.g., POM Hypermethylation in exon 3 of the C gene or intron 2- Hypermethylation at the intron 3 boundary, e.g., intron 2-exon 3 of the POMC gene 3. Those with or characterized as having hypermethylation in the boundary CpG islands It is determined.

[0462] In embodiments, the subject has a PCSK1 mutation described herein, e.g., a heterozygote. Nonsense variant (p.Arg80*) in PCSK1, as listed in the references in Table 3 mutations (e.g., homozygous mutations), or PCSK1 mutations (e.g., In some embodiments, the gene is a heterozygous mutation (e.g., a heterozygous mutation). In this study, the target mutations were Met125Ile, Thr175Met, Asn180Ser, and Ty r181His, Gly262Arg, Ser325Asn, Thr558Ala, As PCSK1 amine selected from n221Asp, Gln665E, or S690Thr The nucleic acid sequence of the ...

[0463] In some embodiments, the PCSK1 mutation is a homozygous mutation. The PCSK1 mutation is a heterozygous mutation (e.g., a compound heterozygous mutation). In embodiments, the PCSK1 mutation is a loss-of-function mutation. The K1 mutation is a partial loss-of-function mutation.

[0464] In embodiments, the subject has a MAGEL2 mutation described herein, e.g., c.16 52delT(p.Val551fs), c.1802delC(p.Pro601fs ), c.3181_3182delAT(p.Ile1061fs), c.3124C> T(p.Gln1024*), or Schaaf et al. Nat. Genet. 45.11(2013):1405-09 or Soden et al. Sci T ransl Med.2014 Dec 3;6(265):265ra168 In some embodiments, the MAGEL In some embodiments, the MAGEL2 mutation is a homozygous mutation. In some embodiments, the MAGEL2 mutation is a compound heterozygous mutation (e.g., a compound heterozygous mutation). The mutation is a loss-of-function mutation. In embodiments, the MAGEL2 mutation is a loss-of-function / activity mutation. causes a decrease.

[0465] In embodiments, the subject has a leptin mutation or leptin-R mutation described herein. In embodiments, the subject has or is identified as having leptin mutations described in the literature, such as guanine nucleotide at codon 133 of the leptin gene Homozygous frameshift mutations resulting in deletion of the nucleotide or amino acid at position 100 (pD Homozygous transfection leading to aspartic acid to tyrosine change in 100Y It has or is identified as having version (c.298G→T). In embodiments, the subject has a leptin-R mutation described herein, e.g., Gln223A rg or Lys656Asn mutation, or any of the mutations listed in the references in Table 5 (e.g., Ho In some embodiments, the individual has or is identified as having a mutation (a monozygous mutation). The subject has a leptin-R mutation (e.g., a homozygous leptin-R mutation) listed in Table 6. In some embodiments, the subject has or is identified as having c.23 96-1G>T, c.1675G>A, p.Cys604Gly, p.Leu786Pr o, p.His800_Asn831del, p.Tyr422His, p.Thr71 1NfsX18, P.535-1G>A, p.166CfsX7, 4-bp del code 22, 11-bp del codon 70, 66-bp del codon 514, Trp31 X, Ala409Glu, Trp664Arg, His684Pro, 1-bp del or have a leptin-R mutation selected from codon 15, or Arg612His or having.

[0466] In embodiments, the leptin or leptin-R mutation is a homozygous mutation. In some embodiments, the leptin or leptin-R mutation is a heterozygous mutation (e.g., In some embodiments, the leptin mutation or leptin In some embodiments, the leptin-R mutation is a loss-of-function mutation. The -R mutation is a partial loss-of-function mutation.

[0467] In embodiments, the subject has a 5-HT2c receptor mutation described herein or In embodiments, the 5-HT2c receptor mutation is In some embodiments, the 5-HT2c receptor mutation is a homozygous mutation. In some embodiments, the 5-HT2c receptor is a 5-HT2c mutation (e.g., a compound heterozygous mutation). In some embodiments, the 5-HT2c receptor mutation is a partial mutation. It is a loss-of-function mutation.

[0468] In embodiments, the subject has an NhLH2 mutation described herein, such as Good e et al. Nat. Genet. 15 (1997): 397-401 In some embodiments, the NhLH2 mutation is In some embodiments, the NhLH2 mutation is a heterozygous mutation (e.g., In some embodiments, the NhLH2 mutation is a loss of function. In some embodiments, the NhLH2 mutation is a partial loss-of-function mutation.

[0469] In embodiments, the subject has a prohormone convertase mutation described herein, e.g., Pritchard et al.J.Endocrinol.172(2002):4 11-21 or a reference in Table 3 or Table 4, In embodiments, the prohormone convertase mutation is In embodiments, the prohormone convertase mutation is a heterozygous mutation. In some embodiments, the prohormone is a compound heterozygous mutation (e.g., a compound heterozygous mutation). The convertase mutation is a loss-of-function mutation. In embodiments, a prohormone convertase mutation is a partial loss-of-function mutation.

[0470] In embodiments, the subject has a CPE mutation described herein, e.g., (c.76_9 8del;p.E26RfsX68), or Alsters et al.PloS ONE.10.6(2015):e0131417 In some embodiments, the CPE mutation is a homozygous mutation. In embodiments, the CPE mutation is a heterozygous mutation (e.g., a compound heterozygous mutation In some embodiments, the CPE mutation is a loss-of-function mutation. Therefore, the CPE mutation is a partial loss-of-function mutation.

[0471] In embodiments, the subject has a SIM1 mutation described herein, e.g., Bonnef ond et al.J.Clin.Invest.123.7(2013):3037 41. In some embodiments, the SIM1 mutation is a homozygous mutation. In some embodiments, the SIM In some embodiments, the SIM1 mutation is a loss-of-function mutation. In some embodiments, the SIM1 mutation is a partial loss-of-function mutation. It is a mutation.

[0472] In embodiments, the methods herein involve activating one or more of the POMC-MC4R pathway. Identifying or selecting subjects with genetic defects, e.g., genetic defects or mutations In embodiments, the methods herein may include determining a genotype, a predetermined sequence, or In embodiments, the methods herein may include obtaining knowledge of the mutations or mutations. For example, POMC, PCSK1, MAGEL2, leptin receptor, leptin, 5-H T2c receptor, NhHL2, prohormone convertase, CPE, MC4R, Sim1, and or the genotype of a mutation in one or more of the other POMC-MC4R pathway genes In embodiments, the agonist may comprise a compound selected from the group consisting of a compound of formula (I) and a compound of formula (II). Gene, POMC, PCSK1, MAGEL2, leptin receptor, leptin, 5-HT2 c receptor, NhHL2, prohormone convertase, CPE, MC4R, Sim1, or others a known sequence, e.g., a known mutation, in one or more of the POMC-MC4R pathway genes of The agent is administered in response to obtaining, e.g., detecting or identifying, a signal.

[0473] In some embodiments, the methods herein involve the use of a POMC gene (e.g., a POMC gene). hypermethylated introns, e.g., methylated cytosines, e.g., 5' Hypermethylation in CpG islands containing methylcytosines, e.g., in the POMC gene In some embodiments, the method may include obtaining knowledge of the methylation status of the target gene (e.g., a gene encoding a gene that is being methylated). Thus, an agonist is administered in response to detection of hypermethylation.

[0474] In embodiments, the methods herein involve obtaining knowledge of the subject's genotype. , e.g., the 15q11-q13 region of chromosome 15 (e.g., paternal allele) or MAG In some embodiments, the agonist may be a genotype-dependent agonist. The stochastic allele is located in the 15q11-q13 region of chromosome 15 (e.g., paternal allele) or MAGE. It is administered in response to the detection of a predetermined sequence, eg, a mutation, in the L2 gene.

[0475] In some embodiments, the gene has a particular genotype or predetermined sequence, e.g., a mutation. Identification or selection of a subject as a specific genotype or a given sequence, e.g., mutation Such knowledge may include acquiring knowledge, as detailed in the "Definitions" section. It can be obtained in several ways.

[0476] In some embodiments, the sequence may be obtained by, for example, "directly obtaining" or is obtained by obtaining ownership of a nucleotide sequence by "indirectly obtaining" "Directly obtaining a sequence" means performing a process to obtain a sequence (e.g. For example, performing synthetic or analytical methods, such as sequencing (e.g., next generation sequencing ( "Indirectly obtaining a sequence" means obtaining a sequence from another party. or the source (e.g., a third-party laboratory that directly obtained the sequence) The term refers to receiving information or knowledge, or receiving the sequence of information or knowledge. The sequence does not have to be a complete sequence, for example, the sequencing of at least one nucleotide, or or a genotype or predetermined sequence disclosed herein, e.g., a mutation, is present in the subject. Obtaining information or knowledge that identifies a particular molecule as such is equivalent to obtaining a sequence.

[0477] In embodiments, the sequence may be obtained directly. This includes physical substances, such as starting materials, e.g., tissue samples, e.g., blood samples or tissue biopsies. A process involving the physical alteration of a sample or the analysis of an isolated nucleic acid (e.g., DNA or RNA) sample. Exemplary transformations include creating a physical entity from two or more starting materials. To produce, shear or fragment materials such as genomic DNA fragments, and separate materials or purifying (e.g., isolating a nucleic acid sample from tissue), Combining substances to form a mixture; chemical reactions involving breaking or forming covalent or non-covalent bonds As mentioned above, direct acquisition of values ​​requires the use of a sample or This includes performing a process involving a physical change of a substance or other material.

[0478] In some embodiments, knowledge of a particular genotype or predetermined sequence, e.g., mutation, is acquired. This involves, for example, obtaining a sample in which a genotype or a predetermined sequence, e.g., a mutation, is to be determined. "Obtaining a sample" as that term is used herein may include , "directly obtaining" or "indirectly obtaining" a sample, e.g., a tissue sample or nucleic acid sample. "Direct acquisition of a sample" refers to the acquisition of ownership of the sample. "To perform" means to perform a process to obtain a sample (e.g., surgery or extraction) "Indirectly obtaining a sample" means obtaining a sample from another party or or source (e.g., a third-party laboratory that directly acquired the sample) Directly obtaining a sample involves obtaining a physical substance, e.g., a starting material, e.g. This includes physical changes to tissue, e.g., tissue from a human patient, or tissue previously isolated from a patient. An exemplary transformation involves creating a physical entity from a starting material. preparing, dissecting or exfoliating tissue, material (e.g., sample tissue or nucleic acid sample) to separate or purify substances, to combine two or more separate entities into a mixture, to form a compound containing a covalent bond Examples of such methods include performing chemical reactions involving the formation or cleavage of non-covalent bonds. Direct acquisition may include, for example, as described above, a physical change in a sample or another substance. This includes performing a process that includes

[0479] In some embodiments, for example, an MC4R agonist, such as an MC4R agonist described herein, Methods for assessing subjects for likelihood of response to an agonist, e.g., setomelanotide Also provided herein are methods for determining the genotype of a subject. In some embodiments, the methods involve determining the genotype of a subject. In some embodiments, the method includes obtaining information related to the POMC-MC4 activity of the subject. information on the presence or absence of a defect in one or more genes of the R pathway, e.g. This includes obtaining

[0480] In embodiments, a subject is administered POMC-MC4R using the methods described herein. Identifying one or more genes in a pathway as having a defect, e.g., a gene defect, e.g., a mutation It can be done.

[0481] In some embodiments, the subject is a person having a defect, e.g., a genetic defect, e.g., a mutation. The identification of the MC4R agonist may be achieved by administering the MC4R agonist to the subject, e.g., the MC4R agonist described herein. likely to respond (e.g., with improvement in one or more symptoms) to a drug such as cetomelanotide In various embodiments, improvement in symptoms may include the outcomes described herein. For example, symptom improvement may be weight loss (e.g., body weight), decreased hunger levels, or decreased energy expenditure. Absence of a detectable decrease in energy expenditure (e.g., resting energy expenditure), Increased resting energy expenditure (e.g., resting energy expenditure) and reduced daily / weekly / monthly food intake , or may include, for example, a reduction in waist circumference compared to a control.

[0482] In some embodiments, the subject is a person having a defect, e.g., a genetic defect, e.g., a mutation. The identification of the subject is carried out by determining whether the subject does not have a genetic defect in the POMC-MC4R pathway (e.g., obesity). subjects of similar age and / or pre-treatment weight), e.g., wild-type obese subjects Rather than MC4R agonists, such as the MC4R agonists described herein, e.g., cetophenone likely to respond (or have a greater response) to melanotide In embodiments, subjects who are more likely to respond are those who are more likely to respond than, for example, controls, e.g. , subjects without a genetic defect in the POMC-MC4R pathway (e.g., obese subjects, e.g., similar subjects of similar age and / or pre-treatment weight), e.g., compared to wild-type obese subjects, In various embodiments, the patient is more likely to have improvement in the above symptoms, such as those described herein. In this study, subjects who are more likely to have a greater response than, for example, a control, e.g., a POMC - Subjects without genetic defects in the MC4R pathway (e.g., obese subjects, e.g., subjects of similar age and and / or pre-treatment weight), e.g., compared to wild-type obese subjects, the symptoms, e.g., Greater improvement in symptoms as described in the fine print, e.g., greater weight loss, greater waist circumference loss , greater increase in resting energy expenditure, greater decrease in food intake, greater hunger likely to have decreased levels.

[0483] In embodiments, the methods described herein identify the presence or absence of a genetic defect. and in some cases providing a subject identifier. In embodiments, the report may include recommendations regarding potential treatment options, efficacy of treatment options, and / or and / or treatment options (e.g., MC4R agonists, e.g., those described herein). Provides recommendations / instructions regarding administration of the MC4R agonists described herein, e.g., setomelanotide. do.

[0484] MC4R agonists Examples of naturally occurring MC4R agonists include α-MSH, β-MSH, and γ-MSH. H, and adrenocorticotropic hormone e) (ACTH) or a functional fragment thereof. Examples of synthetic MC4R agonists include: Details are provided below.

[0485] In an exemplary embodiment, the agonist used in accordance with the methods of the present invention is a known agonist of MC4R. In some exemplary embodiments, the MC4R agonist is not adrenocorticotropic hormone (ACTH) or a fragment thereof.

[0486] In an exemplary embodiment, the MC4R agonist is a compound described in WO 2004 / 022990, which is incorporated herein by reference. Among the peptides disclosed in the international application published under number 2005 / 000339 In particular, examples include peptides of the following structural formula: [ka] are listed, During the ceremony, W is Glu, Gln, Asp, Asn, Ala, Gly, Thr, Ser, Pro, M et, Ile, Val, Arg, His, Tyr, Trp, Phe, Lys, Leu, C ya, or non-existence, R 1 is -H, -C(O)CH3, -C(O)(CH2) 1-4 CH3, -C(O)(C H2) 1-4 NHC(NH)NH2, Tyr-βArg-, Ac-Tyr-β-hArg-, Gluconoyl-Tyr-Arg -, Ac-diaminobutyryl-, Ac-diaminopropionyl, N-propionyl, N-butyryl, N-valeryl -, N-Methyl-Tyr-Arg-, N-Glutaryl-Tyr-Arg-, N-Succinyl -Tyr-Arg-, R 6 -SO2NHC(O)CH2CH2C(O)-, R 6 -SO2NHC(O)CH2 CH2C(O)Arg-, R 6 -SO2NHCH2CH2CH2C(O)-, C3-C7 cycloalkylcarbonyl phenylsulfonyl, C8-C 14 Bicyclic Arylsulfonyl, Phenyl-(CH2) q C(O)-, C8-C 14 Bicyclic Aryl-(CH2) q C(O)-, [ka] (In the formula, R 2 is -H, -NH2, -NHC(O)CH3, -NHC(O)(CH2) 1-4 CH 3. -NH-TyrC(O)CH3, R6 SO2NH-, Ac-Cya-NH-, Tyr- NH-, HO-(C6H5)-CH2CH2C(O)NH-, or CH3-(C6H5)-C (O)CH2CH2C(O)NH-, R 3 is C1-C4 straight or branched alkyl, NH2-CH2-(CH2) q -,HO -CH2-, (CH3)2CHNH(CH2)4-, R 6 (CH2) q -, R 6 SO2NH-, Se r, Ile, [ka] and q is 0, 1, 2, or 3; R 6 is phenyl or C8-C 14 is a bicyclic aryl; m is 1 or 2; n is 1, 2, 3, or 4; R 9 is (CH2) p or (CH3)2C-, p is 1 or 2; R 10 is NH- or absent, R 7 is a 5- or 6-membered heteroaryl, or R 4 5 optionally substituted with a 1- or 6-membered heteroaryl ring; R 4 is H, C1-C4 straight or branched alkyl, phenyl, benzyl, or (C6 H5) -CH2-O-CH2-, R 8 is phenyl, a phenyl ring optionally substituted with X, or cyclohexyl; can be, X is H, Cl, F, Br, methyl, or methoxy; R 11 is -C(O) or -CH2, R 5 are -NH2, -OH, glycinol, NH2-Pro-Ser-, NH2-Pro -Lys-, HO-Ser-, HO-Pro-Ser-, HO-Lys-, Ser-alcohol, -Ser-Pro-alcohol Cole, -Lys-Pro alcohol, HOCH2CH2-O-CH2CH2NH-, NH2-Phe-Arg-, NH2-G lu-, NH2CH2RCH2NH-, RHN-, RO- (where R is a C1-C4 straight chain or is a branched alkyl; L is -SS- or -S-CH2-S-.

[0487] Other examples of MC4R agonists include peptides of the following structural formula: [ka] In the formula: W is a single bond, Glu, Gln, Asp, Asn, Ala, Gly, Thr, Ser, P ro, Met, Ile, Val, Arg, His, Tyr, Trp, or Phe , R 1 is -H, -C(O)CH3, -C(O)(CH2) 1-4 CH3, -C(O)(C H2) 1-4 -NHC(NH)NH2, Tyr-βArg, Gluconoyl-Tyr-Arg, Ac-Dab, Ac-Dap, N -succinyl-Tyr-Arg, N-propionyl, N-valeryl, N-glutaryl-Tyr-Arg, N-butyryl, [ka] (In the formula, R 2 is -H, -NH2, -NHC(O)CH3, -NHC(O)(CH2) 1-4 CH 3, or -NH-TyrC(O)CH3, R 3 is C1-C4 straight or branched alkyl, Ser, Ile, [ka] and q is 0, 1, 2, or 3; m is 1 or 2; p is 1 or 2; R 4 is H or C1-C4 straight or branched alkyl; X is H, Cl, F, Br, methyl, or methoxy; R 5 are -NH2, -OH, glycinol, -Ser-Pro-NH2, -Lys-Pr o-NH2, -Ser-OH, -Ser-Pro-OH, -Lys-Pro-OH-Arg-Phe-NH2, -Gl -NH2, -NHR, or -OR (wherein R is a C1-C4 straight or branched alkyl).

[0488] In yet another exemplary embodiment, the MC4R agonist may be represented by the following structural formula: And, [ka] During the ceremony, W is Glu, Gln, Asp, Ala, Gly, Thr, Ser, Pro, Met, I le, Val, Arg, His, Tyr, Trp, Phe, Lys, Leu, Cya, Ma or non-existence, R 1 is -H, -C(O)CH3, -C(O)(CH2) 1-4 CH3, -C(O)(C H2) 1-4 NHC(NH)NH2, Tyr-βArg-, Ac-Tyr-β-hArg-, Gluconoyl-Tyr-Arg -, Ac-diaminobutyryl-, Ac-diaminopropionyl, N-propionyl, N-butyryl, N-valeryl -, N-Methyl-Tyr-Arg-, N-Glutaryl-Tyr-Arg-, N-Succinyl -Tyr-Arg-, R 6 -SO2NHC(O)CH2CH2C(O)-, R 6 -SO2NHC(O)CH2 CH2C(O)Arg-, R 6 -SO2NHCH2CH2CH2C(O)-, C3-C7 cycloalkylcarbonyl phenylsulfonyl, C8-C 14 Bicyclic Arylsulfonyl, Phenyl-(CH2) q C(O)-, C8- C 14 Bicyclic Aryl-(CH2) q C(O)-, [ka] (In the formula, R 2 is -H, -NH2, -NHC(O)CH3, -NHC(O)(CH2) 1-4 CH 3. -NH-...

Claims

1. 1. A composition comprising an agonist of the melanocortin-4 receptor (MC4R) for treating a disorder characterized by a hypermethylated POMC gene in a subject in need thereof, the subject having or identified as having the hypermethylated POMC gene, the composition being administered in a daily dosage of 0.1 mg to 10 mg; The agonist is Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 (SEQ ID NO: 140); composition.

2. The hypermethylated POMC gene is (i) hypermethylated in the POMC intron; (ii) is hypermethylated in a CpG island of the POMC gene; or (iii) one or more methylated cytosines, optionally including a 5′ methylcytosine; The composition of claim 1.

3. The object is (i) being obese; (ii) have early-onset severe obesity; (iii) excessive appetite, (iv) 25 kg / m before administration of the agonist ２ have a body mass index (BMI) above (v) 35 kg / m before administration of the agonist ２ or (vi) a body mass index (BMI) of greater than 40 kg / m prior to administration of the agonist. ２ have a body mass index (BMI) above (vii) 45 kg / m before administration of the agonist ２ have a body mass index (BMI) above (viii) has failed one or more previous therapies selected from exercise therapy, diet therapy, or behavioral therapy before administration of the agonist; or (ix) having a lower body weight after administration of the agonist than before administration of the agonist; The composition according to claim 1 or 2.

4. The composition of claim 3 , wherein the subject is obese.

5. The composition of claim 3 , wherein the subject has early-onset severe obesity.

6. The composition of claim 3 , wherein the subject has an excess of appetite.

7. The object is 25 kg / m before administration of the agonist ２ have a body mass index (BMI) above 35 kg / m before administration of the agonist ２ have a body mass index (BMI) above 40 kg / m before administration of the agonist ２ or have a body mass index (BMI) of greater than 45 kg / m prior to administration of the agonist. ２ have a body mass index (BMI) of greater than The composition of claim 3.

8. 3. The composition of claim 1 or 2, wherein the subject has failed one or more previous therapies selected from exercise therapy, diet therapy, or behavioral therapy prior to administration of the agonist.

9. 3. The composition of claim 1 or 2, wherein the subject has a lower body weight after administration of the agonist than before administration of the agonist.

10. The subject has a weight of 35 kg / m before administration of the agonist. ２ have a body mass index (BMI) greater than or The administration of the agonist comprises: (i) reducing the subject's body weight by between 1 kg and 3 kg after 1 week of treatment, or between 1 kg and 6 kg after 2 weeks of treatment, or between 2 kg and 12 kg after 4 weeks of treatment, or between 4 kg and 24 kg after 8 weeks of treatment, or between 8 kg and 48 kg after 16 weeks of treatment, compared to the subject's body weight before treatment; (ii) reducing the subject's body weight at a rate of 1 to 2 kg per week; (iii) reducing the subject's hunger level compared to the subject's hunger level before treatment; (iv) does not detectably / significantly reduce the subject's resting energy expenditure (REE) over a period of 24 hours, 1 week, or 30 days or more, e.g., compared to a control REE, wherein the control REE is the subject's REE before treatment or a predetermined REE expressed as REE per kg of lean body mass for a subject with a similar pre-treatment BMI; (v) increasing the subject's resting energy expenditure (REE) over a period of 24 hours, 1 week, or 30 days or more compared to a control REE, wherein the control REE is the subject's REE before treatment or a predetermined REE expressed as REE per kg of lean body mass for a subject with a similar pre-treatment BMI; (vi) reducing food intake by the subject compared to the subject's food intake before treatment, wherein the food intake is daily food intake or food intake over a 24-hour period or a week; (vii) reducing food intake by at least 100 kilocalories compared to the subject's food intake before treatment or a predetermined food intake level, wherein the food intake is daily food intake or food intake over a 24-hour period or a week; (viii) reducing the subject's waist circumference by at least 2 cm when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more weeks after initiation of treatment, compared to the subject's waist circumference before treatment. (ix) does not detectably elevate the subject's blood pressure when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks or more after initiation of treatment compared to the subject's blood pressure prior to treatment. (x) reducing the subject's blood pressure when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more weeks after initiation of treatment, compared to the subject's blood pressure before treatment; (xi) reducing the subject's systolic blood pressure by at least 3 mmHg when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more weeks after initiation of treatment, compared to the subject's blood pressure before treatment; and (xii) reducing the subject's diastolic blood pressure by at least 4 mmHg when measured 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more weeks after initiation of treatment, compared to the subject's blood pressure before treatment. The composition of any one of claims 1 to 9, wherein the composition treats a disorder in a subject in need thereof by effecting one or more of:

11. The composition of claim 10, wherein administration of the agonist results in (i).

12. 12. The composition of claim 10 or 11, wherein administration of the agonist results in (ii).

13. The composition of any one of claims 10 to 12, wherein administration of the agonist results in (iii).

14. The composition of any one of claims 10 to 13, wherein administration of the agonist results in (iv).

15. The composition of any one of claims 10 to 13, wherein administration of the agonist results in (v).

16. The composition of any one of claims 10 to 15, wherein administration of the agonist results in (vi).

17. The composition of any one of claims 10 to 16, wherein administration of the agonist results in (vii).

18. The composition of any one of claims 10 to 17, wherein administration of the agonist results in (viii).

19. The composition of any one of claims 10 to 18, wherein administration of the agonist results in (ix).

20. The composition of any one of claims 10 to 18, wherein administration of the agonist results in (x).

21. 21. The composition of any one of claims 10 to 20, wherein administration of the agonist results in (xi).

22. 22. The composition of any one of claims 10 to 21, wherein administration of the agonist results in (xii).

23. The composition according to any one of claims 1 to 22, characterized in that the composition is administered to the subject in a unit dosage suitable for injection.

24. 24. The composition of claim 23, wherein the unit dose comprises 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5 or 10 mg of the agonist.

25. 25. The composition of claim 23 or 24, wherein the unit dosage is disposed within a delivery device, an implantable device, a needleless hypodermic injection device, an infusion pump, or an osmotic delivery system.

26. The composition according to any one of claims 1 to 25, characterized in that the composition is administered orally or parenterally.

27. The composition of any one of claims 1 to 26, wherein the subject is a mammal.

28. 28. The composition of claim 27, wherein the mammal is a human.

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