WO2001034181A2 - Procedes de traitement des troubles de la petite taille lies au gene (shox) contenant l'homeoboite de la petite taille - Google Patents

Procedes de traitement des troubles de la petite taille lies au gene (shox) contenant l'homeoboite de la petite taille Download PDF

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Publication number
WO2001034181A2
WO2001034181A2 PCT/IB2000/001612 IB0001612W WO0134181A2 WO 2001034181 A2 WO2001034181 A2 WO 2001034181A2 IB 0001612 W IB0001612 W IB 0001612W WO 0134181 A2 WO0134181 A2 WO 0134181A2
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Prior art keywords
shox
growth hormone
subjects
disorder
turner syndrome
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PCT/IB2000/001612
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English (en)
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WO2001034181A3 (fr
Inventor
Gudrun Rappold-Hoerbrand
Ercole Rao
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Rappold Hoerbrand Gudrun
Ercole Rao
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Application filed by Rappold Hoerbrand Gudrun, Ercole Rao filed Critical Rappold Hoerbrand Gudrun
Priority to AU12922/01A priority Critical patent/AU1292201A/en
Priority to HU0204116A priority patent/HUP0204116A3/hu
Priority to EP00974708A priority patent/EP1227832A2/fr
Priority to PL00357471A priority patent/PL357471A1/xx
Priority to CA002390632A priority patent/CA2390632A1/fr
Priority to JP2001536178A priority patent/JP2003513934A/ja
Publication of WO2001034181A2 publication Critical patent/WO2001034181A2/fr
Publication of WO2001034181A3 publication Critical patent/WO2001034181A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/27—Growth hormone [GH], i.e. somatotropin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH

Definitions

  • This invention relates to methods for treating short stature disorders related to the Short Stature Homeobox -containing gene - the SHOX gene - located in the pseudoautosomal region (PAR1) on the short arm of the X chromosome (Xp22.3) and Y chromosome (Ypl 1.3). More particularly, the invention relates to methods for treating a SHOX gene disorder, other than Turner syndrome, due to deficiency of one copy (haploinsufficiency) of the SHOX gene, by administering a human growth hormone.
  • PAR1 pseudoautosomal region
  • the Short Stature Homeobox-containing (SHOX) gene is located in the pseudoautosomal region (PAR1) on the short arm of the X chromosome (Xp22.3) and Y chromosome (Ypl 1.3) (Rao et al. 1997a). Deletion or mutation of the SHOX gene has been found in a number of patients with short stature, either idiopathic, or associated with Leri-Weill syndrome (Rao et al. 1997a; Belin et al. 1998, Shears et al 1998). Patients with Turner syndrome have absence or structural abnormalities of one X chromosome.
  • Turner syndrome is one of the most common genetic disorders with a prevalence of approximately 1 in 2500 liveborn females.
  • One of the cardinal features is extreme short stature of more than 20 cm below the mean height of healthy adult women.
  • Mean adult height of women with Turner syndrome ranges between 136.7 cm (Japan) and 146.9 cm (Germany) (Lyon et al. 1985; Hibi et al.
  • Turner syndrome is caused by the lack of or an alteration in one X chromosome.
  • the most frequent karyotype is 45, X, while other subjects show
  • haploinsufficiency of the SHOX gene is also thought to be the cause of short stature in subjects with Leri-Weill syndrome as it is in Turner syndrome (Rao et al. 1997a). Based on preliminary data produced by the present inventors, the prevalence of SHOX disorder, not associated with Turner syndrome, is estimated to be approximately 1 :5,000 in both sexes.
  • the growth hormones from man and from the common domestic animals are proteins of approximately 191 amino acids, synthesized and secreted from the anterior lope of the pituitary gland. Human growth hormone consists of 191 amino acids. Growth hormone is a key hormone involved in the regulation of not only somatic growth, but also in the regulation of metabolism of proteins, carbohydrates and lipids. The major effect of growth hormone is to promote growth.
  • the organ systems affected by growth hormone include the skeleton, connective tissue, muscles, and viscera such as liver, intestine, and kidneys.
  • the present invention relates to a method for treating short stature in a subject having a SHOX gene disorder other than Turner syndrome.
  • This method comprises administering to such a subject a pharmaceutically active amount of a growth hormone.
  • the subject is a human subject and the growth hormone is human growth hormone.
  • the invention also provides an article of manufacture comprising packaging material and a pharmaceutical composition comprising a growth hormone contained within the packaging material.
  • This pharmaceutical composition is therapeutically effective for treatment of short stature due to a SHOX gene disorder other than Turner syndrome
  • the packaging material comprises a label which indicates that the growth hormone can be administered to a subject with a SHOX gene disorder other than Turner syndrome.
  • the growth hormone is human growth hormone.
  • the invention further provides an article of manufacture comprising packaging material and a pharmaceutical composition comprising a growth hormone contained within said packaging material, where the pharmaceutical composition is therapeutically effective for treatment of short stature due to a SHOX gene disorder other than Turner syndrome.
  • This packaging material comprises a label which indicates that the growth hormone is effective in increasing growth velocity of subjects with a SHOX gene disorder other than Turner syndrome.
  • the growth hormone is human growth hormone.
  • the invention relates to a method of to a method for treating short stature in a subject having a SHOX gene disorder other than Turner syndrome, which method comprises administering to such a subject a pharmaceutically active amount of a growth hormone, particularly in a human subject, administering human growth hormone.
  • a "subject having a SHOX gene disorder” is defined as a subject with a mutation which reduces expression or activity of a product (e.g., mRNA or polypeptide or an activity of a polypeptide, such as a binding activity) encoded by the Short Stature Homeobox-containing (SHOX) gene on at least one chromosome of the subject, which gene in the human genome is located in the pseudoautosomal region (PAR1) on the short arm of the X chromosome (Xp22.3) and Y chromosome (Ypl 1.3) (Rao et al. 1997a).
  • a product e.g., mRNA or polypeptide or an activity of a polypeptide, such as a binding activity
  • SHOX Short Stature Homeobox-containing
  • Subjects with Turner syndrome are defined as follows: Females whose karyotype contains a documented abnormality of the X chromosome involving the short arm (for example, 45,X; 46,X,Xp-; 46X,i[Xq]). Female subjects with a partial deletion of the short arm of the X-chromosome are not defined as having Turner syndrome, if the deletion is located distal to the gene for ocular albinism (OA1) at the junction between Xp22.2 and Xp22.3. Instead, they are defined as having SHOX disorder (Ballabio and Andrea 1992).
  • OA1 ocular albinism
  • a subject with a SHOX gene disorder is considered to have abnormally short stature if the subject has a chronological age of at least 3 years, bone age of less than 10 years for boys and less than 8 years for girls, and height below the 3rd percentile or height below the 10th percentile and growth velocity below the 25th percentile, for an appropriate age-and-sex-matched 'normal' reference population based upon local standards.
  • subjects with a SHOX disorder also are prepubertal (for girls, Tanner stage 1 with respect to breast development; for boys, Tanner stage 1 with respect to genital development and testicular volume of no more than 2 ml).
  • growth hormone may be growth hormone from any origin such as avian, bovine, equine, human, bovine, porcine, salmon, trout or tuna growth hormone, preferably bovine, human or porcine growth hormone, human growth hormone being most preferred.
  • the growth hormone used in accordance with the invention may be native growth hormone isolated from a natural source, e.g. by extracting pituitary glands in a conventional manner, or a growth hormone produced by recombinant techniques, e.g as described in E. B. Jensen and S. Carlsen in Biotech and Bioeng. 36, 1-11 (1990).
  • the "growth hormone” may also be a truncated fo ⁇ n of growth hormone wherein one or more amino acid residues has
  • the preferred growth hormone is hGH.
  • dose of growth hormone refers to that amount that provides therapeutic effect in an administration regimen.
  • the growth hormone is formulated for administering a dose effective for increasing growth rate of a subject having a SHOX gene disorder other than Turner syndrome, for instance, a dose similar to one effective for increasing growth in a Turner syndrome subject.
  • doses for Turner syndrome are known in the art. See also Example 1, below, for preferred dosages in the method of the invention.
  • formulations for parenteral administration are prepared containing amounts of hGH at least about 0.1 mg/ml, preferably upwards of about 10 mg/ml, preferably from about 1 mg ml to about 40 mg/ml, more preferably from about 1 mg/ml to about 25 mg/ml, e.g. from 1 mg/ml to about 5 mg/ml, calculated on the ready-to-use formulation.
  • these compositions in administration to human beings suffering from SHOX disorder, for example, these formulations contain from about 0.1 mg/ml to about 10 mg/ml, corresponding to the currently contemplated dosage regimen for the intended treatment.
  • the concentration range is not critical to the invention and may be varied by the physician supervising the administration.
  • a growth hormone can typically be administered parenterally, preferably by subcutaneous injection, by methods and in formulations well known in the art.
  • a growth hormone can be formulated with typical buffers and excipients employed in the art to stabilize and solubilize proteins for parenteral administration. See, for example, United States Patent No. 5,612,315 to Pikal, et al., hereby incorporated herein by reference, disclosing pharmaceutical growth hormone formulations, and United States Patent No. 5,851,992 to S ⁇ rensen et al., incorporated herein by reference, disclosing human growth hormone formulations which may be used to treat a patient with a disorder associated with growth hormone deficiency.
  • a growth hormone can also be delivered via the lungs, mouth, nose, by suppository, or by oral formulations, using methods known in the art.
  • the hormone can be administered regularly (e.g., once or more each day or week), intermittently (e.g., irregularly during a day or week), or cyclically (e.g., regularly for a period of days or weeks followed by a period without administration).
  • growth hormone is administered once daily for at least about one year, more preferably at least about three years, and most preferably for at least about six or seven years.
  • the present invention also encompasses articles of manufacture comprising packaging material and a pharmaceutical composition comprising a growth hormone contained within the packaging material.
  • This pharmaceutical composition is therapeutically effective for treatment of short stature due to a SHOX gene disorder other than Turner syndrome, and the packaging material comprises a label which indicates that the growth hormone can be administered to a subject with a SHOX gene disorder other than Turner syndrome.
  • a clinical trial of one year duration is conducted to compare the mean growth rate of a group of subjects with SHOX disorder who receive human growth hormone therapy with the mean growth rate of subjects who receive no human growth hormone (nontreatment control).
  • a secondary objective is to compare the mean growth rate of growth hormone-treated subjects with SHOX disorder with that of a group of growth-hormone-treated subjects with Turner syndrome, using a non- inferiority analysis.
  • this study is designed to show that mean first-year growth velocity of patients with SHOX disorder who receive human growth hormone (0.05 mg/kg/day) is significantly greater than that of patients with SHOX disorder who do not receive human growth hormone.
  • the study is divided into four periods: the Screening Period; the Acute Therapy Period, the Extension Therapy Period A and the Extension Therapy Peroid B.
  • the Screening Period patients who fulfil the screening criteria undergo analysis of the SHOX gene. Those with either deletion or mutation of the SHOX gene are potentially eligible for study entry. Patients with proven SHOX gene defects and those with Turner syndrome who do not have evidence of growth hormone deficiency (based on serum concentrations of
  • IGF-I and IGFBP-3 and, if necessary, a growth hormone stimulation test are eligible for study entry.
  • Patients with SHOX disorder who meet entry criteria are randomized at study entry into one of two therapy groups - human growth hormone therapy or non-treatment control. All eligible and consented patients with Turner syndrome receive growth hormone therapy.
  • Efficacy and safety information to be used for registration are collected during the Acute Therapy Period. After one year on study, all patients (treatment and control) participate in the extension. In the first year of the extension, (Extension Part A) treatment is continued exactly as in the acute phase. Thereafter, in Extension Part B, all patients receive human growth hormone and monitoring of efficacy and safety is continued.
  • Turner syndrome subjects are screened to determine that they do not have growth hormone deficiency; non-Turner syndrome subjects are screened to determine that they have SHOX disorder and are not growth hormone deficient.
  • Acute Therapy Period After screening, subjects with SHOX disorder are randomized in a 1 : 1 ratio to either the SHOX disorder somatropin-treatment group or the SHOX disorder nontreatment group. Subjects with Turner syndrome are entered into the Turner syndrome somatropin-treatment group. During this period, subjects in the somatropin treatment groups receive a daily subcutaneous injection of 0.05 mg/kg of somatropin for 1 year. Subjects in the nontreatment control group receive no injections. Subjects in each group are followed at defined intervals for 1 year as outlined below.
  • Extension, Part A Following the Acute Therapy period, all subjects have the option to participate in the Extension. During Extension Part A, subjects continue in their treatment groups assigned during the Acute Therapy Period. Subjects in each group are followed at defined intervals for 1 year as outlined below. Extension, Part B: After completion of Extension Part A, all subjects are given the option to receive somatropin treatment in Extension Part B. Both those who choose somatropin therapy and those who elect not to receive somatropin therapy are monitored in Extension Part B. Study drug is provided for 2 years during Extension Part B.
  • Visit 2 3 months ⁇ 3 weeks after Visit 1
  • Visit 3 6 months ⁇ 4 weeks after Visit 1
  • Visit 4 12 months ⁇ 4 weeks after Visit 1
  • Visit 102 24 months ⁇ 4 weeks after Visit 1
  • Hand/wrist, forearm, and lower leg x-rays are performed to further evaluate the SHOX disorder phenotype and to determine bone ages.
  • Extension. Part B The intent of the Extension Part B is to monitor subjects for safety and efficacy for 2 years. After this 2-year period, each subject is asked to participate in a long-term surveillance study, for continued monitoring. Parental/Sibling Information
  • analysis of their chromosomes or DNA may be sufficient to confirm diagnosis of SHOX disorder.
  • analysis of parental chromosomes may be helpful in clarifying the genotype/phenotype correlation in SHOX disorder. Therefore, parents may be asked to provide blood samples during the screening phase. After confirmation of SHOX disorder, parents (who have not had blood drawn during screening) and siblings of subjects meeting entry criteria are asked to provide blood samples to further understand the genetics of SHOX gene deletions and mutations. Samples from family members will be collected before Visit 4, if possible.. Where appropriate, DNA sequencing of the SHOX genes is performed. In addition, anthropometric data and presence or absence of dysmorphic signs are collected.
  • Subjects may be included in the study only if they meet all of the following criteria: [1] Turner syndrome or SHOX disorder as defined below.
  • bone age For subjects with SHOX disorder, bone age of less than 10 years for boys and less than 8 years for girls. For girls with Turner syndrome, bone age of less than 9 years.
  • the approximate current bone age is estimated based on the most recent X-ray, performed and assessed locally, within 12 months prior to study entry. For example, if the child's bone age was determined 6 months prior to study entry to be 8.0 years, then the bone age to be used for assessment of potential inclusion in the study would be 8.5 years.
  • Subjects with a mutation or deletion in the SHOX gene as identified by DNA analysis or other appropriate molecular technique include those with and without Leri-Weill syndrome.
  • Somatropin will be administered as follows: a single daily subcutaneous injection, preferably before bedtime, at a dose of 0.05 mg/kg/day, rounded appropriately.
  • Efficacy Evaluations Efficacy The primary measure of efficacy is standing height. This is measured at each visit throughout the study, preferably at the same time of day. All measurements are made without shoes. Standing measurements are made using a standard wall- mounted stadiometer. The instrument should be calibrated using a standard calibration rod, to at the start of the study and every 3 months thereafter.
  • the primary response variable to be used to assess efficacy is first-year growth velocity, defined as 1-year height minus baseline height, divided by the exact elapsed time in years (365.25 days per year is assumed throughout).
  • the secondary response variables used to assess efficacy are: 1) Baseline to 1-year change in height standard deviation score, using the height of US males and females at various chronological ages as the reference standard. A standard deviation score for a given variable is derived by subtracting the age-and-sex- matched population mean value for that variable from the subject's value. The value obtained is then divided by the age-and-sex-matched population's standard deviation (Hamill et al. 1977). 2) Baseline to 1-year change in height standard deviation score relative to mid-parental height (target height) standard deviation score. The standing heights of both parents will be required to derive this variable. 3) Second-year growth velocity.
  • this sample size provides approximately 89% power for a two-sided 0.05-level test to detect a mean difference in first-year growth velocity of 2 cm between the SHOX disorder somatropin treatment and nontreatment arms, assuming the standard deviation of growth velocity in each group is 2 cm.
  • the primary analysis is an intent-to-treat analysis.
  • An intent-to-treat analysis is an analysis of data by the groups to which subjects are assigned by random allocation, even if the subject does not take the assigned treatment, does not receive the correct treatment, or otherwise does not follow the protocol.
  • Hypothesis tests are performed at a 2-sided significance level of 0.05. Where computationally feasible, exact tests are substituted for chi-square tests.
  • Baseline values for the Acute Therapy Period are considered to be the initial measurements taken at Visit 1. Endpoint for the Acute Therapy Period is defined as the last non-missing measurement obtained on or prior to Visit 4.
  • Comparisons of treatment groups are made using least-squares means from the relevant statistical model.
  • the primary efficacy analysis includes data from all subjects with SHOX disorder with a baseline standing height measurement and a post-baseline standing height measurement at least 9 weeks past his or her Visit 1 date. (This criterion is included in order to avoid extreme extrapolation of growth velocity data.)
  • a secondary analysis of the primary hypothesis includes data from all subjects with SHOX disorder who have a baseline standing height measurement and a standing height measurement within 4 weeks of one year after his or her Visit 1 date, excluding any subject assigned to the somatropin-treatment arm who did not receive at least 90 days of somatropin therapy.
  • Subject characteristics for example, demographics, baseline height standard deviation score
  • Comparisons of subject characteristics, between the groups, are made for all randomized subjects. Frequencies are analyzed using chi-square tests. Means are analyzed using analysis of variance with treatment group (treated vs. nontreated) as the explanatory variable. Subject characteristics for the Turner syndrome arm are tabulated and reported separately.
  • Efficacy Analyses The primary question to be answered is as follows: Is the mean first-year growth velocity of SHOX disorder somatropin-treated subjects greater than that of SHOX disorder subjects not treated with somatropin? To answer this question, the data is analyzed using an analysis of covariance (ANCOVA) model.
  • the response variable for this model is first-year growth velocity, defined as endpoint height minus baseline height, divided by the exact elapsed time in years.
  • Explanatory variables (fixed effects) are treatment group (SHOX disorder somatropin-treatment group or SHOX disorder nontreatment group), Leri-Weill syndrome (present or absent), gender, and baseline age.
  • Bone ages are assessed in order to compare the rate of skeletal maturation between the SHOX disorder treated and nontreated groups.
  • Secondary Analyses To evaluate the similarity of first-year growth velocities between the two somatropin-treatment groups (SHOX disorder somatropin-treatment group compared with Turner syndrome somatropin-treatment group), a 90% two-sided confidence interval for the mean difference in growth velocity is performed. This confidence interval is based on least-squares means from the model with the response variable of first-year growth velocity and explanatory variables somatropin-treatment group and baseline age.
  • ANCOVA model with response variable of second-year growth velocity, defined as height at Visit 102 minus height at Visit 4, divided by the exact elapsed time in years.
  • Explanatory variables will be treatment group (SHOX disorder somatropin-treatment group or SHOX disorder nontreatment group), Leri-Weill syndrome (present or absent), gender, and baseline age. Subjects who have entered puberty on or prior to Visit 102 may be excluded from this analysis. Subgroup Analyses
  • the consistency of the treatment effect is assessed over subgroups of subjects defined by various characteristics, including the following as examples:
  • Target height Baseline age
  • a linear (possibly mixed effects) model is fitted which includes the following explanatory variables: main effects (including treatment group) and two- way interactions of the above variables with treatment group.
  • the response variable is first-year growth velocity, calculated based on the 1-year height measurement. Appropriate parsimonious models will be developed. The relationship of each important covariate to treatment effect is assessed with the treatment-by-covariate interaction. A significant treatment-by-covariate interaction (P ⁇ 0.05) may imply a differential treatment effect within levels of the covariate.
  • One-year growth velocity is summarized in tables of least-square means for any interesting breakdown of the data by these subgroups.

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Abstract

L'invention concerne des procédés et des produits fabriqués pour traiter les troubles de la petite taille liés au gène contenant l'homéoboîte de la petite taille (gène SHOX) qui, dans le génome humain, se situe dans la zone pseudoautosomale (PAR1) sur le bras court du chromosome X (Xp22,3) et du chromosome Y (Yp11,3). Plus particulièrement, l'invention concerne des procédés de traitement d'un trouble des gènes SHOX, autre que le syndrome de Turner, dû à une déficience d'une copie (haploinsuffisance) du gène SHOX. Ces procédés consistent à administrer une hormone de croissance, et plus particulièrement, à administrer une hormone de croissance humaine à un sujet humain souffrant d'un trouble des gènes SHOX.
PCT/IB2000/001612 1999-11-09 2000-11-08 Procedes de traitement des troubles de la petite taille lies au gene (shox) contenant l'homeoboite de la petite taille WO2001034181A2 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
AU12922/01A AU1292201A (en) 1999-11-09 2000-11-08 Methods of treating short stature disorders related to the short stature homeobox-containing (shox) gene
HU0204116A HUP0204116A3 (en) 1999-11-09 2000-11-08 Methods of treating short stature disorders related to the short stature homeobox-containing (shox) gene
EP00974708A EP1227832A2 (fr) 1999-11-09 2000-11-08 Procedes de traitement des troubles de la petite taille lies au gene (shox) contenant l'homeoboite de la petite taille
PL00357471A PL357471A1 (en) 1999-11-09 2000-11-08 Methods of treating short stature disorders related to the short stature homeobox-containing (shox) gene
CA002390632A CA2390632A1 (fr) 1999-11-09 2000-11-08 Procedes de traitement des troubles de la petite taille lies au gene (shox) contenant l'homeoboite de la petite taille
JP2001536178A JP2003513934A (ja) 1999-11-09 2000-11-08 低身長ホメオボックス（ｓｈｏｘ）遺伝子に関連する低身長障害の治療法

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US16434199P 1999-11-09 1999-11-09
US60/164,341 1999-11-09

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WO2001034181A2 true WO2001034181A2 (fr) 2001-05-17
WO2001034181A3 WO2001034181A3 (fr) 2001-12-06

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EP (1) EP1227832A2 (fr)
JP (1) JP2003513934A (fr)
AU (1) AU1292201A (fr)
CA (1) CA2390632A1 (fr)
CZ (1) CZ20021718A3 (fr)
HU (1) HUP0204116A3 (fr)
PL (1) PL357471A1 (fr)
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Cited By (1)

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Publication number Priority date Publication date Assignee Title
WO2004062555A2 (fr) * 2003-01-13 2004-07-29 Gudrun Rappold-Hoerbrand Utilisation de peptides natriuretiques dans le traitement de troubles affectant la taille associes au gene shox

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US5631225A (en) * 1994-10-13 1997-05-20 Novo Nordisk A/S Pharmaceutical formulation
US5824642A (en) * 1994-04-07 1998-10-20 Genentech, Inc. Treatment of partial growth hormone insensitivity syndrome

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US5824642A (en) * 1994-04-07 1998-10-20 Genentech, Inc. Treatment of partial growth hormone insensitivity syndrome
US5631225A (en) * 1994-10-13 1997-05-20 Novo Nordisk A/S Pharmaceutical formulation

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Title
DATABASE BIOSIS [Online] BIOSCIENCES INFORMATION SERVICE, PHILADELPHIA, PA, US; 1996 THUESTAD INGER JOHANNE ET AL: "Growth hormone treatment in Leri-Weill syndrome." Database accession no. PREV199699060000 XP002168568 & JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM, vol. 9, no. 2, 1996, pages 201-204, *
RAPPOLD G: "SHOX mutations cause growth failure in Turner and Leri-Weill syndrome." HORMONE RESEARCH (BASEL), vol. 51, no. SUPPL. 2, August 1999 (1999-08), page 6 XP001002410 38th Annual Meeting of the European Society for Paediatric Endocrinology;Warsaw, Poland; August 29-September 1, 1999 ISSN: 0301-0163 *
SCHWARZE C P ET AL: "SHOX gene mutations in children with idiopathic short stature - screening and therapy with rhGH." HORMONE RESEARCH (BASEL), vol. 51, no. SUPPL. 2, August 1999 (1999-08), page 34 XP001002411 38th Annual Meeting of the European Society for Paediatric Endocrinology;Warsaw, Poland; August 29-September 1, 1999 ISSN: 0301-0163 cited in the application *
VUGUIN P ET AL: "The effect of growth hormone treatment in idiopathic short stature with SHOX mutation." PEDIATRIC RESEARCH, vol. 43, no. 4 PART 2, April 1998 (1998-04), page 87A XP002168567 Annual Meeting of the American Pediatric Society and the Society for Pediatric Research;New Orleans, Louisiana, USA; May 1-5, 1998 ISSN: 0031-3998 cited in the application *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004062555A2 (fr) * 2003-01-13 2004-07-29 Gudrun Rappold-Hoerbrand Utilisation de peptides natriuretiques dans le traitement de troubles affectant la taille associes au gene shox
WO2004062555A3 (fr) * 2003-01-13 2004-10-28 Gudrun Rappold-Hoerbrand Utilisation de peptides natriuretiques dans le traitement de troubles affectant la taille associes au gene shox

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HUP0204116A2 (hu) 2003-03-28
CZ20021718A3 (cs) 2002-11-13
PL357471A1 (en) 2004-07-26
CA2390632A1 (fr) 2001-05-17
EP1227832A2 (fr) 2002-08-07
AU1292201A (en) 2001-06-06
JP2003513934A (ja) 2003-04-15
HUP0204116A3 (en) 2005-07-28
WO2001034181A3 (fr) 2001-12-06

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