Status of Growth Hormone/ Insulin-like Growth Factor-1 (GH/IGF-1) Axis and Growth Failure in Ataxia Telangiectasia (AT)

Condition(s) targeted: Ataxia Telangiectasia; Growth Failure

Intervention: Somatropin, Clonidine, L-Arginin-Hydrochloride, Estradiol valerate (Drug)

Phase: Phase 4

Status: Recruiting

Sponsored by: Johann Wolfgang Goethe University Hospitals

Official(s) and/or principal investigator(s):
Stefan Zielen, Prof. Dr., Principal Investigator, Affiliation: Children´s Hospital, Goethe-University

Overall contact:
Stefan Zielen, Prof. Dr., Phone: 0049-69-6301-83063, Email: Stefan.Zielen@kgu.de

This study will evaluate the status of the growth hormone/ insulin-like growth factor-1 (GH/IGF-1) axis in relation to growth failure, body weight and composition and neuroprotection in children with Ataxia telangiectasia (AT).

Official title: Status of the Growth Hormone/ Insulin-like Growth Factor-1 (GH/IGF-1) Axis in Relation to Growth Failure, Body Weight and Neuroprotection in Children With Ataxia Telangiectasia

Study design: Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Diagnostic

Primary outcome: To evaluate the GH increase after Arginine Provocation Test

Secondary outcome: The GH increase after Clonidine Provocation Test. To evaluate the safety and efficacy of the IGF-1 generation test. To correlate GH/IgF-1 deficiency to BMI To correlate GH/IgF-1 deficiency to MRI findings

Detailed description: Growth failure and GH/IgF-1 deficiency has been described in patients diagnosed with Ataxia telangiectasia (AT) [Boder et al.,1958]. This condition is a fatal inherited disease caused by a mutation of the ATM gene on chromosome 11 leading to chromosomal instability, immunodeficiency, cancer susceptibility and and endocrinological abnormalities. In this regard, several groups demonstrated a cross-linking of ATM with growth factor pathways. Participation of the ATM protein in insulin signaling through phosphorylation of eIF-4E-binding protein 1 has been postulated [Yang et al.,2000]. Peretz et al.[2001] described that expression of the insulin-like growth factor-I receptor is (IGF-I R) ATM dependent in a pathway regulating radiation response. In addition, Shahrabani-Gargir et al.[2004] found that the ATM gene controls IGF-I R gene expression in a DNA damage response pathway. Suzuki et al.[2004] described that IGF-I phosphorylates AMPK-alpha, a key regulator of cholesterol and fatty acid synthesis, acts in an ATM-dependent manner . We have recently demonstrated reduced levels of circulating Insulin-like growth factor-I (IGF-I) and its main binding protein 3 (IGFBP-3) in AT patients accompanied with decreased body mass index [Schubert et al.,2005]. Furthermore, apart from regulating somatic growth and metabolism, evidence suggests that the GH/IGF-I axis is involved in the regulation of brain growth, development and myelination. Moreover, GH and particularly IGF-1 have potential neuroprotective effects in different in vitro and in vivo experimental models. In addition we have recently shown that extracerebellar MRI-lesions in AT go along with deficiency of the GH/IGF-1 Axis, markedly reduced body weight, high ataxia scores and advanced age [Kieslich et al.,2009]. Supplementation with these growth hormones might overcome the progressive dystrophy and may have clinical benefits against the progression of neurodegeneration and immunodeficiency. We found that supplementation with GH significantly increased longevity of Atm-deficient mice and improve T-cell immunity and locomotor behaviour [Schubert et al.,2009]. Surprisingly IGF-1 was not generated in the ATM deficient mice, indicating that the GH/IGF-1 signalling is impaired. Taken this into account a accurate diagnostic approach of the GH/IGF-1 axis is mandatory including a IGF-1 generation test before long term treatment either with GH or IGF-1 is justified in humans.

Minimum age: 3 Years. Maximum age: 18 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Have a diagnosis of AT

- Have no fusion of epiphyses/closed growth plates as determined by X-ray of left wrist

and hand (special skeletal age film)

- Be between 3 years to 18 years old and have not completed puberty

- Consent to permit blood and/or tissue samples for storage

- Demonstrate growth failure: height below the 10th percentile for chronological age

- Have a primary care physician at home

- Demonstrate growth failure, defined as growth velocity (measured as linear growth)

that is less than 5% to 10% of that expected for children of the same age group, over the past 12 months

- Willingness to remain hospitalized for several days

- Provide evidence of serum IGF-1 level performed within the preceding 6 months and the

results fall below 25% range of normal limits for age Exclusion Criteria:

- Have fusion of epiphyseal plates

- Be under the age of 3 years or have reached completion of puberty

- Have a serum IGF-1 level that is above the 25% range of normal limits for age

- Be above the 10th percentile height for chronological age

- Demonstrate any history of anaphylactic reaction or hypersensitivity to one of the GH

formulation

- Have any active or suspected neoplasia

- Demonstrate signs of intracranial hypertension as evidenced by papilledema upon

examination by fundoscopy

- Have any condition that, in the investigator's opinion, places the patient at undue

risk by participating in the study

- Be unwilling to undergo testing or procedures associated with this protocol

- Have acute or chronic infections

- Have a hypersensitivity to one of the drugs: Clonidine hydrochlorid, Arginine

hydrochlorid, Estradiol valerate, Somatropin

- Have a presence of bradycardia, cardiac arrhythmia, have symptoms of a sick sinus

syndrome

- Suffer from depression

- Have acute or recurrent thrombosis

- Have acute liver diseases

Stefan Zielen, Prof. Dr., Phone: 0049-69-6301-83063, Email: Stefan.Zielen@kgu.de

Children's Hospital, Goethe-University, Frankfurt am Main 60590, Germany; Recruiting
Stefan Zielen, Prof. Dr., Phone: 0049-69-6301-83063, Email: Stefan.Zielen@kgu.de
Ralf Schubert, Dr., Phone: 0049-69-6301-83611, Email: Ralf.Schubert@kgu.de
Stefan Zielen, Prof.Dr., Principal Investigator
Ruth Dresel, Dr., Sub-Investigator
Franziska Hoche, Dr., Sub-Investigator
Martin Christman, Dr., Sub-Investigator

Related publications:

BODER E, SEDGWICK RP. Ataxia-telangiectasia; a familial syndrome of progressive cerebellar ataxia, oculocutaneous telangiectasia and frequent pulmonary infection. Pediatrics. 1958 Apr;21(4):526-54.

Lavin MF. Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer. Nat Rev Mol Cell Biol. 2008 Oct;9(10):759-69. doi: 10.1038/nrm2514. Review. Erratum in: Nat Rev Mol Cell Biol. 2008 Dec;9(12). doi: 10.1038/nrm2514.

Schubert R, Reichenbach J, Zielen S. Growth factor deficiency in patients with ataxia telangiectasia. Clin Exp Immunol. 2005 Jun;140(3):517-9.

Isgaard J, Aberg D, Nilsson M. Protective and regenerative effects of the GH/IGF-I axis on the brain. Minerva Endocrinol. 2007 Jun;32(2):103-13. Review.

Yang DQ, Kastan MB. Participation of ATM in insulin signalling through phosphorylation of eIF-4E-binding protein 1. Nat Cell Biol. 2000 Dec;2(12):893-8.

Peretz S, Jensen R, Baserga R, Glazer PM. ATM-dependent expression of the insulin-like growth factor-I receptor in a pathway regulating radiation response. Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):1676-81. Epub 2001 Feb 6.

Shahrabani-Gargir L, Pandita TK, Werner H. Ataxia-telangiectasia mutated gene controls insulin-like growth factor I receptor gene expression in a deoxyribonucleic acid damage response pathway via mechanisms involving zinc-finger transcription factors Sp1 and WT1. Endocrinology. 2004 Dec;145(12):5679-87. Epub 2004 Sep 2.

Suzuki A, Kusakai G, Kishimoto A, Shimojo Y, Ogura T, Lavin MF, Esumi H. IGF-1 phosphorylates AMPK-alpha subunit in ATM-dependent and LKB1-independent manner. Biochem Biophys Res Commun. 2004 Nov 19;324(3):986-92.

Kieslich M, Hoche F, Reichenbach J, Weidauer S, Porto L, Vlaho S, Schubert R, Zielen S. Extracerebellar MRI-lesions in ataxia telangiectasia go along with deficiency of the GH/IGF-1 axis, markedly reduced body weight, high ataxia scores and advanced age. Cerebellum. 2010 Jun;9(2):190-7. doi: 10.1007/s12311-009-0138-0.

Schubert R, Schmitz N, Pietzner J, Tandi C, Theisen A, Dresel R, Christmann M, Zielen S. Growth hormone supplementation increased latency to tumourigenesis in Atm-deficient mice. Growth Factors. 2009 Oct;27(5):265-73. doi: 10.1080/08977190903112663.

Starting date: January 2010
Last updated: July 2, 2010