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Use of TGF-beta antagonists to treat infants at risk of developing bronchopulmonary dysplasia

A technology of dysplasia and antagonists, which can be used in medical preparations containing active ingredients, anti-animal/human immunoglobulins, and antibody medical ingredients, etc., which can solve problems such as reduction of morbidity.

Inactive Publication Date: 2009-10-07
GENZYME CORP +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Utilization of surfactant therapy and other advanced treatments improves neonatal survival without concomitant reduction in BPD incidence

Method used

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  • Use of TGF-beta antagonists to treat infants at risk of developing bronchopulmonary dysplasia
  • Use of TGF-beta antagonists to treat infants at risk of developing bronchopulmonary dysplasia
  • Use of TGF-beta antagonists to treat infants at risk of developing bronchopulmonary dysplasia

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0096] Example 1: Expression of TGF-β in the developing lung, and modulation of TGF-β signaling with anti-TGF-β antibodies

[0097] Although increased RNA levels of TGF-β1 and TGF-β2 were observed in postnatal rat lung (Zhao et al., Am. J. Physiol. Lung Cell Mol. Physiol. 278: L1231-1239 (2000)), TGF The expression pattern of the -β isoform in the developing lung periphery is poorly understood. Such as figure 1 As indicated, TGF-β1-3 immunoreactivity was detected in the lungs of 10-day-old mouse pups. Similar levels of TGF-β isoforms were observed in large conducting airways, as well as in terminal and respiratory bronchioles. Although TGF-β1 showed the highest immunoreactivity in the peripheral lung, TGF-β2 and TGF-β3 were also detected there. Since it was desired to determine whether inhibition of TGF-β activity in the distal developing lung suppressed the effects of lung injury on alveolar development, we first tested whether a pan-specific TGF-β neutralizing antibody re...

Embodiment 2

[0099] Example 2: Anti-TGF-β antibody treatment improves alveolar production in damaged neonatal lung

[0100] Chronic inhalation of high levels of oxygen in newborn rodents results in lung injury and inhibits terminal lung development in a manner similar to that observed in infants with BPD (Bonikos et al., Lab Invest. 32:619-635 (1975); Frank et al., J. Appl. Physiol. 45: 699-704 (1978); Pappas et al., Lab Invest. 48: 735-748 (1983); Bonikos, Am. J. Pathol. 85: 623-650 (1976) ; Warner et al., Am. J. Physiol. 275:L110-117 (1998)). Therefore, a model of lung injury in hyperoxic mouse pups was used to examine whether treatment with TGF-β neutralizing antibodies improved alveolar development. Neonatal mouse pups were continuously exposed to 85% O 2 10 days, as this level of exposure was observed in preliminary studies to result in reduced alveolar production with concomitant >80% survival. Such as Figure 4 As shown, chronic exposure to 85% O 2 Associated with hypoplasia o...

Embodiment 3

[0105] Example 3: Improvement of elastin structure of alveolar septa in damaged neonatal lungs by anti-TGF-β treatment

[0106] Elastin is an important component of the alveolar wall and pulmonary vasculature, and its biosynthesis and extracellular assembly are critical for normal lung development. In infant lungs with BPD, as in neonatal mice with lung injury (Veness-Meehan et al., Pediatr. Res. 48:434-444 (2002)), the normal structure of elastin is present at the top of the secondary cristae was disrupted, and instead elastin was observed in the distal airway wall. Since TGF-β regulates ECM proteins in mesenchymal cells (Leask et al., Faseb J.18:816-827 (2004)) and lung (Kucich et al., Am.J.Respir.Cell Mol.Biol.17:10 -16 (1997); Parks et al., Am. J. Respir. Cell Mol. Biol. 17:1-2 (1997)), the effect of treatment with 1D11 on extracellular matrix protein deposition was examined. Such as Figure 6 As shown, chronic respiratory high levels of O 2 Associated with changes in ...

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Abstract

The disclosure relates to methods of treating an infant at risk of developing bronchopulmonary dysplasia, including premature infants, by administering a TGF-beta antagonist during the perinatal period, including the prenatal period and / or the postnatal period. For administration during the prenatal period, the TGF-beta antagonist can be administered either directly to the infant in utero, or indirectly by administration to the mother.

Description

[0001] This application claims priority to US Provisional Application No. 60 / 827,933, filed October 3, 2006, which is incorporated herein by reference in its entirety. technical field [0002] The present invention relates to the use of TGF-beta antagonists for the treatment of infants at risk of developing bronchopulmonary dysplasia, including premature infants. Background technique [0003] Babies born at a very early stage of development often suffer from respiratory failure due to their underdeveloped lungs, primitive respiratory drive and susceptibility to infection. Bronchopulmonary dysplasia (BPD), a chronic lung disease of premature infants, was first characterized nearly 40 years ago (Northway, N. Engl. J. Med. 276:357-368 (1967); Jobe et al., Am. J. Resp. Crit. Card. Med. 163:1723-1729 (2001)). As originally described, BPD is a condition that occurs primarily in infants of sufficient size and maturity to survive the damage caused by prolonged exposure to hyperoxia...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395A61P11/00C07K16/22
CPCC07K16/22A61K39/3955A61K45/06A61K2039/505A61P11/00A61K9/0019A61K9/0073A61K9/12C07K2317/76
Inventor J·B·施特赖桑德J·D·小罗伯茨
Owner GENZYME CORP
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