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Prostaglandin e2 modulation and uses thereof

a technology of prostaglandin and e2 is applied in the field of prostaglandin e2 change/modulation, which can solve the problems of mental retardation and delayed motor milestones of children affected by the disease, and achieve the effects of reducing the risk of mental retardation

Inactive Publication Date: 2009-04-02
UNIV LAVAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention relates to the use of inhibitors of prostaglandin E2 (PGE2) biosynthesis or activity for the prevention, diagnosis, and treatment of congenital myotonic dystrophy type 1 (cDM1). The invention provides methods for inhibiting the biosynthesis or activity of PGE2 in a subject by inhibiting the expression or activity of a mediator involved in PGE2 biosynthesis. The invention also provides methods for assessing the level or activity of PGE2, a mediator involved in PGE2 biosynthesis, or both in a biological sample obtained from a subject. The invention further provides methods for increasing the fusion and differentiation of cDM1 muscle cells by contacting them with an inhibitor of PGE2 biosynthesis. The invention also provides a use of an inhibitor of PGE2 biosynthesis for the preparation of a medicament for the prevention, diagnosis, and treatment of cDM1.

Problems solved by technology

Furthermore, children affected by the disease frequently suffer from mental retardation and delayed motor milestones.
Currently there is no curative therapy for this disease, and symptomatic or rehabilitation treatments are only available for the adult form of DM1.

Method used

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  • Prostaglandin e2 modulation and uses thereof
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  • Prostaglandin e2 modulation and uses thereof

Examples

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example 1

Materials and Methods

[0125]Primary human myoblast culture. Normal human myoblasts were derived from a 12-week-old fetus. DM-750, DM-1200 and DM-3200 myoblasts were obtained from the skeletal muscles of 20-, 13- and 15-week-old DM1 fetuses. The length of the CTG repeat expansion in these myoblasts was approximately 750, 1200 and 3200 CTG repeats, respectively, as determined by Southern blot (FIG. 15). Because these myoblasts were obtained from aborted fetuses, it was not determined if they had DM1 or cDM1. All biopsies were obtained in accordance with the Laval University Medical Research Centre ethical committees. Myoblasts were grown in MCDB 120 medium (JRH Biologicals, Lenexa, Kans.) supplemented with 15% heat-inactivated fetal bovine serum, 5 mg / ml insulin, 0.5 mg / ml BSA, 10 ng / ml epidermal growth factor, 0.39 mg / ml dexamethasone, 50 mg / ml streptomycin and 50 mg / ml penicillin (proliferative medium), as previously described (Langlois et al., 2003 Mol. Ther. 7: 670-680; Furling D e...

example 2

CTG Expansion in DM1 Myoblasts

[0139]Because DM1-750 and DM1-1200 myoblasts were obtained from aborted fetuses, it was not clinically determined if they had DM1 or cDM1. The only reliable feature to diagnose the congenital form of the disease at the molecular level is to examine the proximal region of the CTG expansion that was shown to be aberrantly methylated in cDM1 (Steinbach et al., 1998, supra; Filippova et al., 2001. Nat. Genet. 28(4): 335-43). Normal DMPK alleles generate a single 1.8 kb fragment following co-digestion by SacI and HindIII (SI / H) and mutant alleles generate a band augmented by the corresponding length of the CTG expansion. Triple digestion with SacI, SacII and HindIII (SI / SII / H) results in loss of the expansions in normal and in DM1 myoblasts (DM1-750 and DM1-1200) and generate a 1.6 kb fragment (FIG. 15). On the other hand, in cDM1, the expansion is retained in the digested fragment and generate fragments of 11.4 kb, 11.7 kb or 12.9 kb for the cells with 3200...

example 3

Alteration in the Fusion Index of Myoblasts from cDM1 Subjects

[0140]To investigate the mechanism involved in impaired myogenesis and subsequently to the defective muscle development observed in the severe congenital cDM1, myogenic differentiation of primary myoblasts isolated from cDM1 patients but also from DM1, DM2 and non-affected individual (CON) was assessed in vitro (see FIGS. 1 and 13). Fusion of cDM1 myoblasts associated with large expansion (>3000 CTG) was significantly reduced by 70-80% when compared to DM2 and CON muscle cells (FIG. 13a). A slight decrease of fusion index (25%) was also measured in DM1 cells containing 750 CTG and 1200 CTG suggesting that an additional mechanism may trigger the altered differentiation of cD Ml myoblasts.

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Abstract

Methods, uses, kits and products are described for the prognosis, diagnosis, prevention and treatment of myotronic dystrophy type 1 (DM1), and more particularly for the prognosis, diagnosis, prevention and treatment of the congenital form of myotronic dystrophy type 1 (cDM1), based on changes in / modulation of prostaglandin E2 (PGE2).

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]The present application claims the benefit, under 35 U.S.C. § 119(e), of U.S. Provisional Application Ser. No. 60 / 971,392, filed Sep. 11, 2007, which is incorporated herein by reference in its entirety.FIELD OF THE INVENTION[0002]The present invention relates to changes in / modulation of prostaglandin E2 (PGE2) levels, and uses thereof for prognosis, diagnosis, prevention and treatment of myotronic dystrophy type 1 (DM1), and more particularly for the prognosis, diagnosis, prevention and treatment of the congenital form of myotronic dystrophy type 1 (cDM1).BACKGROUND OF THE INVENTION[0003]Myotonic dystrophy type 1 (DM1), also known as Steinert's disease, is an autosomal, dominantly inherited neuromuscular disorder with a global incidence of 1 per 8000 (Harper P S: Myotonic Dystrophy 2nd ed., 1989, W. B. Saunders, London). The mutation responsible for the disease is a (CUG)n repeat expansion in the 3′ untranslated region of the DM protein k...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/7105A61K31/60C12Q1/02C12Q1/68G01N33/566
CPCA61K31/60A61K31/7105C12Q2600/158C12Q1/6883C12Q2600/106G01N33/88A61P21/00
Inventor PUYMIRAT, JACKBEAULIEU, DANIELCHAPDELAINE, PIERRE
Owner UNIV LAVAL
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