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Use of aminoglycoside analogs in the treatment of rett syndrome

a technology of aminoglycosides and rett syndrome, applied in the field of therapy, can solve the problems of reducing the suppression efficiency at subtoxic doses, compromising the clinical applicability of aminoglycosides of the gentamicin family,

Inactive Publication Date: 2017-12-21
ELOXX PHARM LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a method for treating Rett syndrome in a subject in need thereof by administering a therapeutically effective amount of a compound represented by formula I. The compound is a MECP2 inhibitor that can specifically target the premature stop codon mutation associated with Rett syndrome. The compound can be administered as a pharmaceutical composition or a salt thereof. The technical effect of the invention is to provide an effective treatment for Rett syndrome.

Problems solved by technology

However, clinical applicability of aminoglycosides of the gentamicin family has been compromised by parallel findings of significant toxicity associated with its long-term administration and with reduced suppression efficiency at subtoxic doses [Kerem E (2004) Curr Opin Pulm Med 10: 547-552], in addition to its limited permeability through the blood-brain-barrier [Keeling K M, Bedwell D M (2005) Current Pharmacogenomics 3:259-269].

Method used

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  • Use of aminoglycoside analogs in the treatment of rett syndrome
  • Use of aminoglycoside analogs in the treatment of rett syndrome
  • Use of aminoglycoside analogs in the treatment of rett syndrome

Examples

Experimental program
Comparison scheme
Effect test

example 1

MECP2 Readthrough in Rett Human R294X Cells

[0198]Fibroblasts derived from Human R294X Rett syndrome male and female patients were plated in a 384 black clear bottom plate at 750 cells / well. Cells were treated with 100, 200 and 400 μg / mL of NB124 for 3 days. Localization of endogenous MeCP2 protein was visualized by using a specific MeCP2 antibody detecting the C-terminal part of the protein and immunofluorescent microscopy.

[0199]FIG. 1 presents high content screening automated microscope pictures obtained for cells treated with 400 μg / mL of NB124 compared with non-treated cells, and show MECP2 nuclei localization and translation in all tested samples, and enhanced MECP2 translation in the treated samples.

[0200]The localization of MECP2 in the nuclai of the cell indicates that the protein retained is functionality and was able to return from the plasma to the nuclai.

[0201]The number of MECP2 positive cells was calculated using an automate algorithm and the obtained data is presented ...

example 2

In Vitro Studies of Readthrough Efficacy

[0202]Readthrough activity was assayed using TNT reticulocyte lysate (i-vitro),and the nucleic acid constructs: Rett R168X, R270X & R294X for the nonsense mutations tested, as depicted in FIG. 3.

[0203]The obtained plasmids in the presence of 0-50 μM of the tested aminoglycoside transcribed and translated using the TNT reticulocyte lysate quick-coupled transcription / translation system. Luciferase activity was determined 90 minutes post incubation at 30° C., using Dual luciferase reporter assay system, and read-through was calculated as shown in the follow equation:

%Readthrough=Luminescence(FFmut) / Luminescence(Renillamut)Luminescence(FFwt) / Luminescence(Renillawt)

[0204]The obtained data is presented in Table 1 below.

TABLE 1Translational InhibitionIC50 [μm]2,3(TI) [μm]2,3TI / IC503Compound1R168XR270XR294XR168XR270XR294XR168XR270XR294XRT %4NB1220.400.160.224.103.755.021023235.3%NB1231.661.391.7522.2314.4860.841310353.8%NB1240.880.430.766.675.325.6581...

example 3

Ex-Vivo Readthrough Efficacy and Toxicity Assays

[0207]Nucleic acid constructs harboring Rett R168X, R270X, and R294X mutations were inserted into HEK-293 (human embryonic kidney) cells using Calcium Phosphate method. Six hours post-transfection, the tested aminoglycosides, at a concentration of 0.3 or 1 mM were added. The cells were harvested following 16 hours incubation with the tested aminoglycoside using passive lysis buffer. Readthrough activity was calculated as described hereinabove (see, Example 2).

[0208]For the cytotoxicity assays, HEK-293 cells were grown in 96-well plates, the tested synthetic aminoglycosides, at various concentrations, were thereafter added (10 μL, per well), and the cells were incubated for additional 24 hours. A cell proliferation assay (wst-1 based calorimetric assay), was performed by using 3-hour incubation. Optical density was measured using an ELISA plate reader.

[0209]The obtained data are presented in Table 3 (readthrough activity) and Table 4 (t...

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Abstract

Compounds, methods and uses of pseudo-trisaccharide aminoglycosides represented by the general formula I:or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of alkyl, cycloalkyl and aryl; and all other variables and features are as described in the specification, in the treatment of Rett syndrome are disclosed.

Description

FIELD AND BACKGROUND OF THE INVENTION[0001]The present invention, in some embodiments thereof, relates to therapy and, more particularly, but not exclusively, to compositions and methods utilizing aminoglycoside analogs in the treatment of Rett syndrome.[0002]Rett syndrome (RTT, MIM 312750) is an X-linked postnatal neurodevelopmental disorder predominantly occurring in girls with a worldwide incidence of 1 / 10,000-15,000 female births. After normal development, during the first 6 to 18 months developmental stagnation and then regression occurs. During the phase of regression, purposeful hand use and language are lost while gross motor functions are relatively preserved. After the phase of regression the clinical picture remains stable for many years.[0003]The major causative factor of RTT is deficiency of the X-linked methyl CpG-binding protein 2 (MeCP2) at Xq28, in which over 200 mutations have been identified so far in classical and atypical RTT patients. The majority of RTT causat...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/7036
CPCA61K31/7036A61P25/00A61P43/00
Inventor BAASOV, TIMORTUVIA, SHMUELPELLED, DORI
Owner ELOXX PHARM LTD
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