30 results about "Frataxin" patented technology

This invention relates generally to methods for the diagnosis and therapeutic treatment of Friedreich Ataxia. Friedreich ataxia (FRDA) is an autosomal recessive, degenerative disease that involves the central and peripheral nervous system and the heart. A gene, X25, was identified in the critical region for the FRDA locus on chromosome 9q13. The gene encodes a 210 amino acid protein, frataxin, that has homologues in distant species such as C. elegans and yeast. A few FRDA patients have been found to have point mutations in X25, but the vast majority are homozygous for a variable, unstable GAA trinucleotide expansion in the first X25 intron. Mature X25 mRNA was severely reduced in abundance in individuals with FRDA. Carriers and individuals at risk for developing FRDA can be ascertained by the methods of the present invention. Further, the methods of the present invention provide treatment to those individuals having FRDA.

Methods of treating mitochondrial disorders that are not respiratory chain disorders using compositions comprising EPO mimetic compounds or compounds capable of increasing endogenous EPO levels or stimulating erythropoiesis are disclosed. Methods of treating Friedreich's ataxia, Leigh's syndrome, or other disorders by increasing the expression of frataxin with an EPO mimetic compound or a compound capable of increasing endogenous EPO levels or stimulating erythropoiesis are also disclosed.

The present invention relates to a method for identifying and / or validating candidate substances for the treatment of Friedreich Ataxia (FRDA). Furthermore, the present invention relates to the use of selenium, Ebselen and Glutathione peroxidase (GPX) mimetics for the preparation of a medicament for the treatment of FRDA. Another aspect of the present invention relates to the use of cells with reduced frataxin expression for identifying and / or validating candidate substances for the treatment of Friedreich Ataxia.

A method for preventing or treating cardiomyopathy due to energy failure in a subject in need thereof is provided. The method comprises administering to the subject a therapeutically effective amount of a vector which comprises a nucleic acid sequence encoding a gene that can reverse energy failure. An exemplary cardiomyopathy is that which is associated with Friedreich ataxia and an exemplary nucleic acid sequence comprises a nucleic acid that encodes frataxin (FXN).

The present invention provides, among other things, compositions and methods for treatment of Friedrich's Ataxia based on effective targeting of a therapeutic moiety to mitochondria that can substitute for natural FXN protein activity or rescue one or more phenotypes or symptoms associated with frataxin-deficiency. In some embodiments, the present invention provides a targeted therapeutic comprising a therapeutic moiety, which is a polypeptide having an N-terminus and a C-terminus, a mitochondrial targeting sequence associated with the therapeutic moiety at the N-terminus, and a mitochondrial membrane-penetrating peptide associated with the therapeutic moiety at the C-terminus, wherein the therapeutic moiety is targeted to mitochondria upon cellular entry.

Provided herein are methods for increasing Frataxin (FXN) expression that involve targeting or expressing regulatory factors that modulate the epigenetic state of FXN genes. Also provided herein are methods for increasing FXN expression using inhibitors of a negative epigenetic regulator of FXN. Compositions and methods for treating Friedrich's ataxia are also provided.

The present invention relates to antisense oligonucleotides that modulate the expression of and / or function of Frataxin (FXN), in particular, by targeting natural antisense polynucleotides of Frataxin (FXN). The invention also relates to the identification of these antisense oligonucleotides and their use in treating diseases and disorders associated with the expression of FXN.

Described herein are compositions and methods for treating Friedreich's Ataxia (FRDA) with interferon gamma. In some aspects, methods for increasing expression of frataxin in cells and for treating Friedreich's Ataxia are provided. In some additional aspects, methods increasing aconitase activity in cells are provided.

Methods and products (e.g., recombinant proteins) are described for increasing frataxin expression / levels in a cell, as well as uses of such methods and products, for example for the treatment of Friedreich ataxia in a subject suffering therefrom.

The disclosure relates to compositions and methods for altering, e.g., enhancing, the expression of frataxin (FXN), whether in vitro and / or in vivo including, but not limited to, the exploitation of engineered promoters. Such compositions include delivery via administration of an adeno-associated viral (AAV) particle. The compositions and methods of the present disclosure are useful in the treatment of subjects diagnosed with, or suspected of having Friedreich's ataxia or another neuromuscular or neurological condition resulting from a deficiency in the quantity and / or function of frataxin or associated with decreased expression or protein levels of frataxin.

Methods and products (e.g., gRNAs, recombinant fusion proteins, frataxin targeting systems, compositions and kits) are described for increasing frataxin expression / levels in a cell, as well as uses of such methods and products, for example for the treatment of Friedreich ataxia in a subject suffering therefrom.

Methods of modifying a frataxin gene are disclosed, comprising removing some or all of endogenous GAA trinucleotide repeats within the frataxin gene, e.g., within an intron (e.g., intron 1) of the frataxin gene. The removal may be effected using a CRISPR / CAS nuclease system. Such modification may be used to increase frataxin expression in the cell, and also to treat a subject suffering from Friedreich ataxia. Reagents, kits and uses of the method are also disclosed, for example to modify a frataxin gene and to treat a subject suffering from Friedreich ataxia.

Provided herein are methods for treating a disease or disorder associated with mitochondrial dysfunction through ex vivo introduction of a nucleic acid molecule into hematopoietic stem and progenitor cells (HSPCs) followed by transplantation of the HSPCs into a subject in need of treatment. The nucleic acid molecule may include a functional human frataxin (hFXN) or may include a gene editing system that when transfected into the cells removes a trinucleotide extension mutation of endogenous hFXN.

The disclosure provides methods for the treatment of Friedreich's ataxia (FRDA), an autosomal recessive ataxia caused by mutation of the FXN gene, by administering to a subject a therapeutically effective amount of etravirine, or a pharmaceutically acceptable salt thereof. Etravirine is demonstrated to increase the levels of frataxin precursor and intermediate and mature forms of frataxin.

The purpose of the invention is to provide a drug effective in the treatment and prevention of diseases and the like caused by a decrease in frataxin production. The invention provides a frataxin enhancer containing 5-aminolevulinic acid (ALA) or a derivative thereof or a salt of these, and a therapeutic agent and / or prophylactic agent for diseases caused by a decrease in frataxin production.

The present invention relates to a vector which comprises a nucleic acid sequence encoding for the frataxin (FXN) gene for use in the prevention and treatment of neurological phenotype associated with Friedreich ataxia in a subject in need thereof.

The invention provides compositions and methods useful for the treatment of Friedreich's ataxia. In some embodiments, the invention provides compositions and methods useful for inhibiting the ubiquitination of frataxin.

The invention provides p38 MAPK inhibitors that compensate for a frataxin deficiency or mutation and methods of using the same (e.g., to treat Friedreich's ataxia).

Isolated transduced cells exhibiting FRDA characteristics in an inducible fashion are disclosed. Isolated transduced cells comprise an expression vector having a nucleic acid sequence encoding an shRNA for frataxin protein knockdown and a heterologous expression control sequence. Additionally, methods of screening for a candidate therapeutic agent for treating Friedreich's Ataxia using isolated transduced cells are disclosed. Further, a recombinant nucleic acid construct for frataxin knockdown is disclosed that comprises a nucleic acid encoding an shRNA operably linked to a heterologous expression control sequence and expressing an shRNA molecule in a dose-responsive fashion.

Disclosed herein are methods for assaying the concentration of frataxin in biofluids, and kits, reagents, and uses thereof.

Friedreich ataxia (FRDA) is caused by a GAA repeat expansion in FXN gene that encodes a mitochondrial protein, frataxin, involved in iron sulfur complex (ISC) assembly. Frataxin deficiency results in abnormal ISC containing proteins, namely respiratory chain complex I-III and aconitases and accumulation of iron in brain and heart of patients. Here, the inventors show that FRDA fibroblasts are unable to limit iron uptake inducing a massive cytosolic iron accumulation and to a lesser extent in mitochondria. The inventors also observed increased transferrin receptor (TfR1) steady state levels and membrane TfR1 accumulation that they ascribed to impaired post-translational modification by palmitoylation as well as delayed transferrin recycling. Finally, the inventors showed that artesunate, dichloroacetate and Coenzyme-A improved TfR1 palmitoylation and thus represent candidate molecules for the treatment of patients with Friedreich ataxia. Thus the present invention relates to methods of treating Friedreich ataxia (FRDA) as well as to methods of predicting whether a patient suffering from FRDA will achieve a therapeutic response.

The invention provides an application of SIRT3 mediated macrophage Fraxin deacetylation modification in improvement of inflammatory diseases. The invention reveals that the SIRT3 and the Fraaxin can interact for the first time, and the SIRT3 can mediate the deacetylation modification of the Fraaxin, so that the polarization of the macrophage is regulated. M2-type polarization of macrophages can be adjusted by adjusting the interaction between SIRT3 and Frataxin, so that inflammation-related diseases such as hypertension can be relieved or treated. The invention has important significance for preventing and treating diseases related to mitochondrial metabolism and blood pressure disorder.

The object of the present invention to provide an agent effective for treating and preventing e.g. a disease caused by reduction in frataxin production. The present invention provides a frataxin enhancer comprising 5-aminolevulinic acid (ALA) or a derivative thereof or salts thereof, as well as a therapeutic and / or prophylactic agent for a disease caused by reduction in frataxin production.

The present invention provides methods and compositions of treating Friedreich's ataxia (FRDA) based on administering an mRNA encoding a frataxin protein.

Isolated transduced cells exhibiting FRDA characteristics in an inducible fashion are disclosed. Isolated transduced cells comprise an expression vector having a nucleic acid sequence encoding an shRNA for frataxin protein knockdown and a heterologous expression control sequence. Additionally, methods of screening for a candidate therapeutic agent for treating Friedreich's Ataxia using isolated transduced cells are disclosed. Further, a recombinant nucleic acid construct for frataxin knockdown is disclosed that comprises a nucleic acid encoding an shRNA operably linked to a heterologous expression control sequence and expressing an shRNA molecule in a dose-responsive fashion.

The present disclosure is based, at least in part, on providing a set of markers, also referred to herein as FXN-sensitive genomic markers (or FSGMs), each expression level of which exhibits a positive or negative correlation with an ataxin (FXN) level in a cell. Thus, these FSGMs may be used to determine, assess, and / or monitor the efficacy of FXN replacement therapy in a subject.