30 results about "Ataxia-telangiectasia" patented technology

Inoculation of ATM-deficient mice with probiotic microorganisms, such as L. johnsonii, changed immune parameters, decreased a marker of DNA damage and increased the lifespan of the mice. Compositions and methods described herein are useful for the treatment and prevention of Ataxia telangiectasia and other cancer-prone disease, such as p53 deficiency-associated cancers. Compositions and methods of the present invention are also useful for treating and preventing radiation-induced toxicity to normal tissue in a subject being exposed to radiation. Compositions and methods of the invention can increase lifespans in a simple, non-invasive manner.

The present invention relates to a process for preparing erythrocytes loaded with one or more substance of pharmaceutical interest. The present invention is also directed to loaded erythrocytes thus obtained and pharmaceutical compositions comprising said population of loaded erythrocytes as well as therapeutic application thereof, in particular in the treatment of Ataxia telangiectasia.

The current invention provides new methods and means for the prevention and treatment of ageing-related symptoms and diseases. The invention discloses mannitol 5 and / or proline containing compositions that are particularly useful for the treatment of premature ageing related symptoms in mammalian subjects suffering from genetic defects in DNA damage response and genome maintenance pathways. Humans suffering from Cockayne syndrome (CS), Xeroderma pigmentosum (XP), combined XPCS, trichothiodystrophy (TTD), COFS (cerebro-oculo-facio-skeletal syndrome), 10 XFE disorder (Xpf-Erccl syndrome), Bloom Syndrome (BS), Werner Syndrome (WS), Ataxia telangiectasia (AT), Fanconi Anemia (FA), Hutchinson Guilford Progeria (HGP) may be treated with pharmaceutical compositions comprising mannitol and / or proline according to this invention.

The invention relates to a DNA library for detecting and diagnosing pathogenic genes of multiple cafe-au-lait macules related diseases and the application thereof. The library includes 51 pathogenic genes of multiple cafe-au-lait macules related diseases. According to the invention, 51 pathogenic genes of multiple cafe-au-lait macules related diseases are selected, a probe pool is designed, and atarget region library for the 51 pathogenic genes of multiple cafe-au-lait macules is established. The library is used to perform sequencing and find pathogenic mutations by a high-throughput sequencing technology, provides genetic and molecular biological basis for clinical diagnosis, and is accurate, fast, flexible and low-cost. The 51 gene detection regions involved in the invention can detecta variety of multiple cafe-au-lait macules related diseases such as genetic pigment abnormality, Cowden syndrome, ataxia telangiectasia, Noonan syndrome, etc. The DNA library provided by the inventionhas important significance and clinical value for the etiology analysis and differential diagnosis of multiple cafe-au-lait macules.

The invention discloses application of a composition containing an MG 53 mutant in preparation of neuroprotective drugs. The research results prove that the MG53 mutant has a prominent neuroprotectiveeffect and can cross the blood-brain barrier, thus being applied to prevention or treatment of multiple neurodegenerative diseases such as ischemic stroke, brain atrophy, senile dementia, multiple system atrophy, brain atrophy, motor neuron diseases, ataxia telangiectasia, spinal muscular atrophy and optic atrophy.

Novel methods are provided for identifying heterozygous carriers of autosomal recessive disorders such as Ataxia telangiectasia.

ATM kinase is shown to regulate proteasome-mediated protein turnover through suppression of the expression of the ubiquitin-like protein ISG15 (Interferon Stimulated Gene 15). Silencing of the ISG15 pathway restored both the ubiquitin and autophagy pathways, and the UV-mediated degradation of their substrates in A-T cells. The ATM kinase negatively regulates the ISG15 pathway, and the constitutively elevated ISG15 pathway induces proteinopathy in A-T cells, and in A-T patients. These findings indicate that proteasome-mediated protein degradation is impaired in A-T cells due to elevated expression of the ISG15 conjugation pathway, which contributes to progressive neurodegeneration in A-T patients. The ISG15 pathway is a new target for both detection and treatment of A-T Inhibitors if ISG15 expression can be used to inhibit or attenuate neurodegeneration in A-T patients. In addition, an inhibitor of the early phase of autophagy, 3-MA, was shown to be effective in decreasing the impaired proteasome-mediated protein degradation in A-T cells, and thus would be effective in decreasing the neurodegeneration in A-T patients.

Disclosed are compounds and pharmaceutically acceptable salts thereof that may be used in the treatment of subjects in need thereof. The compounds disclosed herein may be inhibitors of Ataxia-telangiectasia and RAD-3-related protein kinase (ATR). Also disclosed are pharmaceutical compositions containing the compounds or pharmaceutically acceptable salts thereof and methods of their preparation and use.

The present disclosure concerns methods for recombinantly producing functional ataxia-telangiectasia (ATM) protein, methods for isolating recombinant functional ATM protein, and uses of ATM protein. In particular, a method is disclosed for using a vaccinia virus vector to express ATM, and using immunoprecipitation or affinity tagging to isolate recombinant ATM.

Although tumor-associated macrophages have been extensively studied in the control of response to radiotherapy, the molecular mechanisms involved in the ionizing radiation-mediated activation of macrophages remain elusive. Here the present inventors show that ionizing radiation induces the expression of interferon-regulatory factor 5 (IRF5) promoting thus macrophage activation toward a pro-inflammatory phenotype. They reveal that the activation of the Ataxia telangiectasia mutated (ATM) kinase is required for ionizing radiation-elicited macrophage activation, but also for macrophage reprogramming after treatments with γ-interferon, lipopolysaccharide or chemotherapeutic agent (such as cis-platin), underscoring the fact that the kinase ATM plays a central role during macrophage phenotypic switching toward a proinflammatory phenotype. They further demonstrate that NADPH oxidase 2 (NOX2)-dependent ROS production is upstream to ATM activation and is essential during this process. They also report that hypoxic conditions and the inhibition of any component of this signaling pathway (NOX2, ROS and ATM) impairs pro-inflammatory activation of macrophages and predicts a poor tumor response to preoperative radiotherapy in locally advanced rectal cancer. Altogether, these results identify a novel signaling pathway involved in macrophage activation that may enhance effectiveness of radiotherapy through the re-programming of tumor infiltrating macrophages.

The present disclosure relates to methods for performing an assay to identify ataxia-telangiectasia homozygotes or heterozygotes. Some embodiments include the use of a rapid flow cytometry-based ataxiatelangiectasia (ATM) kinase assay that measures ATM-dependent phosphorylation of SMC1 following DNA damage.

Clinical diagnosis and newborn screening for primary immunodeficiencies (PIDDs) is described. The PIDDs include X-linked chronic granulomatous disease (X-CGD), X-linked lymphoproliferative syndrome (XLP1; SH2D1A deficiency), familial hemophagocytic lymphohistiocytosis 2 (FHL2), ataxia telangiectasia (AT), common variable immunodeficiency (CVID; B-cell dysfunctions), severe combined immunodeficiency (SCID), adenosine deaminase (ADA) deficiency, and dedicator of cytokinesis 8 (DOCKS) deficiency. Additionally, cell specific markers for platelets (CD42), natural killer (NK) cells (CD56), and T cells (CD3epsilon and CD3delta) can be used as secondary markers to provide support for diagnosis of disease.

The present invention relates to Ataxia-Telangiectasia Mutated and Rad3-related protein kinase (ATR) inhibitors for use in methods of treating BAF-complex deficient cancer. The present invention further provides methods for identifying ATR inhibitors for use in the treatment of BAF complex gene mutant or deficient cancers. Medical uses and methods relating to the treatment of synovial sarcoma using ATR inhibitors are also provided.

ATM kinase is shown to regulate proteasome-mediated protein turnover through suppression of the expression of the ubiquitin-like protein ISG15 (Interferon Stimulated Gene 15). Silencing of the ISG15 pathway restored both the ubiquitin and autophagy pathways, and the UV-mediated degradation of their substrates in A-T cells. The ATM kinase negatively regulates the ISG15 pathway, and the constitutively elevated ISG15 pathway induces proteinopathy in A-T cells, and in A-T patients. These findings indicate that proteasome-mediated protein degradation is impaired in A-T cells due to elevated expression of the ISG15 conjugation pathway, which contributes to progressive neurodegeneration in A-T patients. The ISG15 pathway is a new target for both detection and treatment of A-T Inhibitors if ISG15 expression can be used to inhibit or attenuate neurodegeneration in A-T patients. In addition, an inhibitor of the early phase of autophagy, 3-MA, was shown to be effective in decreasing the impaired proteasome-mediated protein degradation in A-T cells, and thus would be effective in decreasing the neurodegeneration in A-T patients.

The present invention provides transgenic, large non-human animal models of Ataxia-Telangiectasia, as well as methods of using such animal models in the identification and characterization of therapies for Ataxia-Telangiectasia.

Novel methods are provided for identifying heterozygous carriers of autosomal recessive disorders such as Ataxia telangiectasia.

In some embodiments, disclosed herein are oligomeric compounds which include one or more tricyclo-deoxyribonucleic acid (tc-DNA) nucleosides and one or more 2′-modified ribonucleic acid (2′-modified-RNA) nucleosides, and which optionally also include one or more non-nucleotides, each of which is joined by a plurality of internucleoside linkages, including pharmaceutical compositions and methods of using the pharmaceutical compositions for the treatment of diseases including Duchenne muscular dystrophy treatment of familial dysautonomia, spinal muscular atrophy, ataxia telangiectasia, congenital disorder of glycosylation, fronto-temporal dementia, Parkinsonism linked to chromosome 17, Niemann-Pick disease type C, neurofibromatosis type 1, neurofibromatosis type 2, megalencephalic leukoencephalopathy with subcortical cysts type 1, Pelizaeus-Merzbacher disease, Pompe disease, myotonic dystrophy type 2 (DM2 or proximal myotonic myopathy), and myotonic dystrophy type 1 (DM1 or Steinert disease).

In some embodiments, disclosed herein are oligomeric compounds which include one or more tricyclo-deoxyribonucleic acid (tc-DNA) nucleosides and one or more 2′-modified ribonucleic acid (2′-modified-RNA) nucleosides, and which optionally also include one or more non-nucleotides, each of which is joined by a plurality of internucleoside linkages, including pharmaceutical compositions and methods of using the pharmaceutical compositions for the treatment of diseases including Duchenne muscular dystrophy treatment of familial dysautonomia, spinal muscular atrophy, ataxia telangiectasia, congenital disorder of glycosylation, fronto-temporal dementia, Parkinsonism linked to chromosome 17, Niemann-Pick disease type C, neurofibromatosis type 1, neurofibromatosis type 2, megalencephalic leukoencephalopathy with subcortical cysts type 1, Pelizaeus-Merzbacher disease, Pompe disease, myotonic dystrophy type 2 (DM2 or proximal myotonic myopathy), and myotonic dystrophy type 1 (DM1 or Steinert disease).

The present invention relates to a process for preparing erythrocytes loaded with one or more substance of pharmaceutical interest. The present invention is also directed to loaded erythrocytes thus obtained and pharmaceutical compositions comprising said population of loaded erythrocytes as well as therapeutic application thereof, in particular in the treatment of Ataxia telangiectasia.

The invention discloses a 1, 3, 4-oxadiazole derivative, and discloses different preparation methods of the 1, 3, 4-oxadiazole derivative and an application thereof. The compound can be used for preparing inhibitors and anti-tumor drugs of ataxia telangiectasia mutant genes and Rad3 related kinase (ATR). The 1, 3, 4-oxadiazole derivative disclosed by the invention is novel in structure, and an electron withdrawing group (nitryl) of a side-chain benzene ring is beneficial to improving the anti-tumor activity of the 1, 3, 4-oxadiazole derivative. Compared with a traditional preparation method of the 1, 3, 4-oxadiazole derivative, the preparation method of the 1, 3, 4-oxadiazole derivative can overcome the defects that under the high-temperature reaction condition, a dehydration cyclizing agent is high in toxicity, prone to corrosion and the like, dibromotriphenylphosphine is adopted as a dehydration cyclizing agent in the preparation method, reaction can be conducted at the room temperature, and the preparation method is environmentally friendly.

The present invention relates to a novel procedure for evaluating the response of patients affected by Ataxia Talangiectasia (A-T) to glucocorticoids treatment. In particular, the procedure provides a step of qualitative and / or quantitative identification in the blood of said patients of the expression of a mRNA variant of the ATM (Ataxia-Talangiectasia-Mutated) gene produced by non-canonical splicing induced by glucocorticoid (GC). In fact, it was demonstrated that mRNA variant expression is present in the blood of patients who responded positively to treatment with GC.

The invention provides a crystal, pharmaceutical composition and an application of compound N-butyl-2,2'-imino-bis(8-quinolinamine). The crystalline compound N-butyl-2,2'-imino-bis(8-quinolinamine) has excellent drug preparation characteristics, and can be used for treating diseases related to metal ion metabolism imbalance, as well as neurodegenerative diseases comprising diseases associated withabnormal Tau protein metabolism and abnormal beta-amyloid protein, for example, amyotrophic lateral sclerosis, spinal muscular atrophy, ataxia telangiectasia, Creutzfeldt-Jakob disease, Huntington'sdisease, spinocerebellar ataxia, multiple sclerosis, Parkinson's disease, Alzheimer's disease, primary lateral sclerosis and the like.

The invention discloses an ATR (ataxia telangiectasia-mutated and Rad3-related) gene mutation detection liquid chip and specific primers. The liquid chip mainly comprises each ASPE (allele specific primer extension) primer formed by tag sequences at 5' terminal and specific primer sequences aiming at target gene mutation sites at 3' terminal, microspheres coated by anti-tag sequences as well as amplification primers, wherein the specific primer sequences are SEQ ID NO.7 and SEQ ID NO.8 aiming at G632A sites, SEQ ID NO.9 and SEQ ID NO.10 aiming at T7301G sites and / or SEQ ID NO.11 and SEQ ID NO.12 aiming at G946A sites. The liquid chip has the advantages that the coincidence rate of the detection results of the detection liquid chip provided by the invention and a sequencing method is as high as 100%; and parallel detection of wild types and mutant types of a plurality of mutation sites is achieved.

Disclosed are compounds of formula (I) or a pharmaceutically acceptable salt thereof wherein-is a single bond and each Y is N or CR4; or-absent and each Y is NRY, carbonyl or C (RY) 2 wherein each R1 is H or optionally substituted C1-6 alkyl; r1 is optionally substituted C1-6 alkyl or H; r3 is an optionally substituted heteroaryl group with 1 to 9 carbon atoms or an optionally substituted heteroaryl group with 1 to 6 alkyl groups with 1 to 9 carbon atoms; each R4 is hydrogen, halogen, an optionally substituted C1-6 alkyl group, an optionally substituted C2-6 alkenyl group, or an optionally substituted C2-6 alkynyl group; x is hydrogen or halogen; and R2 is as defined in claim 1. Also disclosed are pharmaceutical compositions containing the compounds of formula (I) and methods of making the same. The compounds of formula (I) may be inhibitors of ataxia telangiectasia and RAD-3 associated protein kinase (ATR) and are useful in the treatment of diseases or conditions such as cancer.

The invention provides crystals, pharmaceutical compositions and applications of the compound N-butyl-2,2'-imino-bis(8-quinolinamine). The crystalline compound N-butyl-2,2'-imino-bis(8-quinolinamine) of the present invention has good medicinal properties, and can be used to treat diseases related to metal ion metabolic imbalance, as well as disorders including Tau protein metabolism, Beta-amyloid-related disorders such as amyotrophic lateral sclerosis, spinal muscular atrophy, ataxia-telangiectasia, Creutzfeldt-Jakob disease, Huntington's disease, cerebellar atrophy, multiple sclerosis , Parkinson's disease, Alzheimer's disease, primary lateral sclerosis and other diseases including neurodegenerative diseases.

The present invention relates to a novel procedure for evaluating the response of patients affected by Ataxia Talangiectasia (A-T) to glucocorticoids treatment. In particular, the procedure provides a step of qualitative and / or quantitative identification in the blood of said patients of the expression of a mRNA variant of the ATM (Ataxia-Talangiectasia-Mutated) gene produced by non-canonical splicing induced by glucocorticoid (GC). In fact, it was demonstrated that mRNA variant expression is present in the blood of patients who responded positively to treatment with GC.