Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0016719 (Friedreich's ataxia)
 2,098 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several neuromuscular and neurodegenerative diseases are caused by genetically unstable triplet repeat sequences (CTG.CAG, CGG.CCG, or AAG.CTT) in or near the responsible genes. We implemented novel cloning strategies with chemically synthesized oligonucleotides to clone seven of the triplet repeat sequences (GTA.TAC, GAT.ATC, GTT.AAC, CAC.GTG, AGG.CCT, TCG.CGA, and AAG.CTT), and the adjoining paper (Ohshima, K., Kang, S., Larson, J. E., and Wells, R. D.(1996) J. Biol. Chem. 271, 16784-16791) describes studies on TTA.TAA. This approach in conjunction with in vivo expansion studies in Escherichia coli enabled the preparation of at least 81 plasmids containing the repeat sequences with lengths of approximately 16 up to 158 triplets in both orientations with varying extents of polymorphisms. The inserts were characterized by DNA sequencing as well as DNA polymerase pausings, two-dimensional agarose gel electrophoresis, and chemical probe analyses to evaluate the capacity to adopt negative supercoil induced non-B DNA conformations. AAG.CTT and AGG.CCT form intramolecular triplexes, and the other five repeat sequences do not form any previously characterized non-B structures. However, long tracts of TCG.CGA showed strong inhibition of DNA synthesis at specific loci in the repeats as seen in the cases of CTG.CAG and CGG.CCG (Kang, S., Ohshima, K., Shimizu, M., Amirhaeri, S., and Wells, R. D.(1995) J. Biol. Chem. 270, 27014-27021). This work along with other studies (Wells, R. D.(1996) J. Biol. Chem. 271, 2875-2878) on CTG.CAG, CGG.CCG, and TTA.TAA makes available long inserts of all 10 triplet repeat sequences for a variety of physical, molecular biological, genetic, and medical investigations. A model to explain the reduction in mRNA abundance in Friedreich's ataxia based on intermolecular triplex formation is proposed.
 ...
PMID:Cloning, characterization, and properties of seven triplet repeat DNA sequences. 866 77

It is well established that GAA/TTC base triplet expansion is the cause of degenerative disorder in Freidreich's Ataxia. It is also known that these repeat sequences fold back to form the unusual intramolecular triple helix structures in DNA of the type Pyrimidine *Purine *Pyrimidine or Purine *Purine*Pyrimidine. In this paper we report on the stability of Purine *Purine*Pyrimidine intermolecular triple helix DNA containing GAA/TTC repeats under physiological conditions. Using the oligonucleotides 5' TCGC GAA GAA GAA GAA GAA CGCT 3', 5'-AGCG TTC TTC TTC TTC TTC GCGA-3' for duplex and 5'-AAG AAG AAG AAG AAG -3' as triplex forming strand (TFO), we have established the formation of triplex by UV-melting temperature (Tm), stoichiometry of mixing and circular dichroic spectra. This was further confirmed by gel-retardation assay. The thermodynamic parameters Delta G, Delta H and Delta S for both duplex and triplex formation were determined at different salt concentrations. The results suggest the formation of a stable intermolecular, anti - parallel triplex in GAA/TTC repeat sequences where each repeat unit contains two A*A*T and one G*G*C triplet. The therapeutic agents and TFOs, which competitively inhibit the in-vivo intra-molecular triplex by formation of a more stable inter-molecular triplex, could be used to reverse the transcription deficit in GAA/TTC expansions in Frataxin gene.
 ...
PMID:Formation and thermodynamic stability of intermolecular (R*R*Y) DNA triplex in GAA/TTC repeats associated with Freidreich's ataxia. 1184 30

Friedreich's Ataxia (FRDA) is an incurable genetic disease caused by an expanded trinucleotide AAG repeat within intronic RNA of the frataxin (FXN) gene. We have previously demonstrated that synthetic antisense oligonucleotides or duplex RNAs that are complementary to the expanded repeat can activate expression of FXN and return levels of FXN protein to near normal. The potency of these compounds, however, was too low to encourage vigorous pre-clinical development. We now report testing of "gapmer" oligonucleotides consisting of a central DNA portion flanked by chemically modified RNA that increases binding affinity. We find that gapmer antisense oligonucleotides are several fold more potent activators of FXN expression relative to previously tested compounds. The potency of FXN activation is similar to a potent benchmark gapmer targeting the nuclear noncoding RNA MALAT-1, suggesting that our approach has potential for developing more effective compounds to regulate FXN expression in vivo.
 ...
PMID:Progress towards drug discovery for Friedreich's Ataxia: Identifying synthetic oligonucleotides that more potently activate expression of human frataxin protein. 3227 20