Referencias científicas Nº 155

Measuring Inhibition and Cognitive Flexibility in Friedreich Ataxia

  • Authors
  • Authors and affiliations
  • Louise A. Corben
  • Felicity Klopper
  • Monique Stagnitti
  • Nellie Georgiou-Karistianis
  • John L. Bradshaw
  • Gary Rance
  • Martin B. Delatycki


Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder with subtle impact on cognition. Inhibitory processes and cognitive flexibility were examined in FRDA by assessing the ability to suppress a predictable verbal response. We administered the Hayling Sentence Completion Test (HSCT), the Trail Making Test, and the Stroop Test to 43 individuals with FRDA and 42 gender- and age-matched control participants. There were no significant group differences in performance on the Stroop or Trail Making Test whereas significant impairment in cognitive flexibility including the ability to predict and inhibit a pre-potent response as measured in the HSCT was evident in individuals with FRDA. These deficits did not correlate with clinical characteristics of FRDA (age of disease onset, disease duration, number of guanine-adenine-adenine repeats on the shorter or larger FXN allele, or Friedreich Ataxia Rating Scale score), suggesting that such impairment may not be related to the disease process in a straightforward way. The observed specific impairment of inhibition and predictive capacity in individuals with FRDA on the HSCT task, in the absence of impairment in associated executive functions, supports cerebellar dysfunction in conjunction with disturbance to cortico-thalamo-cerebellar connectivity, perhaps via inability to access frontal areas necessary for successful task completion.

E3 Ligase RNF126 Directly Ubiquitinates Frataxin, Promoting Its Degradation: Identification of a Potential Therapeutic Target for Friedreich Ataxia

Monica Benini

, Silvia Fortuni

, Ivano Condò

, Giulia Alfedi

, Florence Malisan

, Nicola Toschi

, Dario Serio

, Damiano Sergio Massaro

, Gaetano Arcuri

, Roberto Testi

, Alessandra Rufini


  • Screening of a siRNA library identifies RNF126 as the frataxin E3 ligase
  • RNF126 promotes frataxin ubiquitination and degradation
  • RNF126 knockdown induces frataxin accumulation in cells derived from FRDA patients
  • RNF126 represents a potential therapeutic target for Friedreich ataxia


Friedreich ataxia (FRDA) is a severe genetic neurodegenerative disease caused by reduced expression of the mitochondrial protein frataxin. To date, there is no therapy to treat this condition. The amount of residual frataxin critically affects the severity of the disease; thus, attempts to restore physiological frataxin levels are considered therapeutically relevant. Frataxin levels are controlled by the ubiquitin-proteasome system; therefore, inhibition of the frataxin E3 ligase may represent a strategy to achieve an increase in frataxin levels. Here, we report the identification of the RING E3 ligase RNF126 as the enzyme that specifically mediates frataxin ubiquitination and targets it for degradation. RNF126 interacts with frataxin and promotes its ubiquitination in a catalytic activity-dependent manner, both in vivo and in vitro. Most importantly, RNF126 depletion results in frataxin accumulation in cells derived from FRDA patients, highlighting the relevance of RNF126 as a new therapeutic target for Friedreich ataxia.

A study of CTI-1601 for the treatment of Friedreich’s Ataxia.


Phase of Trial: Phase I

Latest Information Update: 14 Feb 2017

At a glance

  • DrugsCTI 1601 (Primary)
  • IndicationsFriedreich’s ataxia
  • FocusAdverse reactions

Most Recent Events

  • 14 Feb 2017New trial record
  • 06 Feb 2017According to a Chondrial Therapeutics media release, company is planning to file an Investigational New Drug (IND) application with the U.S. Food and Drug Administration (FDA) and after acceptance of the IND, company will initiate this trial.



Ghayath Janoudi, William Amegatse, Brendan McIntosh, Chander Sehgal, and Trevor Richter; Orphanet J Rare Dis. 2016; 11: 164. doi:10.1186/s13023-016-0539-3

A shift in biochemical research towards drugs for rare diseases has created new challenges for the pharmaceutical industry, government regulators, health technology assessment agencies, and public and private payers. In this article, we aim to comprehensively review, characterize, identify possible trends, and explore reasons for negative reimbursement recommendations in submissions made to the Common Drug Review (CDR) for drugs for rare diseases (DRD) at the Canadian Agency for Drugs and Technologies in Health (CADTH), a publicly funded pan-Canadian health technology assessment agency.
>From 2004 to 2015, 63 of 434 submissions to the CDR were for DRD (range: 1 submission in 2005 to 10 submissions in 2013). Most (74.6%) submissions included at least one double-blind randomized controlled trial (RCT). The average study size was 190 patients (range: 20 to 742). The average annual treatment cost was C$215,631 (range: $9,706 to $940,084). Reimbursement recommendations were positive for 54% of the submissions. Negative reimbursement recommendations were made due to a lack of clinical effectiveness (38.5%), insufficient evidence (30.8%), multiple reasons (23.1%), or lack of cost effectiveness/high cost (7.7%).
The number of DRD submissions to CDR increased since 2013; from 4 to 5 per year between 2004 and 2012, to 10, 9, and 8 in 2013, 2014, and 2015 respectively. More than half of DRD submissions received positive reimbursement recommendation. Poor quality evidence and/or lack of supportive clinical evidence was at least partly responsible for a negative reimbursement recommendation in all cases. Although the average cost of DRD treatments was high, high cost was a reason for a negative reimbursement recommendation in only two (7.7%) of negative reimbursement recommendations.

Industrializing rare disease therapy discovery and development

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To the Editor:

If it were possible to develop a treatment for a disease for a few million dollars or less, the implications would be far-reaching. There are over 7,000 rare diseases, ~75% of which affect children, and only 340 of these disorders currently have treatments. Research for rare diseases has…
Mitochondria-penetrating peptides conjugated to desferrioxamine as chelators for mitochondrial labile iron

  • Roxana Y. P. Alta,
  • Hector A. Vitorino,
  • Dibakar Goswami,
  • Cleber W. Liria,
  • Simon P. Wisnovsky,
  • Shana O. Kelley,
  • Terêsa Machini  ,
  • Breno P. Espósito


Desferrioxamine (DFO) is a bacterial siderophore with a high affinity for iron, but low cell penetration. As part of our ongoing project focused on DFO-conjugates, we synthesized, purified, characterized and studied new mtDFOs (DFO conjugated to the Mitochondria Penetrating Peptides TAT49-57, 1A, SS02 and SS20) using a succinic linker. These new conjugates retained their strong iron binding ability and antioxidant capacity. They were relatively non toxic to A2780 cells (IC50 40–100 μM) and had good mitochondrial localization (Rr +0.45 –+0.68) as observed when labeled with carboxy-tetramethylrhodamine (TAMRA) In general, mtDFO caused only modest levels of mitochondrial DNA (mtDNA) damage. DFO-SS02 retained the antioxidant ability of the parent peptide, shown by the inhibition of mitochondrial superoxide formation. None of the compounds displayed cell cycle arrest or enhanced apoptosis. Taken together, these results indicate that mtDFO could be promising compounds for amelioration of the disease symptoms of iron overload in mitochondria.

Shire divests mRNA platform to RaNa

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RNA activation specialist RaNa Therapeutics has acquired Shire’s messenger RNA drug discovery platform, along with the scientists who have worked to develop it over the last eight years. Dublin-based Shire receives an equity stake in RaNa and is eligible for future milestones and royalties on products developed with the technology.… 

Comparison of Two Different PCR-based Methods for Detection of GAA Expansions in Frataxin Gene





Background: Expansion of GAA trinucleotide repeats is the molecular basis of Friedreich’s ataxia (FRDA). Precise detection of the GAA expansion repeat in frataxin gene has always been a challenge. Different molecular methods have been suggested for detection of GAA expansion, including; short-PCR, long-PCR, Triplet repeat primed-PCR (TP-PCR) and southern blotting. The aim of study was to evaluate two PCR-based methods, TP-PCR and long-PCR, and to explore the use of TP-PCR accompanying with long-PCR for accurate genotyping of FRDA patients.

Methods: Blood samples were collected from six Iranian patients suspected to FRDA, who referred to the Department of Medical Genetics at Tehran University of Medical Sciences during the year 2014. For one of these patients’ four asymptomatic members of the family were also recruited for the analysis. DNA extraction was performed by two different methods. TP-PCR and long-PCR were carried out in all samples. The type of this study is assessment / investigation of methods.

Results: Using a combination of the above methods, the genotypes of all samples were confirmed as five homozygous mutants (expanded GAA repeats), two heterozygous and three homozygous normal (normal repeat size). The results obtained by TP-PCR are consistent with long-PCR results.

Conclusion: The presence or absence of expanded alleles can be identified correctly by TP-PCR. Performing long-PCR and Fluorescent-long-PCR enables accurate genotyping in all samples. This approach is highly reliable. It could be successfully used for detection of GAA expansion repeats.

MiRNA-145 Regulates the Development of Congenital Heart Disease Through Targeting FXN

  • Authors
  • Lei Wang
  • Danqiu Tian
  • Jihua Hu
  • Haijian Xing
  • Min Sun
  • Juanli Wang
  • Qiang Jian
  • Hua Yang



Congenital heart disease (CHD) is the leading cause of death in infants in the world. The study of CHDs has come a long way since their classification and description. Although transcriptional programmes that are impaired in individuals with CHDs are being identified, the mechanisms of how these deficiencies translate to a structural defect are unknown. In this study, using high-throughput microarray analysis and molecular network analysis, FXN was identified to be the most differentially expressed key gene in CHD. By TargetScan analysis, we predicted FXN was the target gene of miRNA-145 and miRNA-182. Through real-time PCR analysis of clinical samples and experiments in cell lines, we confirmed that miRNA-145 but not miRNA-182 directly binds to the 3′ UTR region of FXN and negatively regulates its expression. We further found that through targeting FXN, miRNA-145 regulates apoptosis and mitochondrial function. In general, our study confirmed the differentially expressed FXN regulates the development of CHD and the differential expression was under the control of miRNA-145. These results might provide new insight into the understanding of the CHD pathogenesis and may facilitate further therapeutic studies.

Using the shared genetics of dystonia and ataxia to unravel their pathogenesis


In this review we explore the similarities between spinocerebellar ataxias and dystonias, and suggest potentially shared molecular pathways using a gene co-expression network approach. The spinocerebellar ataxias are a group of neurodegenerative disorders characterized by coordination problems caused mainly by atrophy of the cerebellum. The dystonias are another group of neurological movement disorders linked to basal ganglia dysfunction, although evidence is now pointing to cerebellar involvement as well. Our gene co-expression network approach identified 99 shared genes and showed the involvement of two major pathways: synaptic transmission and neurodevelopment. These pathways overlapped in the two disorders, with a large role for GABAergic signaling in both. The overlapping pathways may provide novel targets for disease therapies. We need to prioritize variants obtained by whole exome sequencing in the genes associated with these pathways in the search for new pathogenic variants, which can than be used to help in the genetic counseling of patients and their families.


  • AMPAR, α-amino-3-hydroxyl-5methyl-4-isoxazole-proprionate Receptor;
  • BDNF, brain derived neurotrophic factor;
  • CB, cerebellum;
  • DCN, deep cerebellar nuclei;
  • EBCC, eye blink classical conditioning;
  • GABA, gamma aminobutyric acid;
  • NGS, next generation sequencing;
  • NMDA, N-methyl-d-aspartate;
  • PC, Purkinje Cell;
  • SCA, spinocerebellar ataxia