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Scientific News

FARA funds research progress

In this section, you will find the most recent FA research publications, many of which are funded by FARA, as well as information on upcoming conferences and symposiums. You can search for articles by date using the archive box in the right hand column. To locate FARA Funded or Supported Research, click the hyperlink in the right hand column. You may also search for specific content using key words or phrases in the search button at the top right of your screen. Please be sure to visit other key research sections of our website for information on FARA’s Grant Program and the Treatment Pipeline.

Distribution of Particles in Human Stem Cell-Derived 3D Neuronal Cell Models: Effect of Particle Size, Charge, and Density

Neurodegenerative diseases are generally characterized by a progressive loss of neuronal subpopulations, with no available cure to date. One of the main reasons for the limited clinical outcomes of new drug formulations is the lack of appropriate in vitro human cell models for research and validation. Stem cell technologies provide an opportunity to address this challenge by using patient-derived cells as a platform to test various drug formulations, including particle-based drug carriers. The therapeutic efficacy of drug delivery systems relies on efficient cellular uptake of the carrier and can be dependent on its size, shape, and surface chemistry. Although considerable efforts have been made to understand the effects of the physiochemical properties of particles on two-dimensional cell culture models, little is known of their effect in three-dimensional (3D) cell models of neurodegenerative diseases. Herein, the authors investigated the role of particle size (235-1000 nm), charge (cationic and anionic), and density (1.05 and 1.8 g cm-3) on the interactions of particles with human embryonic stem cell-derived 3D cell cultures of sensory neurons, called sensory neurospheres (sNSP). Templated layer-by-layer particles, with silica or polystyrene cores, and self-assembled glycogen/DNA polyplexes were used. Particles with sizes <280 nm effectively penetrated sNSP. Additionally, effective plasmid DNA delivery was observed up to 6 days post-transfection with glycogen/DNA polyplexes. The findings provide guidance in nanoparticle design for therapies aimed at neurodegenerative diseases, in particular Friedreich's ataxia, whereby sensory neurons are predominantly affected. They also demonstrate the application of 3D models of human sensory neurons in preclinical drug development.

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Identification of a Novel Oleic Acid Analog with Protective Effects in Multiple Cellular Models of Friedreich Ataxia

Previous studies suggested that cell death in (Friedreich Ataxia) FRDA may involve ferroptosis, an iron-dependent form of cell death requiring lipid peroxidation. Based on reports that oleic acid acts as a ferroptosis inhibitor, the authors evaluated whether it, other fatty acids, and fatty acid derivatives could rescue viability in cellular models of FRDA. they identified a trifluoromethyl alcohol analog of oleic acid that was significantly more potent than oleic acid itself. Further evaluation indicated that the effects were stereoselective, although a specific molecular target has not yet been identified. This work provides a potential starting point for therapeutics to treat FRDA, as well as a valuable probe molecule to interrogate FRDA pathophysiology.

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R-loops promote trinucleotide repeat deletion through DNA base excision repair enzymatic activities

Trinucleotide repeat (TNR) expansion and deletion are responsible for over 40 neurodegenerative diseases and associated with cancer. TNR can undergo somatic instability that is mediated by DNA damage and repair, and gene transcription. Recent studies have pointed towards a role for R-loops in causing TNR expansion and deletion, and it's been shown that base excision repair (BER) can result in CAG repeat deletions from R-loops in yeast. However, it remains unknown how BER in R-loops can mediate TNR instability. In this study, using biochemical approaches, the authors examined BER enzymatic activities and their influence on TNR-R-loops. This study found that AP endonuclease 1 incised an abasic site on the non-template strand of a TNR R-loop, creating a double-flap intermediate containing an RNA-DNA hybrid that subsequently inhibited pol β DNA synthesis of TNRs. This stimulated flap endonuclease 1 (FEN1) cleavage of TNRs engaged in an R-loop. Moreover, the authors showed that FEN1 also efficiently cleaved the RNA strand, facilitating pol β loop/hairpin bypass synthesis and the resolution of TNR R-loops through BER. Consequently, this resulted in fewer TNRs synthesized by pol β than those removed by FEN1, thereby leading to repeat deletion. These results indicate that TNR R-loops preferentially lead to repeat deletion during BER by disrupting the balance between the addition and removal of TNRs. These discoveries open a new avenue for the treatments and prevention of repeat expansion diseases and cancer.

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Onset features and time to diagnosis in Friedreich's Ataxia

In rare disorders diagnosis may be delayed due to limited awareness and unspecific presenting symptoms. This study addresses the issue of diagnostic delay in Friedreich's Ataxia (FRDA). Six hundred eleven genetically confirmed FRDA patients were recruited within a multicentric natural history study conducted by the EFACTS (European FRDA Consortium for Translational Studies, -Identifier NCT02069509). Age at first symptoms as well as age at first suspicion of FRDA by a physician were collected retrospectively at the baseline visit. In 554 of cases (90.7%), disease presented with gait or coordination disturbances. In the others (n = 57, 9.3%), non-neurological features such as scoliosis or cardiomyopathy predated ataxia. Before the discovery of the causal mutation in 1996, median time to diagnosis was 4(IQR = 2-9) years and it improved significantly after the introduction of genetic testing (2(IQR = 1-5) years, p < 0.001). Still, after 1996, time to diagnosis was longer in patients with a) non-neurological presentation (mean 6.7, 95%CI [5.5,7.9] vs 4.5, [4.2,5] years in those with neurological presentation, p = 0.001) as well as in b) patients with late-onset (3(IQR = 1-7) vs 2(IQR = 1-5) years compared to typical onset < 25 years of age, p = 0.03). Age at onset significantly correlated with the length of the shorter GAA repeat (GAA1) in case of neurological onset (r = - 0,6; p < 0,0001), but not in patients with non-neurological presentation (r = - 0,1; p = 0,4). Across 54 siblings' pairs, differences in age at onset did not correlate with differences in GAA-repeat length (r = - 0,14, p = 0,3). In the genetic era, presentation with non-neurological features or in the adulthood still leads to a significant diagnostic delay in FRDA. Well-known correlations between GAA1 repeat length and disease milestones are not valid in case of atypical presentations or positive family history.

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A Drosophila model of Friedreich Ataxia with CRISPR/Cas9 insertion of GAA repeats in the frataxin gene reveals in vivo protection by N-acetyl cysteine

Thanks to the high degree of frataxin conservation, the Drosophila melanogaster fruitfly appears as an adequate animal model to study Friedreich Ataxia (FA) and to evaluate therapeutic interventions. The authors generated a Drosophila model of FA with CRISPR/Cas9 insertion of approximately 200 GAA in the intron of the fly frataxin gene fh. These flies exhibit a developmental delay and lethality associated with decreased frataxin expression. Preadult lethality was by-passed using genetic tools to overexpress frataxin only during the developmental period. These frataxin-deficient adults are short-lived and present strong locomotor defects. RNA-Seq analysis identified deregulation of genes involved in amino-acid metabolism and transcriptomic signatures of oxidative stress. In particular, this group observed a progressive increase of Tspo expression, fully rescued by adult frataxin expression. Thus, Tspo expression constitutes a molecular marker of the disease progression in this fly model and might be of interest in other animal models or in patients. Finally, in a candidate drug screening, it was observed that N-acetyl cysteine improved the survival, locomotor function, resistance to oxidative stress and aconitase activity of frataxin-deficient flies. Therefore, this model provides the opportunity to elucidate in vivo the protective mechanisms of this molecule of therapeutic potential. This study also highlights the strength of the CRISPR/Cas9 technology to introduce human mutations in endogenous orthologous genes, leading to Drosophila models of human diseases with improved physiological relevance.

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