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FARAFARA Cure FA

 

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.

 


 

Efficient Electroporation of Neuronal Cells Using Synthetic Oligonucleotides: Identifying Duplex RNA and Antisense Oligonucleotide Activators of Human Frataxin Expression

Oligonucleotide drugs are experiencing greater success in the clinic, encouraging the initiation of new projects. Resources are insufficient to develop every potentially important project and persuasive experimental data using cell lines close to disease target tissue is needed to prioritize candidates. This group has previously shown that synthetic nucleic acids can activate FXN expression in human patient-derived cells. They further tested these compounds in patient derived cells formed into cells that develop into neurons (iPSC-NPCs). Here we describe methods to deliver oligonucleotides and duplex RNAs into iPSC-NPC's cells using electroporation. Activation of FXN expression is potent, easily reproducible, and potencies parallel those determined using previous cell types. Oligonucleotides with various chemical modifications were active, providing multiple starting points for further development and highlighting improved potency as an important goal for preclinical development. This data support the conclusion that ASO-mediated activation of FXN is a feasible approach for treating FA and that electroporation is a robust method for introducing ASOs to modulate gene expressions in neuronal cells.

Read the entire article HERE

Pharmacokinetics and pharmacodynamics of the novel Nrf2 activator omaveloxolone in primates

Omaveloxolone is a potential therapy thatactivates Nrf2, a master transcription factor that regulates genes with antioxidative, anti-inflammatory, and mitochondrial bioenergetic properties, and is being evaluated in patients with Friedreich's ataxia. This study evaluated the pharmacokinetics (PK), pharmacodynamics (PD) and tissue distribution of omaveloxolone in monkeys after single and multiple oral doses, and then compared these data to initial results in Friedreich's ataxia patients. A PK/PD model was generated with the monkey data, and used to further evaluate the Friedreich's ataxia patient PK profile. The authors found that oral administration of omaveloxolone to monkeys was associated with dose-linear plasma PK and readily measurable and dose-proportional concentrations in liver, lung, and brain. Dose-dependent induction of Nrf2 target genes was also observed. Clinically, oral administration of omaveloxolone to Friedreich's ataxia patients at incremental doses from 2.5 to 300 mg produced dose-proportional systemic exposures. Clinical doses of at least 80 mg were associated with meaningful improvements in neurological function in patients and generated plasma omaveloxolone concentrations consistent with those significantly inducing Nrf2 target genes in monkeys, as shown with the monkey PK/PD model. Overall, the monkey data demonstrate a well-characterized and dose-proportional PK and tissue distribution profile after oral administration of omaveloxolone, which was associated with Nrf2 activation. Further, systemic exposures to omaveloxolone that produce Nrf2 activation in monkeys were readily achievable in Friedreich's ataxia patients after oral administration.

Read the entire article HERE

Erythropoietin and Friedreich Ataxia: Time for a Reappraisal?

FA is a rare neurological disorder due to deficiency of the mitochondrial protein frataxin. Frataxin deficiency results in impaired mitochondrial function and iron deposition in affected tissues. Erythropoietin (EPO) is a cytokine which was mostly known as a key regulator of erythropoiesis until cumulative evidence showed additional neurotrophic and neuroprotective properties. These features offered the rationale for advancement of EPO in clinical trials in different neurological disorders in the past years, including FA. Several mechanisms of action of EPO may be beneficial in FA. First of all, EPO exposure results in some frataxin upregulation in vitro and in vivo. By promoting erythropoiesis, EPO influences iron metabolism and induces shifts in iron pool which may ameliorate conditions of free iron excess and iron accumulation. Furthermore, EPO signaling is crucial for mitochondrial gene activation and mitochondrial biogenesis. Up to date nine clinical trials investigated the effects of EPO and derivatives in FA. The majority of these studies had a proof-of-concept design. Considering the natural history of FA, all of them were too short in duration and not powered for clinical changes. However, these studies addressed significant issues in the treatment with EPO, such as (1) the challenge of the dose finding, (2) stability of frataxin up-regulation, (3) continuous versus intermittent stimulation with EPO/regimen, or (4) tissue changes after EPO exposure in humans in vivo (muscle biopsy, brain imaging). The recent development of small EPO mimetics which maintain cytoprotective properties without erythropoietic action may open a new era in EPO research for the treatment of FA.

Read the entire article HERE

Peripapillary retinal nerve fibre layer thickness in Friedreich's ataxia: a biomarker for trials?

This letter describes data comparing retinal nerve fiber layer thinning measured by optical coherence tomography (OCT) to other clinical measures of FA progression. It shows that OCT measurements correlate to GAA1 length, disease duration, SARA score and activities of daily living scores, offering potential as a biomarker for clinical trials.

Read the entire article HERE

New Insights into the Hepcidin-Ferroportin Axis and Iron Homeostasis in iPSC-Derived Cardiomyocytes from Friedreich's Ataxia Patient

Iron balance in the cardiac tissue as well as the involvement of the hepcidin-ferroportin (HAMP-FPN) axis in this process and in cardiac functionality are not fully understood. Imbalance of iron occurs in several cardiac diseases, including iron-overload cardiomyopathies such as Friedreich's ataxia (FA). Using induced pluripotent stem cells (iPSCs) to create heart cells (cardiomyocytes) from cells from a FRDA patient and of a healthy control subject in order to study the cardiac iron balance and the HAMP-FPN axis. FA cardiomyocytes maintain the FA-like phenotype. They found that FA cardiomyocytes show an increase in the protein expression of hepcidin and ferroportin. Moreover, they found an unexpected nuclear localization of ferroportin in both affected and unaffected cardiomyocytes. However, the amount of the nuclear ferroportin was lower in FA cardiomyocytes than in controls. These and other data suggest that iron handling and the HAMP-FPN axis regulation in FA cardiac cells are hampered and that ferroportin may have new, still not fully understood, functions.

Read the entire article HERE

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