Strategic discussion on funding and access to therapies targeting rare diseases in Spain: an expert consensus paper

Zozaya, N., Villaseca, J., Abdalla, F., Ancochea, A., Málaga, I., Trapero-Bertran, M., … Hidalgo-Vega, A. (2023). Strategic discussion on funding and access to therapies targeting rare diseases in Spain: an expert consensus paper. Orphanet Journal of Rare Diseases, 18(1), 41. doi:10.1186/s13023-023-02635-3

The FINEERR project may provide a starting point for stakeholders involved in the process of funding and access to RD-targeted therapies to provide the necessary resources and implement measures to improve both the quality of life and life expectancy of patients with RDs. A coordinated effort is required from the different stakeholders, including the pharmaceutical industry, with clear leadership of healthcare authorities, to allow the overall healthcare system to meet the technical, political, economic, and social challenges ahead. Future studies should explore this issue further to assess how best to implement these recommendations over time.

Ataxia de friedreich, revisión bibliográfica

Investigación, R. S. (2023, febrero 22). Ataxia de friedreich, revisión bibliográfica. Recuperado el 23 de febrero de 2023, de ▷ RSI - Revista Sanitaria de Investigación website: https://revistasanitariadeinvestigacion.com/ataxia-de-friedreich-revision-bibliografica/ 

La ataxia de Friedreich es una enfermedad hereditaria y neurodegenerativa rara que afecta a personas jóvenes que se caracteriza por un deterioro lentamente progresivo de la coordinación en la marcha y en la capacidad para mantener correctamente la postura corporal, así como otros signos y síntomas neurológicos. Es la ataxia hereditaria más común con un patrón de herencia autosómica recesiva. La enfermedad causa en quienes la padecen un deterioro progresivo del cerebelo y ganglios espinales dorsales. Esta degeneración provoca en los afectados, de manera imparable, una pérdida progresiva de muchas de las funciones necesarias para una autonomía personal: pérdida de sensibilidad, descoordinación en los movimientos, escoliosis, disfagia, disartria, inmunodeficiencia, y predisposición al cáncer y en muchos casos diabetes y problemas cardíacos graves, causantes de la muerte en la mayoría de los casos. Los afectados por esta enfermedad, en un tiempo más o menos corto, acaban perdiendo toda autonomía personal.

Insights from yeast: Transcriptional reprogramming following metformin treatment is similar to that of deferiprone in a yeast Friedreich's ataxia model

Börklü E. Insights from yeast: Transcriptional reprogramming following metformin treatment is similar to that of deferiprone in a yeast Friedreich's ataxia model. Yeast (Chichester, England). 2023 Feb. DOI: 10.1002/yea.3845. PMID: 36755518. 

The comparative inquiry of transcriptome data reveals new promising roles for metformin in FRDA treatment since deferiprone and metformin treatments produce overlapping transcriptional and phenotypic responses in YFH1Δ cells. The results revealed that both deferiprone and metformin treatment does not rescue aerobic respiration in YFH1Δ cells, but they alleviate the FRDA phenotype probably by triggering the retrograde mitochondria-to-nucleus signaling.

Frataxin-deficient human brain microvascular endothelial cells lose polymerized actin and are paracellularly permeable -implications for blood-brain barrier integrity in Friedreich's Ataxia

Smith, F. M., & Kosman, D. J. (2023). Frataxin-deficient human brain microvascular endothelial cells lose polymerized actin and are paracellularly permeable -implications for blood-brain barrier integrity in Friedreich's Ataxia. bioRxiv : the preprint server for biology, 2023.02.09.527936. doi.org/10.1101/2023.02.09.527936 

We identified that insufficient FXN levels in the hBMVEC BBB model causes changes in cytoskeletal architecture and increased barrier permeability, cell pathologies that may be related to patient brain iron accumulation, neuroinflammation, neurodegeneration, and stroke. Our findings implicate other barrier cells, e.g., the cardiac microvasculature, likely contributory also to disease pathology in FRDA.

EvolClustDB: exploring eukaryotic gene clusters with evolutionarily conserved genomic neighbourhoods, Journal of Molecular Biology

Marcet-Houben, M., Collado-Cala, I., Fuentes-Palacios, D., Gómez, A. D., Molina, M., Garisoain-Zafra, A., … Gabaldón, T. (2023). EvolClustDB: exploring eukaryotic gene clusters with evolutionarily conserved genomic neighbourhoods. Journal of Molecular Biology, (168013), 168013. doi:10.1016/j.jmb.2023.168013 

The search also revealed that there were multiple CF found in the insect dataset containing Frataxin homologs (CI_005786, CI_005711, CI_005644, CI_000213, among others) and in the fungal dataset (CF_012296 and CF_009163). This shows that the Frataxin genomic context tends to be conserved, but that the specific neighboring genes are clade-specific. The functional relationship between the Frataxin-surrounding genes and Frataxin in the different clades is unknown and deserves further investigation.

Liquid chromatography-mass spectrometry analysis of frataxin proteoforms in whole blood as biomarkers of the genetic disease friedreich’s ataxia

Rojsajjakul, T., Wu, L., Grady, C. B., Hwang, W.-T., Mesaros, C., Lynch, D. R., & Blair, I. A. (2023). Liquid chromatography-mass spectrometry analysis of frataxin proteoforms in whole blood as biomarkers of the genetic disease friedreich’s ataxia. Analytical Chemistry. doi:10.1021/acs.analchem.3c00091 

These findings auger well for using frataxin levels measured by the validated stable isotope dilution ultrahigh-performance liquid chromatography–multiple reaction monitoring/mass spectrometry assay to monitor therapeutic interventions and the natural history of FRDA. Our study also illustrates the utility of using whole blood for protein disease biomarker discovery and validation.

Substitution to hydrophobic linker and formation of host-guest complex enhanced the effect of synthetic transcription factor made of pyrrole-imidazole polyamide

Hatanaka J, Hashiya K, Bando T, Sugiyama H. Substitution to hydrophobic linker and formation of host-guest complex enhanced the effect of synthetic transcription factor made of pyrrole-imidazole polyamide. Bioorganic & Medicinal Chemistry. 2023 Feb;81:117208. DOI: 10.1016/j.bmc.2023.117208. PMID: 36780807. 

Here, we report the synthesis of a compound that increases the transcription of FXN in cells derived from an FRDA patient. The compound was effective in lower (one tenth) concentration than the compound that previously reported. High concentration of the compound is toxic, but toxicity was reduced with a host-guest complex.

Removal of the GAA repeat in the heart of a Friedreich’s ataxia mouse model using CjCas9

Pouiré Yaméogo, Catherine Gérard, Nathalie Majeau & Jacques P. Tremblay. Removal of the GAA repeat in the heart of a Friedreich’s ataxia mouse model using CjCas9. Gene Ther (2023). doi:10.1038/s41434-023-00387-0

We are therefore aiming to develop FRDA treatment based on the deletion of GAAr with CRISPR/Cas9 technology using a single AAV expressing a small Cas9 (CjCas9) and two single guide RNAs (sgRNAs) targeting the FXN gene. This AAV was intraperitoneally administrated to YG8sR (250–300 GAAr) and to YG8-800 (800 GAAr) mice. DNA and RNA were extracted from different organs a month later. PCR amplification of part of intron 1 of the FXN gene detected some GAAr deletion in some cells in heart and liver of both mouse models, but the editing rate was not sufficient to cause an increase in frataxin mRNA in the heart. However, the correlation observed between the editing rate and the distribution of AAV suggests a possible therapy based on the removal of the GAAr with a better delivery tool of the CRISPR/Cas9 system.

Pathways to healing: plants with therapeutic potential for neurodegenerative diseases

Tyler, S. E. B., & Tyler, L. D. K. (2023). Pathways to healing: plants with therapeutic potential for neurodegenerative diseases. IBRO Neuroscience Reports. doi:10.1016/j.ibneur.2023.01.006 

This study aimed to find plants with therapeutic bioactivities for a range of NDs. 1339 of the 2001 plant species were found to have a bioactivity from the literature of therapeutic relevance to NDs such as Parkinson’s disease, Huntington’s disease, AD, motor neurone diseases, multiple sclerosis, prion diseases, Neimann-Pick disease, glaucoma, Friedreich's ataxia and Batten disease. 43 types of bioactivities were found, such as reducing protein misfolding, neuroinflammation, oxidative stress and cell death, and promoting neurogenesis, mitochondrial biogenesis, autophagy, longevity, and anti-microbial activity. Ethno-led plant selection was more effective than random selection of plant species. Our findings indicate that ethnomedicinal plants provide a large resource of ND therapeutic potential.

Bioactive fumarate improves cardiac function and expands lifespan in Friedrech’s ataxia

Salinas, L., Figueroa, F., Montgomery, C. B., Thai, P. N., Chiamvimonvat, N., Dugar, S., Sen, S., Cortopassi, G., & Dedkova, E. N. (2023). Bioactive fumarate improves cardiac function and expands lifespan in Friedrech’s ataxia. Biophysical Journal, 122(3), 96a. doi:10.1016/j.bpj.2022.11.714 

 Friedreich's ataxia (FA) is a recessive ataxia caused by reduction of mitochondrial protein, frataxin (FXN). Cardiomyopathy is the leading cause of death in FA patients due to deficient FXN expression in the heart. We have developed a novel monomethyl fumarate prodrug, IMF, which has improved pharmacokinetic profile and compared its effect to fumarate prodrug dimethyl fumarate (DMF, Tecfidera).

Genome-Wide Identification, Characterization and Expression Profiling of Potato (Solanum tuberosum) Frataxin (FH)

Kurt F, Filiz E, Yildiz K, Akbudak MA. Genome-Wide Identification, Characterization and Expression Profiling of Potato (Solanum tuberosum) Frataxin (FH) Gene. Genes. 2023; 14(2):468. https://doi.org/10.3390/genes14020468 

The FH genes were found to have a lineage-specific distribution and were more conserved in monocots than in dicots. While multiple copies of FH genes have been reported in some species, including plants, only one isoform of FH was found in potato. The expression of StFH in leaves and roots was analyzed under two different abiotic stress conditions, and the results showed that StFH was upregulated more in leaves and that its expression levels increased with the severity of the stress. This is the first study to examine the expression of an FH gene under abiotic stress conditions.

Pseudodominance in Friedreich ataxia – impact of high prevalence of carriers and intrafamilial clinical variation

Malaquias, M.J., Oliveira, J., Santos, M., Brandão, A.F., Sardoeira, A., Sequeiros, J., Barros, J. and Damásio, J. (2023), Pseudodominance in Friedreich ataxia – impact of high prevalence of carriers and intrafamilial clinical variation. Mov Disord Clin Pract. Accepted Author Manuscript. https://doi.org/10.1002/mdc3.13694 

 Clinicians should be aware of the possibility of pseudodominance when facing an apparent autosomal dominant pedigree, particularly in disorders with high frequency of carriers and variable expression. Otherwise, genetic diagnoses may be delayed.

Small molecule modulators of chromatin remodeling: from neurodevelopment to neurodegeneration

Jiang D, Li T, Guo C, Tang TS, Liu H. Small molecule modulators of chromatin remodeling: from neurodevelopment to neurodegeneration. Cell & Bioscience. 2023 Jan;13(1):10. DOI: 10.1186/s13578-023-00953-4. PMID: 36647159; PMCID: PMC9841685. 

This review first gives an overview of the regulatory mechanisms of chromatin remodeling. We then focus mainly on discussing the physiological functions of chromatin remodeling, particularly histone and DNA modifications and the four classes of ATP-dependent chromatin-remodeling enzymes, in the central and peripheral nervous systems under healthy and pathological conditions, that is, in neurodegenerative disorders. Finally, we provide an update on the development of potent and selective small molecule modulators targeting various chromatin-modifying proteins commonly associated with neurodegenerative diseases and their potential clinical applications.

Leveraging Computational Intelligence Techniques for Diagnosing Degenerative Nerve Diseases: A Comprehensive Review, Open Challenges, and Future Research Directions

Bhachawat S, Shriram E, Srinivasan K, Hu YC. Leveraging Computational Intelligence Techniques for Diagnosing Degenerative Nerve Diseases: A Comprehensive Review, Open Challenges, and Future Research Directions. Diagnostics (Basel, Switzerland). 2023 Jan;13(2):288. DOI: 10.3390/diagnostics13020288. PMID: 36673100; PMCID: PMC9858227. 

 Negenerative nerve diseases have been a popular topic of interest for a very long time. These disorders are untreatable and worsen the patient’s condition with time. The only measure we can currently take is to slow down the progression of these diseases. The early diagnosis of these diseases can enable patients to practice preventive measures before the disease progresses to an uncontrollable stage; hence, the early diagnosis and progression tracking of these disorders are crucial. Through this paper, we assessed the role of machine learning and deep learning in the diagnosis of these disorders and identified various algorithms that have shown promising results when used for the diagnosis of degenerative nerve diseases.

Comparative multi-omics analyses of cardiac mitochondrial stress in three mouse models of frataxin deficiency

Sayles, N. M., Napierala, J. S., Anrather, J., Diedhiou, N., Li, J., Napierala, M., Puccio, H., & Manfredi, G. (2023). Comparative multi-omics analyses of cardiac mitochondrial stress in three mouse models of frataxin deficiency. bioRxiv; doi:10.1101/2023.02.03.526305 

Transcriptional changes were found in all models, but differentially expressed genes consistent with cardiomyopathy and ISRmt were only identified in FxnG127V hearts. However, these changes were surprisingly mild even at an advanced age (18-months), despite a severe decrease in FXN levels to 1% of WT. These findings indicate that the mouse heart has extremely low reliance on FXN, highlighting the difficulty in modeling genetically relevant FA cardiomyopathy.

Synaptic activity regulates mitochondrial iron metabolism to enhance neuronal bioenergetics

Tena-Morraja, P., Riqué-Pujol, G., Müller-Sánchez, C., Reina, M., Martínez-Estrada, O. M., & Soriano, F. X. (2023). Synaptic activity regulates mitochondrial iron metabolism to enhance neuronal bioenergetics. International Journal of Molecular Sciences, 24(2), 922. doi:10.3390/ijms24020922 

 We show that an episode of synaptic activity increases mitochondrial bioenergetics beyond the duration of the synaptic activity by transcriptionally inducing the expression of iron metabolism genes with the consequent enhancement of cellular and mitochondrial iron uptake. Iron is a necessary component of the electron transport chain complexes, and its chelation or knockdown of mitochondrial iron transporter Mfrn1 blocks the activity-mediated bioenergetics boost. We found that Mfrn1 expression is regulated by the well-known regulator of synaptic plasticity CREB, suggesting the coordinated expression of synaptic plasticity programs with those required to meet the associated increase in energetic demands

Redox sensitive human mitochondrial aconitase and its interaction with frataxin: In vitro and in silico studies confirm that it takes two to tango

Mansilla, S., Tórtora, V., Pignataro, F., Sastre, S., Castro, I., Chiribao, M. L., Robello, C., Zeida, A., Santos, J., & Castro, L. (2023). Redox sensitive human mitochondrial aconitase and its interaction with frataxin: In vitro and in silico studies confirm that it takes two to tango. Free radical biology & medicine, S0891-5849(23)00049-7. Advance online publication. doi:10.1016/j.freeradbiomed.2023.01.028 

 Multimer modeling and protein-protein docking predicted an ACO2-FXN complex where the metal ion binding region of FXN approaches the [3Fe-4S]+ cluster, supporting that FXN is a partner for reactivation of ACO2 upon oxidative cluster inactivation.

Brain-protective mechanisms of autophagy associated circRNAs: Kick starting self-cleaning mode in brain cells via circRNAs as a potential therapeutic approach for neurodegenerative diseases

Basri, R., Awan, F. M., Yang, B. B., Awan, U. A., Obaid, A., Naz, A., Ikram, A., Khan, S., Haq, I. U., Khan, S. N., & Aqeel, M. B. (2023). Brain-protective mechanisms of autophagy associated circRNAs: Kick starting self-cleaning mode in brain cells via circRNAs as a potential therapeutic approach for neurodegenerative diseases. Frontiers in molecular neuroscience, 15, 1078441. doi:10.3389/fnmol.2022.1078441

 

n this review, we aimed to summarize the latest studies on the role of brain-protective mechanisms of autophagy associated circRNAs in neurodegenerative diseases (including Alzheimer's disease, Parkinson's disease, Huntington's disease, Spinal Muscular Atrophy, Amyotrophic Lateral Sclerosis, and Friedreich's ataxia) and how this knowledge can be leveraged for the development of novel therapeutics against them. Autophagy stimulation might be potential one-size-fits-all therapy for neurodegenerative disease as per considerable body of evidence, therefore future research on brain-protective mechanisms of autophagy associated circRNAs will illuminate an important feature of nervous system biology and will open the door to new approaches for treating neurodegenerative diseases.

Omaveloxolone: An activator of Nrf2 for the treatment of Friedreich's ataxia

Profeta, V., McIntyre, K., Wells, M., Park, C., & Lynch, D. R. (2023). Expert opinion on investigational drugs, 10.1080/13543784.2023.2173063. Advance online publication. doi:10.1080/13543784.2023.2173063 

 Although the neurologic phenotype of FRDA is well-defined, there are currently no established pharmacological treatments. Omaveloxolone, a nuclear factor erythroid 2-related factor 2 (Nrf2) activator, is currently under review by the Food and Drug Administration (FDA) and has the potential to be the first approved treatment for FRDA. In the present report, we have reviewed the basic and clinical literature on Nrf2 deficiency in FRDA, and evidence for the benefit of omaveloxolone.

Iron Metabolism in Cardiovascular Disease: Physiology, Mechanisms, and Therapeutic Targets

Konrad Teodor Sawicki, Adam De Jesus and Hossein Ardehali; Circulation Research. 2023;132:379–396, doi:10.1161/CIRCRESAHA.122.321667 

 Iron dysregulation ranges from iron deficiency to iron overload and is seen in many types of cardiovascular disease, including heart failure, myocardial infarction, anthracycline-induced cardiotoxicity, and Friedreich’s ataxia. Recently, the use of intravenous iron therapy has been advocated in patients with heart failure and certain criteria for iron deficiency. Here, we provide an overview of systemic and cellular iron homeostasis in the context of cardiovascular physiology, iron deficiency, and iron overload in cardiovascular disease, current therapeutic strategies, and future perspectives.

Deficient mitochondrial respiration impairs sirtuin activity in dorsal root ganglia in Friedreich Ataxia mouse and cell models

Arabela Sanz-Alcazar, Elena Britti, Fabien Delaspre, Marta Medina-Carbonero, Maria Pazos-Gil, Jordi Tamarit, Joaquim ROS, Elisa Cabiscol bioRxiv 2023.02.01.526688; doi:10.1101/2023.02.01.526688

In the present study, we found that in primary cultures of DRG neurons as well as in DRGs from the FXNI151F mouse model, frataxin deficiency resulted in lower activity and levels of the electron transport complexes, mainly complexes I and II. As a consequence, the NAD+/NADH ratio was reduced and SirT3, a mitochondrial NAD+-dependent deacetylase, was impaired. We identified alpha tubulin as the major acetylated protein from DRG homogenates whose levels were increased in FXNI151F mice compared to WT mice.

Multifaceted nanoparticles: emerging mechanisms and therapies in neurodegenerative diseases

Mistretta, M., Farini, A., Torrente, Y., & Villa, C. (2023). Brain : a journal of neurology, awad014. Advance online publication. doi:10.1093/brain/awad014 

 This review focuses on the use of nanosystems as an encouraging therapeutic approach targeting molecular pathways involved in localized and systematic neurodegenerative diseases. Among this latter, Friedreich's ataxia is an untreatable complex multisystemic disorder and the most spread type of ataxia, that represents a test case to validate the clinical potential of therapeutic strategies based on nanoparticles with pleiotropic effects.