CRISPR/Cas9-Based Edition of Frataxin Gene in Dictyostelium discoideum

Hernan Gustavo Gentili, María Florencia Pignataro, Justo Facundo Olmos, María Florencia Paván, Lorena Itatí Ibáñez, Javier Santos, Francisco Velazquez Duarte; CRISPR/Cas9-Based Edition of Frataxin Gene in Dictyostelium discoideum. Biochem J 2023; BCJ20230244. doi:10.1042/BCJ20230244 

The results of the study suggest that this new D. discoideum strain offers a wide range of possibilities to easily explore diverse FA FXN variants. This can facilitate the development of straightforward drug screenings to look for new therapeutic strategies.

Long non-coding RNA TUG1 is down-regulated in Friedreich's ataxia

Long non-coding RNA TUG1 is down-regulated in Friedreich's ataxia. Mert Koka, Hui Li, Rumana Akther, Susan Perlman, Darice Wong, Brent L Fogel, David R Lynch, Vijayendran Chandran, bioRxiv 2023.09.22.558879; doi: 10.1101/2023.09.22.558879 

This suggests that elevated TUG1 levels correlate with earlier onset and more severe cases. In summary, this study highlights Tug1 as a crucial blood-based biomarker for FRDA. Tug1's consistent expression variance across human and mouse tissues is closely associated to disease severity and key FRDA pathways. It also correlates strongly with Fxn levels, making it a promising early, non-invasive marker. TUG1 offers potential for FRDA monitoring and therapeutic development, warranting further clinical research.

Innovative thinking of clinical investigation for rare disease drug development

Wang, P., Chow, SC. Innovative thinking of clinical investigation for rare disease drug development. Orphanet J Rare Dis 18, 299 (2023). doi:10.1186/s13023-023-02909-w 

Many clinical trials for drug development are powered on effectiveness only, and safety issue is considered as the secondary objective. This practice has made some approved drugs have safety concerns, and some are even withdrawn or recalled. One possible reason for researchers not power on safety is that testing for safety requires a much larger sample size. As for orphan drug development, this problem is even worse due to the limited availability of participants.

Periodontal Treatment of Norwegian Patients With Rare Diseases: A Commentary

Øystein Fardal, Irene Skau, Jostein Grytten, Periodontal Treatment of Norwegian Patients With Rare Diseases: A Commentary, International Dental Journal, 2023, doi:10.1016/j.identj.2023.07.009. 

 An autosomal recessive disease that causes neurodegeneration. It results in muscle weakness and loss of sensation and proprioception, causing problems with movement as well as impaired speech. The symptoms tend to worsen as time progresses, so many patients end up in wheelchairs, lose their vision and hearing, and experience other medical complications such as diabetes mellitus and scoliosis. The cause of the disease is a reduction in frataxin, which is necessary for the production of mitochondrial adenosine triphosphate (ATP) and the management of iron stores. No previous connections with periodontal complications have been reported; however, diabetes is a known risk factor. In addition, the inability to perform adequate oral hygiene due to the disability may be an important risk factor.

Analytical Method and Stability Study for Oral Suspension of Idebenone in Syrspend

Porru, E.; Piro, F.; Comito, R.; Mosendz, A.; Minniti, E.; Conti, M.; Stancari, A.; Violante, F.S. Analytical Method and Stability Study for Oral Suspension of Idebenone in Syrspend. Separations 2023, 10, 517. doi:10.3390/separations10090517 

The greatest disadvantage of IDB is its low solubility in water, resulting in low bioavailability. Galenic preparations of IDB in customized doses are common for pediatric patients, which can often prove to be the only option for access to therapy. As an antioxidant, the chemical stability of IDB is an essential guarantee for exerting the desired antioxidant action. Stability studies are essential to know the effect of storage conditions of a galenic product. For the first time, a stability-indicating LC-MS method has been developed to define the stability of IDB suspensions in SyrSpend® Sugar-Free Unflavored (Fagron), a carrier phase formulated for setting up suspensions of active pharmaceutical ingredients (APIs) insoluble or poorly insoluble in water and compatible with it.

Patient-derived iPSC models of Friedreich ataxia: a new frontier for understanding disease mechanisms and therapeutic application

Maheshwari S, Vilema-Enríquez G, Wade-Martins R. Patient-derived iPSC models of Friedreich ataxia: a new frontier for understanding disease mechanisms and therapeutic application. Transl Neurodegener. 2023 Sep 20;12(1):45. doi: 10.1186/s40035-023-00376-8. PMID: 37726850. 

These models enable studies of the molecular mechanisms underlying GAA-induced pathology, as well as providing an exciting tool for the screening and testing of novel disease-modifying therapies. This review explores how the use of iPSCs to study FRDA has developed over the past decade, as well as discussing the enormous therapeutic potentials of iPSC-derived models, their current limitations and their future direction within the field of FRDA research.

Butyrate prevents visceral adipose tissue inflammation and metabolic alterations in a Friedreich’s ataxia mouse model

Turchi R, Sciarretta F, Ceci V, Tiberi M, Audano M, Pedretti S, Panebianco C, Nesci V, Pazienza V, Ferri A, Carotti S, Chiurchiù V, Mitro N, Lettieri-Barbato D, Aquilano K. Butyrate prevents visceral adipose tissue inflammation and metabolic alterations in a Friedreich's ataxia mouse model. iScience. 2023 Aug 28;26(10):107713. doi: 10.1016/j.isci.2023.107713. PMID: 37701569; PMCID: PMC10494209.  

Metagenomic analysis indicated a reduction in fecal butyrate-producing bacteria, known to exert antidiabetic effects. A butyrate-enriched diet restrained vWAT abnormalities and mitigated diabetes features in KIKO mice. Our work emphasizes the role of vWAT in FA-related metabolic issues and suggests butyrate as a safe and promising adjunct for FA management.

Neurologic orphan diseases: Emerging innovations and role for genetic treatments

Kioutchoukova IP, Foster DT, Thakkar RN, Foreman MA, Burgess BJ, Toms RM, Molina Valero EE, Lucke-Wold B. Neurologic orphan diseases: Emerging innovations and role for genetic treatments. World J Exp Med 2023; 13(4): 59-74 [DOI: 10.5493/wjem.v13.i4.59]. 

 Neurologic orphan diseases are rare conditions that impact a small percentage of the population. Through new advances in technology and research, the use of genetic treatment for these conditions is increasing. Recent advances in clustered regularly interspaced palindromic repeats/Cas9, adeno-associated viral vectors, antisense oligonucleotides, and mammalian target of rapamycin inhibitors have shown improvements in the care of patients and their quality of life.

SIRT3 Regulates Clearance of Apoptotic Cardiomyocytes by Deacetylating Frataxin

Jing Gao, Chenglin Huang, Linghui Kong, Wugang Zhou, Mengwei Sun, Tong Wei and Weili Shen; SIRT3 Regulates Clearance of Apoptotic Cardiomyocytes by Deacetylating Frataxin. Circulation ResearchVolume 133, Issue 7, 15 September 2023; Pages 631-647 doi:1161/CIRCRESAHA.123.323160  

The SIRT3-FXN axis has the potential to resolve cardiac inflammation by increasing macrophage efferocytosis and anti-inflammatory activities.

Friedreich's ataxia: new insights

Krasilnikova MM, Humphries CL, Shinsky EM. Friedreich's ataxia: new insights. Emerg Top Life Sci. 2023 Sep 12:ETLS20230017. doi: 10.1042/ETLS20230017. Epub ahead of print. PMID: 37698160. 

 Friedreich ataxia (FRDA) is an inherited disease that is typically caused by GAA repeat expansion within the first intron of the FXN gene coding for frataxin. This results in the frataxin deficiency that affects mostly muscle, nervous, and cardiovascular systems with progressive worsening of the symptoms over the years. This review summarizes recent progress that was achieved in understanding of molecular mechanism of the disease over the last few years and latest treatment strategies focused on overcoming the frataxin deficiency.

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

Nicole M. Sayles, Jill S. Napierala, Josef Anrather, Nadège Diedhiou, Jixue Li, Marek Napierala, Hélène Puccio, Giovanni Manfredi; Comparative multi-omics analyses of cardiac mitochondrial stress in three mouse models of frataxin deficiency. Dis Model Mech 2023; dmm.050114. doi: doi:10.1242/dmm.050114

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 low reliance on FXN, highlighting the difficulty in modeling genetically relevant FA cardiomyopathy.

Propensity matched comparison of omaveloxolone treatment to Friedreich ataxia natural history data

Lynch, D.R., Goldsberry, A., Rummey, C., Farmer, J., Boesch, S., Delatycki, M.B., Giunti, P., Hoyle, J.C., Mariotti, C., Mathews, K.D., Nachbauer, W., Perlman, S., Subramony, S.H., Wilmot, G., Zesiewicz, T., Weissfeld, L. and Meyer, C. (2023), Propensity matched comparison of omaveloxolone treatment to Friedreich ataxia natural history data. Ann Clin Transl Neurol. doi:10.1002/acn3.51897 

These results suggest a meaningful slowing of Friedreich ataxia progression with omaveloxolone, and consequently detail how propensity-matched analysis may contribute to understanding of effects of therapeutic agents. This demonstrates the direct value of natural history studies in clinical trial evaluations.

Proprioceptive and tactile processing in individuals with Friedreich Ataxia, an fMRI study

Destrebecq Virginie, Rovai Antonin, Trotta Nicola, Comet Camille, Gilles Naeije, Front. Neurol. Sec. Movement Disorders, Volume 14 - 2023, doi: 10.3389/fneur.2023.1224345

Our study captured the difference between tactile and proprioceptive impairments in FA using somatosensory fMRI paradigms. The lack of correlation between the proprioceptive paradigm and ataxia clinical parameters supports a low contribution of afferent ataxia to FA clinical severity