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

SIRT3 Regulates Clearance of Apoptotic Cardiomyocytes by Deacetylating Frataxin

Jing Gao, Chenglin Huang, Linghui Kong, Wugang Zhou, Mengwei Sun, Tong Wei and Weili Shen. Circulation Research. 2023;0. Originally published 30 Aug 2023 doi:10.1161/CIRCRESAHA.123.323160  

We showed that SIRT3 deficiency exacerbated Ang II–induced downregulation of the efferocytosis receptor MerTK (c-Mer tyrosine kinase) and proinflammatory cytokine production, accompanied by disrupted mitochondrial iron homeostasis in cardiac macrophages. Quantitative acetylome analysis revealed that SIRT3 deacetylated FXN (frataxin) at lysine 189. Ang II attenuated SIRT3 activity and enhanced the acetylation level of FXN K189. Acetylated FXN further reduced the synthesis of ISCs (iron-sulfur clusters), resulting in mitochondrial iron accumulation. Phagocytic internalization of apoptotic cardiomyocytes increased myoglobin content, and derived iron ions promoted mitochondrial iron overload and lipid peroxidation. An iron chelator deferoxamine improved the levels of MerTK and efferocytosis, thereby attenuating proinflammatory macrophage activation. FXNK189R mice showed improved macrophage efferocytosis, reduced cardiac inflammation, and suppressed cardiac fibrosis.

Replication Stalling at Friedreich's Ataxia (GAA)n Repeats In Vivo

Maria M. Krasilnikova & Sergei M. Mirkin (2004) Replication Stalling at Friedreich's Ataxia (GAA)n Repeats In Vivo, Molecular and Cellular Biology, 24:6, 2286-2295, DOI: 10.1128/MCB.24.6.2286-2295.2004

 We believe that repeat-caused replication attenuation in vivo is due to triplex formation. The apparent link between the replication stalling and length polymorphism of the repeat points to a new model for the repeat expansion.

Longitudinal changes of SARA scale in Friedreich ataxia: Strong influence of baseline score and age at onset

Porcu, L., Fichera, M., Nanetti, L., Rulli, E., Giunti, P., Parkinson, M.H., Durr, A., Ewenczyk, C., Boesch, S., Nachbauer, W., Indelicato, E., Klopstock, T., Stendel, C., Rodríguez de Rivera, F.J., Schöls, L., Fleszar, Z., Giordano, I., Didszun, C., Castaldo, A., Rai, M., Klockgether, T., Pandolfo, M., Schulz, J.B., Reetz, K., Mariotti, C. and (2023), Longitudinal changes of SARA scale in Friedreich ataxia: Strong influence of baseline score and age at onset. Ann Clin Transl Neurol. doi:10.1002/acn3.51886 

 Analyses of statistical properties of SARA suggest a variable sensitivity of the scale at different disease stages, and provide important information for population selection and result interpretation in future clinical trials.

Sarepta Therapeutics to Collaborate With Lexeo on Heart Disease Gene Therapy Pipeline

Aug 28, 2023, NEW YORK – Sarepta Therapeutics has invested an undisclosed sum in Lexeo Therapeutics, and the two companies on Monday said they will explore opportunities to further develop gene therapies in Lexeo's preclinical pipeline for cardiovascular disease.