Patient Dosing Complete for Part 1 of Gene Therapy Trial in Friedreich Ataxia Cardiomyopathy

Neurologylive; Jul 20, 2023. According to a recent announcement, patient dosing in the first cohort of the SUNRISE-FA study (NCT05445323), a phase 1/2 trial assessing LX2006 (Lexeo Therapeutics), an adeno-associated virus (AAV) gene therapy, in patients with friedreich ataxia (FA) cardiomyopathy, has completed. 

The first patient in the second dose cohort of the trial has commenced as well. Thus far, preliminary data from the first dose cohort indicated that the therapy was well tolerated, with no unexpected events or toxicities.

 "We look forward to continuing to progress this program with data readouts expected in the first half of 2024."

Quantification of human mature frataxin protein expression in nonhuman primate hearts after gene therapy

Ian Blair, Teerapat Rojsajjakul, Juliette Hordeaux et al. Quantification of human mature frataxin protein expression in nonhuman primate hearts after gene therapy, 29 June 2023, PREPRINT (Version 1) available at Research Square doi:10.21203/rs.3.rs-3121549/v1 

Therefore, increasing expression of heart hFXN-M using gene therapy offers a way to prevent early mortality in FRDA. We used rhesus macaque monkeys to test the pharmacology of an adeno-associated virus (AAV)hu68.CB7.hFXN therapy. The advantage of using non-human primates for hFXN-M gene therapy studies is that hFXN-M and monkey FXN-M (mFXN-M) are 98.5% identical, which limits potential immunologic side-effects.

PPAR-gamma agonist pioglitazone recovers mitochondrial quality controls in fibroblasts from PITRM1-deficient patients

DArio Brunetti, A. D., Donfrancesco, C., Berlingieri, C., Frascarelli, M., Giacomello, A. P., Magalhaes Rebelo, L., Bindoff, S., Reeval, P., Filippo, M., Santorelli, G., Massaro, C. F., Viscomi, M., & Zeviani, D. (s/f). PPAR-gamma agonist pioglitazone recovers mitochondrial quality controls in fibroblasts from PITRM1-deficient patients. Front. Pharmacol. Sec. Experimental Pharmacology and Drug Discovery, 14. doi:10.3389/fphar.2023.1220620 

 We found that the pharmacological stimulation of Peroxisome Proliferator-Activated Receptor Gamma (PPARG) by Pioglitazone upregulates IDE and also PITRM1 protein levels restoring the presequence processing machinery and improving Frataxin maturation and mitochondrial function. Our findings provide mechanistic insights and suggest a potential pharmacological strategy for this rare neurodegenerative mitochondrial disease.

Non-B DNA structures as a booster of genome instability

Renée C. Duardo, Federico Guerra, Simona Pepe, Giovanni Capranico, Non-B DNA structures as a booster of genome instability, Biochimie, 2023, ISSN 0300-9084, doi:10.1016/j.biochi.2023.07.002.

Transcription-dependent R-loops can also alter the expression levels of genes involved in various disorders. For example, it has been reported that R-loops cause gene silencing at expanded trinucleotide repeats at FXN and FMR1 genes consequently proving an R-loop role in Friedreich's ataxia and X fragile syndrome. Anyway, transcription-mediated R-loop harmful effects are mostly related to the replication process.

Targeting Ion Channels and Purkinje Neuron Intrinsic Membrane Excitability as a Therapeutic Strategy for Cerebellar Ataxia

Huang H, Shakkottai VG. Targeting Ion Channels and Purkinje Neuron Intrinsic Membrane Excitability as a Therapeutic Strategy for Cerebellar Ataxia. Life (Basel, Switzerland). 2023 Jun;13(6):1350. DOI: 10.3390/life13061350. PMID: 37374132; PMCID: PMC10302946. 

We further propose that treatments aimed at restoring Purkinje neuron intrinsic membrane excitability have the potential to be a shared therapy in cerebellar ataxia akin to levodopa for Parkinson's disease.

Novel Therapeutic Approaches in Inherited Neuropathies: A Systematic Review

Hustinx M, Shorrocks AM, Servais L. Novel Therapeutic Approaches in Inherited Neuropathies: A Systematic Review. Pharmaceutics. 2023 May;15(6):1626. DOI: 10.3390/pharmaceutics15061626. PMID: 37376074; PMCID: PMC10305260.

 Multiple trials have been conducted in subjects with FRDA in recent years, and our search yielded seven publications since 2018, assessing six different drugs. Most trials used the Friedreich Ataxia Rating Scale (FARS) or modified FARS (mFARS), 9-hole peg test (9HPT), and 25 or 8 min walk tests to assess the efficacies of the drugs. However, none of these tests are specific to neuropathy progression.

Direct Cysteine Desulfurase Activity Determination by NMR and the Study of the Functional Role of Key Structural Elements of Human NFS1

Sewell KE, Gola GF, Pignataro MF, et al. Direct Cysteine Desulfurase Activity Determination by NMR and the Study of the Functional Role of Key Structural Elements of Human NFS1. ACS Chemical Biology. 2023 Jul. DOI: 10.1021/acschembio.3c00147. PMID: 37410592.

We identified CTS as a key element that established interactions with ISCU2 and FXN concurrently; we found specific interactions that are established when FXN is present, reinforcing the idea that FXN not only forms part of the iron-sulfur cluster assembly site but also modulates the internal motions of ISCU2.

Alpha-tocopherylquinone differentially modulates claudins to enhance intestinal epithelial tight junction barrier via AhR and Nrf2 pathways

Ashwinkumar Subramenium Ganapathy, Kushal Saha, Alexandra Wang, Priya Arumugam, Viszwapriya Dharmaprakash, Gregory Yochum, Walter Koltun, Meghali Nighot, Gary Perdew, Todd A. Thompson, Thomas Ma, Prashant Nighot, Alpha-tocopherylquinone differentially modulates claudins to enhance intestinal epithelial tight junction barrier via AhR and Nrf2 pathways, Cell Reports, Volume 42, Issue 7,2023, 112705, doi:10.1016/j.celrep.2023.112705. 

 A clinical trial has examined the potential value of TQ in the treatment of Friedreich’s ataxia.

AI-based tools for the diagnosis and treatment of rare neurological disorders

Molnar, M.J., Molnar, V. AI-based tools for the diagnosis and treatment of rare neurological disorders. Nat Rev Neurol (2023). doi:10.1038/s41582-023-00841-y 

 AI-based methods have also been shown to accurately classify individuals with Friedreich ataxia and control individuals on the basis of kinematic biomarkers.

Decreased filamentous actin and tight junction protein expression, and paracellular permeability in Frataxin-deficient human brain microvascular endothelial cells – implications for blood-brain barrier integrity in Friedreich's Ataxia

Smith FM, Kosman DJ. Decreased filamentous actin and tight junction protein expression, and paracellular permeability in Frataxin-deficient human brain microvascular endothelial cells – implications for blood-brain barrier integrity in Friedreich's Ataxia. Research Square; 2023. DOI: 10.21203/rs.3.rs-3025871/v1. 

 We identified that insufficient FXN levels in the hBMVEC BBB model causes changes in cytoskeletal architecture and tight junction protein abundance, co-incident with increased barrier permeability. Changes in the integrity of the BBB may be related to patient brain iron accumulation, neuroinflammation, neurodegeneration, and stroke. Furthermore, our findings implicate other barrier cells, e.g. , the cardiac microvasculature, likely contributory also to disease pathology in FRDA.