Frataxin deficiency in proprioceptive neurons is causal to inflammatory and glial responses in dorsal root ganglia

Frataxin deficiency in proprioceptive neurons is causal to inflammatory and glial responses in dorsal root ganglia, Pauline Meriau, Laure Weill, Hélène Puccio, Cendra Agulhon, bioRxiv 2024.04.16.589410; doi:10.1101/2024.04.16.589410 

Our study revealed that proprioceptor FXN deficiency causes major changes in inflammatory macrophage and SGC gene transcription as well as macrophage and SGC number, highlighting molecular and cellular pathways that were sequentially altered, thus representing temporal signatures of FA ganglionopathy progression.

Deciphering the mechanisms of gene silencing induced by triplet-repeat expansions

Deciphering the mechanisms of gene silencing induced by triplet-repeat expansions. Nat. Plants (2024). doi:10.1038/s41477-024-01673-4 

A triplet repeat expansion in Arabidopsis induces gene silencing that results in a severe growth defect. We show that an interplay between a SUMO protease and histone readers of active and inactive marks is required for this gene silencing, which highlights the importance of post-translational modifiers in chromatin remodelling. 

Uncovering key players in gene silencing: Insights into plant growth and human diseases. APRIL 19, 2024​. Monash University biologists have shed light on the intricate molecular mechanisms that are responsible for gene silencing induced by expanded repeats in an international study published today in Nature Plants.

Frataxin deficiency shifts metabolism to promote reactive microglia via glucose catabolism

NEWS PROVIDED BY Life Science Alliance - New York April 17, 2024

Immunometabolism investigates the intricate relationship between the immune system and cellular metabolism. This study delves into the consequences of mitochondrial frataxin (FXN) depletion, the primary cause of Friedreich’s ataxia (FRDA), a debilitating neurodegenerative condition characterized by impaired coordination and muscle control. By using single-cell RNA sequencing, we have identified distinct cellular clusters within the cerebellum of an FRDA mouse model, emphasizing a significant loss in the homeostatic response of microglial cells lacking FXN. Remarkably, these microglia deficient in FXN display heightened reactive responses to inflammatory stimuli. Furthermore, our metabolomic analyses reveal a shift towards glycolysis and itaconate production in these cells. Remarkably, treatment with butyrate counteracts these immunometabolic changes, triggering an antioxidant response via the itaconate-Nrf2-GSH pathways and suppressing the expression of inflammatory genes. Furthermore, we identify Hcar2 (GPR109A) as a mediator involved in restoring the homeostasis of microglia without FXN. Motor function tests conducted on FRDA mice underscore the neuroprotective attributes of butyrate supplementation, enhancing neuromotor performance. In conclusion, our findings elucidate the role of disrupted homeostatic function in cerebellar microglia in the pathogenesis of FRDA. Moreover, they underscore the potential of butyrate to mitigate inflammatory gene expression, correct metabolic imbalances, and improve neuromotor capabilities in FRDA. 

 Sciarretta F, Zaccaria F, Ninni A, Ceci V, Turchi R, Apolloni S, Milani M, Della Valle I, Tiberi M, Chiurchiù V, D'Ambrosi N, Pedretti S, Mitro N, Volontè C, Amadio S, Aquilano K, Lettieri-Barbato D. Frataxin deficiency shifts metabolism to promote reactive microglia via glucose catabolism. Life Sci Alliance. 2024 Apr 17;7(7):e202402609. doi: 10.26508/lsa.202402609. PMID: 38631900; PMCID: PMC11024345.

A genome-wide spectrum of tandem repeat expansions in 338,963 humans

Ya Cui, Wenbin Ye, Jason Sheng Li, Jingyi Jessica Li, Eric Vilain, Tamer Sallam, Wei Li, A genome-wide spectrum of tandem repeat expansions in 338,963 humans, Cell, Volume 187, Issue 9, 2024, Pages 2336-2341.e5, doi:10.1016/j.cell.2024.03.004. 

Similarly, the prevalence of expanded GAA TR units in FXN, linked to Friedreich ataxia (FRDA), is less prevalent in East Asian samples than in other ancestries (Figure S1B). This observation again mirrors the low frequency of reported cases of FRDA in Japan.

A clinical-stage Nrf2 activator suppresses osteoclast differentiation via the iron-ornithine axis

Yimin Dong, Honglei Kang, Renpeng Peng, Zheming Liu, Fuben Liao, Shi-an Hu, Weizhong Ding, Pengju Wang, Pengchao Yang, Meipeng Zhu, Sibo Wang, Minglong Wu, Dawei Ye, Xin Gan, Feng Li, Kehan Song, A clinical-stage Nrf2 activator suppresses osteoclast differentiation via the iron-ornithine axis, Cell Metabolism, 2024, doi:10.1016/j.cmet.2024.03.005. 

Activating Nrf2 by small molecules is a promising strategy to treat postmenopausal osteoporosis. However, there is currently no Nrf2 activator approved for treating chronic diseases, and the downstream mechanism underlying the regulation of Nrf2 on osteoclast differentiation remains unclear. Here, we found that bitopertin, a clinical-stage glycine uptake inhibitor, suppresses osteoclast differentiation and ameliorates ovariectomy-induced bone loss by activating Nrf2. Mechanistically, bitopertin interacts with the Keap1 Kelch domain and decreases Keap1-Nrf2 binding, leading to reduced Nrf2 ubiquitination and degradation. Bitopertin is associated with less adverse events than clinically approved Nrf2 activators in both mice and human subjects. Furthermore, Nrf2 transcriptionally activates ferroportin-coding gene Slc40a1 to reduce intracellular iron levels in osteoclasts. Loss of Nrf2 or iron supplementation upregulates ornithine-metabolizing enzyme Odc1, which decreases ornithine levels and thereby promotes osteoclast differentiation. Collectively, our findings identify a novel clinical-stage Nrf2 activator and propose a novel Nrf2-iron-ornithine metabolic axis in osteoclasts.

Emerging therapies for childhood-onset movement disorders

Vogt, Lindseya,∗; Quiroz, Vicenteb,∗; Ebrahimi-Fakhari, Dariusb,c. Emerging therapies for childhood-onset movement disorders. Current Opinion in Pediatrics 36(3):p 331-341, June 2024. | DOI: 10.1097/MOP.0000000000001354 

 We highlight reports of new small molecule drugs for Tourette syndrome, Friedreich's ataxia and Rett syndrome. We also discuss developments in gene therapy for aromatic l-amino acid decarboxylase deficiency and hereditary spastic paraplegia, as well as current work exploring optimization of deep brain stimulation and lesioning with focused ultrasound.

Perioperative management and outcomes for posterior spinal fusion in patients with Friedreich ataxia: A single-center, retrospective study

O'Brien EM, Neiswinter N, Lin KY, Lynch D, Baldwin K, Profeta V, Flynn JM, Muhly WT. Perioperative management and outcomes for posterior spinal fusion in patients with Friedreich ataxia: A single-center, retrospective study. Paediatr Anaesth. 2024 Apr 24. doi: 10.1111/pan.14896. Epub ahead of print. PMID: 38655751. 

Seventeen patients were included in the final analysis. The mean age was 15 ± 2 years old and 47% were female. Preoperatively, 35% were wheelchair dependent, 100% had mild-to-moderate hypertrophic cardiomyopathy with preserved systolic function and no left ventricular outflow tract obstruction, 29% were on cardiac medications, and 29% were on pain medications. Intraoperatively, 53% had transesophageal echocardiography monitoring; 12% had changes in volume status on echo but no changes in function. Numerous combinations of total intravenous anesthetic agents were used, most commonly propofol, remifentanil, and ketamine. Baseline neuromonitoring signals were poor in four patients and one patient lost signals, resulting in 4 (24%) wake-up tests. The majority (75%) were extubated in the operating room. Postoperative complications were high (88%) and ranged from minor complications like nausea/vomiting (18%) to major complications like hypotension/tachycardia (29%) and need for extracorporeal membrane oxygenation support in one patient (6%).

Localized Changes in Dentate Nucleus Shape and Magnetic Susceptibility in Friedreich Ataxia

Harding, I.H., Nur Karim, M.I., Selvadurai, L.P., Corben, L.A., Delatycki, M.B., Monti, S., Saccà, F., Georgiou-Karistianis, N., Cocozza, S. and Egan, G.F. (2024), Localized Changes in Dentate Nucleus Shape and Magnetic Susceptibility in Friedreich Ataxia. Mov Disord. doi:10.1002/mds.29816 

 Changes in the structure of the dentate nuclei in FRDA are not spatially uniform. Atrophy is greatest in areas with high gray matter density, whereas increases in susceptibility—reflecting iron concentration, demyelination, and/or gliosis—predominate in the medial white matter.

Vesigen to Present New Preclinical Data on Engineered ARMMs Technology at 2024 ASGCT Annual Meeting

Provided by Business Wire. Apr 22, 2024. Engineering ARMMs with Engagers to Direct Biodistribution to Specific Neurons as a Therapeutic Strategy for Friedreich Ataxia.

Lexeo Enters License Agreement for Friedreich Ataxia Treatment

04.22.24. LEXEO Therapeutics, Inc., a clinical stage genetic medicine company, entered an in-license agreement with Cornell University to expedite development of the investigational gene therapy candidate LX2006 for the treatment of Friedreich ataxia (FA) cardiomyopathy. Under the license agreement, Lexeo has acquired certain rights, including rights to current and future data generated in an ongoing investigator-initiated Phase 1A trial of AAVrh.10hFXN to treat FA cardiomyopathy (NCT05302271). 

The agreement will support Lexeo’s efforts to develop a potentially life-changing therapy for this unmet need. Lexeo previously licensed know-how relating to AAVrh.10hFXN from Weill Cornell Medicine and collaborated with researchers there to further study the candidate, which Lexeo refers to as LX2006. Lexeo is studying LX2006 in the company-sponsored, open label, dose-ascending, multicenter SUNRISE-FA Phase 1/2 trial (NCT05445323).

Recent Advances in the Treatment Strategies of Friedreich’s Ataxia: A Review of Potential Drug Candidates and their Underlying Mechanisms

S. Saini, Kumar Aman,A nil, Neha,Vijay, N. Ardra,Mangla, Bharti,Javed, Shamama,Kumar, Pankaj,Ahsan, Waquar, Recent Advances in the Treatment Strategies of Friedreich’s Ataxia: A Review of Potential Drug Candidates and their Underlying Mechanisms,Current Pharmaceutical Design, volume 30, issue , pages 1-18, year 2024, issn 1381-6128/1873-4286, doi 10.2174/0113816128288707240404051856  

While there has been significant progress in the development of treatment strategies for FRDA, further research is needed to optimize these approaches and identify the most effective and safe treatment options for patients. The integration of multiple therapeutic strategies may be necessary to achieve the best outcomes in FRDA management.

The Role of Verbal Fluency in the Cerebellar Cognitive Affective Syndrome Scale in Friedreich Ataxia

Corben LA, Blomfield E, Tai G, Bilal H, Harding IH, Georgiou-Karistianis N, Delatycki MB, Vogel AP. The Role of Verbal Fluency in the Cerebellar Cognitive Affective Syndrome Scale in Friedreich Ataxia. Cerebellum. 2024 Apr 20. doi: 10.1007/s12311-024-01694-x. Epub ahead of print. PMID: 38642239. 

 The presence of dysarthria in many individuals with ataxia, particularly FRDA, may confound results on some items of the CCAS-S resulting in false-positive scores. This study explored the relationship between performance on the CCAS-S and clinical metrics of disease severity in 57 adults with FRDA. In addition, this study explored the relationship between measures of intelligibility and naturalness of speech and scores on the CCAS-S in a subgroup of 39 individuals with FRDA. We demonstrated a significant relationship between clinical metrics and performance on the CCAS-S.

Muscular Dystrophy Association and Friedreich’s Ataxia Research Alliance Announce Collaborative Research Grant Using Novel Gene Editing Technology to Address Root Cause of Friedreich’s Ataxia Disease

NEW YORK, April 17, 2024 – The Muscular Dystrophy Association (MDA) and Friedreich’s Ataxia Research Alliance (FARA) announced today a collaborative grant for $300,000 awarded to Jonathan Watts, PhD, professor of RNA therapeutics; Erik Sontheimer, PhD, the Pillar Chair in Biomedical Research and professor of RNA therapeutics; Scot Wolfe, PhD, professor of molecular, cell & cancer biology; Wen Xue, PhD, associate professor of RNA therapeutics, a team of investigators at UMass Chan Medical School. This funding will further research into using novel genetic technologies to treat Friedreich’s ataxia (FA). The grant, Paired Prime Editors to treat Friedreich’s Ataxia, involves prime editing (PE), a next-generation CRISPR gene editing tool that can precisely target the removal of the GAA expansions in the frataxin (FXN) gene. 

The team will compare several PE approaches for their ability to remove the GAA repeats in FA cells with the goal to identify the optimal tool that can provide high efficiency of editing and reduced rate of off-target modifications to the genome. The investigators have also devised a system called split prime editing, in which two halves of the prime editing machinery are delivered as separate molecules. This approach allows them to rapidly test combinations of editing enzymes with desirable properties.

LEXEO THERAPEUTICS GRANTED FDA FAST TRACK DESIGNATION FOR LX2006, AN AAV-BASED GENE THERAPY CANDIDATE FOR THE TREATMENT OF FRIEDREICH’S ATAXIA CARDIOMYOPATHY

NEW YORK, April 16, 2024 (GLOBE NEWSWIRE) -- Lexeo Therapeutics, Inc. today announced the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to LX2006, the company’s AAVrh.10hFXN-based gene therapy candidate for the treatment of Friedreich’s ataxia (FA) cardiomyopathy. LX2006 is designed to deliver a functional frataxin gene to promote frataxin protein expression and restore mitochondrial function in myocardial cells.“We believe today’s Fast Track designation, along with the previously announced Rare Pediatric Disease and Orphan Drug designations granted to LX2006, will allow for enhanced regulatory interactions and the potential for this life-improving therapy to reach FA patients more quickly.” LX2006 is administered as a one-time intravenous infusion to patients in at least two ascending-dose cohorts with the potential for a third cohort. Long-term safety and efficacy will be evaluated for an additional four years following completion of the initial year of the trial, resulting in data from a total of five years post-LX2006 treatment.

Pharmacotherapeutic strategies for Friedreich Ataxia: a review of the available data

Gunther, K. and Lynch, D. R. (2024) ‘Pharmacotherapeutic strategies for Friedreich Ataxia: a review of the available data’, Expert Opinion on Pharmacotherapy. doi: 10.1080/14656566.2024.2343782. 

 The approval of omaveloxolone provides a major advance in FRDA therapeutics. Although well tolerated, it is not curative. Reversal of deficient frataxin levels with gene therapy, protein replacement, or epigenetic approaches provides the most likely prospect for enduring, disease modifying therapy in the future.

Expression and processing of mature human frataxin after gene therapy in mice

Rojsajjakul, T., Selvan, N., De, B. et al. Expression and processing of mature human frataxin after gene therapy in mice. Sci Rep 14, 8391 (2024). doi:10.1038/s41598-024-59060-0 

AAVrh.10hFXN induced mature hFXN expression in mouse heart and liver at levels that approximated endogenous mFXN levels. These results suggest that AAVrh.10hFXN can likely induce expression of therapeutic levels of mature hFXN in mice.

Chaperone function in Fe–S protein biogenesis: Three possible scenarios

Jaroslaw Marszalek, Elizabeth A. Craig, Marcin Pitek, Rafal Dutkiewicz, Chaperone function in Fe–S protein biogenesis: Three possible scenarios., Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Volume 1871, Issue 5, 2024, 119717, ISSN 0167-4889, doi:10.1016/j.bbamcr.2024.119717.

 

AAV gene therapy to treat Friedreich’s ataxia cardiomyopathy

Ferreira, J. AAV gene therapy to treat Friedreich’s ataxia cardiomyopathy. Lab Anim 53, 86 (2024). doi:10.1038/s41684-024-01351-0

NeuroVoices: Francesco Saccà, MD, PhD, on Crossing Over Dimethyl Fumarate in Friedriech Ataxia

NeurologyLive. April 3, 2024. We completed the enrollment in February. All 40 patients were enrolled. We are expecting to have the last patient last visit by the end of July. This means that we could probably get some data, at least the primary and many of the secondary endpoints, by September or October of this year. By the end of the year, we will close the entire analysis.

Approval of omaveloxolone for Friedreich ataxia

Boesch, S., Indelicato, E. Approval of omaveloxolone for Friedreich ataxia. Nat Rev Neurol (2024). doi:10.1038/s41582-024-00957-9 

The recent approval of omaveloxolone for the treatment of Friedreich ataxia in the USA and Europe represents an important milestone in the field of rare neurological diseases. However, many challenges lie ahead, including the translation of trial results into clinical practice, and the management of patients’ expectations.

Evaluating mFARS in pediatric Friedreich's ataxia: Insights from the FACHILD study

Rummey C, Perlman S, Subramony SH, Farmer J, Lynch DR. Evaluating mFARS in pediatric Friedreich's ataxia: Insights from the FACHILD study. Ann Clin Transl Neurol. 2024 Mar 31. doi: 10.1002/acn3.52057. Epub ahead of print. PMID: 38556905. 

Results confirmed the general usefulness of the mFARS score in children, but also highlighted issues, particularly with the upper limb subscore (FARS B). Increased variability, limited homogeneity across study subgroups, and potential training effects might limit mFARS application in clinical trials in pediatric populations. 

 Interpretation: The FARS E (Upright Stability) score might be a preferred outcome measure in this patient population.