Insights into the effects of Friedreich ataxia on the left ventricle using T1 mapping and late gadolinium enhancement

Peverill RE, Lin KY, Fogel MA, Cheung MMH, Moir WS, Corben LA, et al. (2024) Insights into the effects of Friedreich ataxia on the left ventricle using T1 mapping and late gadolinium enhancement. PLoS ONE 19(5): e0303969. https://doi.org/10.1371/journal.pone.0303969

In conclusion, there is an association between diffuse interstitial LV myocardial fibrosis and genetic severity in FRDA, with this effect being independent of the FRDA-associated LV changes in LVEDVI and LVMI. Localised replacement fibrosis was found in a minority of subjects with FRDA, this minority including both children and adults, and subjects with and without a reduction of LVEF. In contrast to T1 mapping variables, LGE in subjects with a normal LVEF was not associated with genetic severity, and was also not associated with LVM or LVEDV, consistent with the development of LGE in FRDA having an idiosyncratic element. There is the potential for roles of both T1 mapping and LGE in the assessment and monitoring of the cardiomyopathy of FRDA, but information will be required about their prognostic significance, and more data will also be required regarding the reproducibility of T1 mapping variables.

Larimar Therapeutics Selected by FDA to Participate in START Pilot Program for Nomlabofusp in Friedreich’s Ataxia

BALA CYNWYD, Pa., May 30, 2024 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (Larimar).United States Food and Drug Administration (FDA) has selected nomlabofusp to participate in the Support for Clinical Trials Advancing Rare Disease Therapeutics (START) pilot program. 

The START pilot program was launched by the FDA in September 2023 to further accelerate the pace of development, with an initial selection of up to six novel drugs, three by the Center for Drug Evaluation and Research (CDER) and three by the Center for Biologics Evaluation and Research (CBER), intended to treat a rare disease or other serious condition with high unmet medical need through an enhanced mechanism for communication with the FDA. Sponsors selected can benefit from more frequent and rapid ad-hoc interactions with the FDA to help facilitate the development of programs to the pivotal clinical study or pre-BLA meeting stage, and to generate high-quality and reliable data intended to support a BLA or New Drug Application (NDA). 

 Nomlabofusp is currently being evaluated in an ongoing open label extension (OLE) study to assess the long-term safety and tolerability, pharmacokinetics, and frataxin levels in peripheral tissues in patients with FA. Interim data from the OLE study is expected in the fourth quarter of 2024.

An In Silico Analysis of Genetic Variants and Structural Modeling of the Human Frataxin Protein in Friedreich’s Ataxia

Da Conceição, L.M.A.; Cabral, L.M.; Pereira, G.R.C.; De Mesquita, J.F. An In Silico Analysis of Genetic Variants and Structural Modeling of the Human Frataxin Protein in Friedreich’s Ataxia. Int. J. Mol. Sci. 2024, 25, 5796. doi:10.3390/ijms25115796 

Overall, 226 missense mutations in human frataxin were compiled from the literature and databases, which underwent a thoroughly functional characterization in silico. This study also provided an unprecedented, complete, and accurate three-dimensional model of human frataxin, serving as a basis for constructing the structure of clinically relevant variants, I154F and W155R. Our MD findings suggest that these mutations disturb FXN’s inherent structure and dynamics, primarily within the N-terminal domain. This behavior could compromise the protein’s ability to adopt functional conformations, potentially leading to impaired recognition and cleavage by the MPP protein, which is directly involved in FXN maturation, as outlined in previous studies. Thus, our findings provide valuable insights into the molecular basis of FXN dysfunction in FRDA, shedding light on future directions that could be explored for developing new therapeutic strategies.

Patient experiences of interprofessional collaboration and intersectoral communication in rare disease healthcare in Germany – a mixed-methods study

Inhestern, L., Otto, R., Brandt, M. et al. Patient experiences of interprofessional collaboration and intersectoral communication in rare disease healthcare in Germany – a mixed-methods study. Orphanet J Rare Dis 19, 197 (2024). doi:10.1186/s13023-024-03207-9 

Our findings indicate the high relevance of transferring affected patients to specialized care as fast as possible to provide best medical treatment and increase patient satisfaction. Intersectoral collaboration should exceed written information exchange and should unburden patients of being and feeling responsible for communication between sectors and specialists. Results indicate a lack of inclusion of psychosocial aspects in routine care, which suggests opportunities for necessary improvements.

Friedreich Ataxia Caregiver-Reported Health Index: Development of a Novel, Disease-Specific Caregiver-Reported Outcome Measure

Seabury J, Varma A, Weinstein J, Rosero SJ, Engebrecht C, Khosa S, Zizzi C, Wagner ES, Alexandrou D, Cohen BL, Dilek N, Heatwole JM, Lynch DR, Park CC, Wells M, Subramony SH, Heatwole CR. Friedreich Ataxia Caregiver-Reported Health Index: Development of a Novel, Disease-Specific Caregiver-Reported Outcome Measure. Neurol Clin Pract. 2024 Jun;14(3):e200303. doi: 10.1212/CPJ.0000000000200300. Epub 2024 May 10. PMID: 38751829; PMCID: PMC11092940. 

Initial evaluation of the FACR-HI supports its content validity, test-retest reliability, and construct validity as a caregiver-reported outcome measure for assessing how pediatric individuals with FRDA feel and function. The FACR-HI provides a potential mechanism to quantify changes in multifactorial FRDA disease burden during future clinical trials.

Glial cell activation precedes neurodegeneration in the cerebellar cortex of the YG8-800 murine model of Friedreich’s ataxia

Glial cell activation precedes neurodegeneration in the cerebellar cortex of the YG8-800 murine model of Friedreich’s ataxia. Andrés Vicente-Acosta, Saúl Herranz-Martín, María Ruth Pazos, Jorge Galán-Cruz, Mario Amores, Frida Loria, Javier Díaz-Nido bioRxiv 2024.05.17.594658;  doi:10.1101/2024.05.17.594658 

Our results show how the YG8-800 mouse model exhibits a stronger phenotype than previous experimental murine models, reliably recapitulating some of the features observed in the human condition. Accordingly, this humanized model could represent a valuable tool to study Friedreich’s ataxia molecular disease mechanisms and for preclinical evaluation of possible therapies.

Glial overexpression of Tspo extends lifespan and protects against frataxin deficiency in Drosophila

Estelle Jullian, Maria Russi, Ema Turki, Margaux Bouvelot, Laura Tixier, Sandrine Middendorp, Elodie Martin, Véronique Monnier, Glial overexpression of Tspo extends lifespan and protects against frataxin deficiency in Drosophila, Biochimie, 2024, ISSN 0300-9084, doi:10.1016/j.biochi.2024.05.003. 

 We further overexpressed Tspo specifically in glial cells and observed improved survival. Finally, we investigated the effects of Tspo overexpression in healthy flies. Increased longevity was conferred by glial-specific overexpression, with opposite effects in neurons. Overall, this study highlights protective effects of glial TSPO in Drosophila both in a neurodegenerative and a healthy context.

Characterizing the molecular basis of Friedreich's ataxia using molecular dynamics

Characterizing the molecular basis of Friedreich's ataxia using molecular dynamics. Fox, David J., David R. Koes. Biophysical Journal, Volume 123, Issue 3, 138a, doi:10.1016/j.bpj.2023.11.950

Using weighted ensemble molecular dynamics, we are able to simulate the dynamics of this process both with and without FXN. From these simulations we are able to derive models of the mobile loop dynamics, FXN’s function, and how the lack of FXN in this process may cause FRDA. This work provides novel and necessary information for the understanding of FRDA as well as the development of treatments for FRDA.

An RNA-seq study in Friedreich ataxia patients identified hsa-miR-148a-3p as a putative prognostic biomarker of the disease

Vancheri, C., Quatrana, A., Morini, E. et al. An RNA-seq study in Friedreich ataxia patients identified hsa-miR-148a-3p as a putative prognostic biomarker of the disease. Hum Genomics 18, 50 (2024).doi:10.1186/s40246-024-00602-y

 Our findings support the evaluation of combined expression levels of different circulating miRNAs as potent epi-biomarkers in FRDA. Moreover, we found hsa-miR-148a-3p significantly over-expressed in Intermediate and Late-Onset Friedreich Ataxia patients’ group (IOG and LOG, respectively) compared to healthy individuals, indicating it as a putative prognostic biomarker in this pathology.

Larimar Therapeutics Announces FDA has Removed Partial Clinical Hold for Nomlabofusp Program in Friedreich’s Ataxia

BALA CYNWYD, Pa., May 20, 2024 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (Larimar) (Nasdaq: LRMR), a clinical-stage biotechnology company focused on developing treatments for complex rare diseases, today announced the U.S. FDA has removed the partial clinical hold previously placed on the company's nomlabofusp (CTI-1601) clinical program.

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, Long non-coding RNA TUG1 is down-regulated in Friedreich’s ataxia, Brain Communications, 2024;, fcae170, doi:10.1093/braincomms/fcae170 

This study identifies TUG1 as a potential blood-based biomarker for FRDA, showing consistent expression variance in human and mouse tissues related to disease severity and key FRDA pathways. It correlates with frataxin levels, indicating its promise as an early, non-invasive marker. TUG1 holds potential for FRDA monitoring and therapeutic development, meriting additional research.

Characterization of clinical serum cardiac biomarker levels in individuals with Friedreich ataxia

David R. Lynch, Sonal Sharma, Patrick Hearle, Nathaniel Greeley, Katherine Gunther, Medina Keita, Cassandra Strawser, Lauren Hauser, Courtney Park, Kimberly Schadt, Kimberly Y. Lin, Characterization of clinical serum cardiac biomarker levels in individuals with Friedreich ataxia, Journal of the Neurological Sciences, 2024, 123053, doi:10.1016/j.jns.2024.123053 

In subjects with multiple assessments, mean unprovoked troponin I levels decreased slightly over time. The presence of abnormal troponin I values and their levels were predicted by echocardiographic measures of hypertrophy. In addition, troponin I levels predicted long-term markers of clinical cardiac dysfunction over time to a modest degree. Consequently, troponin I values provide a marker of hypertrophy but only a minimally predictive biomarker for later cardiac manifestations of disease such as systolic dysfunction or arrhythmia.

Deciphering the ferroptosis pathways in dorsal root ganglia of Friedreich ataxia models. The role of LKB1/AMPK, KEAP1, and GSK3beta in the impairment of the NRF2 response

Deciphering the ferroptosis pathways in dorsal root ganglia of Friedreich ataxia models. The role of LKB1/AMPK, KEAP1, and GSK3beta in the impairment of the NRF2 response. Arabela Sanz-Alcazar, Marta Portillo-Carrasquer, Fabien Delaspre, Maria Pazos-Gil, Jordi Tamarit, Joaquim Ros, Elisa Cabiscol. bioRxiv 2024.05.10.593481; doi: 10.1101/2024.05.10.593481 

This study demonstrated that frataxin deficiency in DRG neurons disrupts iron homeostasis and the intricate regulation of molecular pathways affecting NRF2 activation and the cellular response to oxidative stress, leading to ferroptosis.

1. WO2024097772 - COMPOSITIONS AND METHODS FOR TREATMENT OF FRIEDREICH'S ATAXIA

N.º de publicación WO/2024/097772. Fecha de publicación 10.05.2024. Nº de la solicitud internacional PCT/US2023/078373. Fecha de presentación internacional 01.11.2023.

The present application provides compositions for treatment of Friedreich's Ataxia (FA). These include, but are not limited to, nucleic acid constructs and recombinant AAV7 vectors comprising a human frataxin 5' untranslated region (5'UTR FXN) and a human frataxin (FXN).

Ferrostatin-1 specifically targets mitochondrial iron-sulfur clusters and aconitase to improve cardiac function in Sirtuin 3 cardiomyocyte knockout mice

Ferrostatin-1 specifically targets mitochondrial iron-sulfur clusters and aconitase to improve cardiac function in Sirtuin 3 cardiomyocyte knockout mice, Cantrell, Aubrey C. et al. Journal of Molecular and Cellular Cardiology, Volume 0, Issue 0. DOI:10.1016/j.yjmcc.2024.05.003 

Inhibition of ferroptosis ameliorated cardiac dysfunction by specifically targeting mitochondrial aconitase and iron‑sulfur clusters. Blockade of mitochondrial ferroptosis may be a novel therapeutic target for mitochondrial cardiomyopathies.

Larimar Therapeutics Reports First Quarter 2024 Operating and Financial Results

BALA CYNWYD, Pa., May 09, 2024 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. In March 2024, the first patient was dosed in the OLE study evaluating daily subcutaneous injections of 25 mg of nomlabofusp self-administered or administered by a caregiver. Participants who completed treatment in the Phase 2 dose exploration study, or who previously completed a prior clinical trial of nomlabofusp, are potentially eligible to screen for the OLE study. The OLE study will evaluate the safety and tolerability, pharmacokinetics, and frataxin levels in peripheral tissues as well as other exploratory pharmacodynamic markers (lipid profiles and gene expression data) following long-term subcutaneous administration of nomlabofusp. Dose escalation in the OLE study is contingent on the FDA’s review of data from the 50 mg cohort of the Phase 2 study and available data from the OLE study, due to the continued partial clinical hold. Interim data is expected in the fourth quarter of 2024. In addition, clinical assessments collected during the study will be compared to data from a matched control arm derived from participants in the Friedreich’s Ataxia Clinical Outcomes Measures Study (FACOMS) database.

Stealth BioTherapeutics’ SBT-589 Shows Cardioprotective Effects in Preclinical Models of Friedreich Ataxia

May 3, 2024. New data on SBT-589 (Stealth BioTherapeutics) presented at the 2024 Wellcome Trust Conference on Mitochondrial Medicine – Therapeutic Development, held March 18-20, in Cambridge, England, demonstrated cardioprotective effects across preclinical models of Friedreich ataxia (FA).1,2 These findings support further development of SBT-589, a novel molecule that can act on mitochondrial pathways that are impaired, and suggest the compound could be a disease-modifying therapy in FA cardiomyopathy. 

Our major finding was that the novel compound, SBT-589, improved metrics of adverse cardiac growth (hypertrophy) in a highly aggressive mouse model of FA cardiomyopathy. Transgenic FA mice showed increased left ventricular mass (normalized to body weight) and increased left ventricular wall thickness compared with control mice. We found that 3 weeks of daily SBT-589 treatment prevented cardiac hypertrophy

Design Therapeutics Announces First Quarter 2024 Financial Results and Highlights Upcoming Program Milestones

CARLSBAD, Calif., May 08, 2024 (GLOBE NEWSWIRE) -- Design Therapeutics, Inc.Friedreich Ataxia (FA) Design’s new drug product for FA, DT-216P2, demonstrates an improved pharmacokinetic (PK) profile, injection site profile and sustained drug exposure in nonclinical studies compared to the prior formulation. Design is on track to complete GLP studies for DT-216P2 by year-end 2024 to start patient trials in 2025.

Elevated Bile Acid 3β,5α,6β-Trihydroxycholanoyl Glycine in a Subset of Adult Ataxias Including Niemann–Pick Type C

Motamed-Gorji, N.; Khalil, Y.; Gonzalez-Robles, C.; Khan, S.; Mills, P.; Garcia-Moreno, H.; Ging, H.; Tariq, A.; Clayton, P.T.; Giunti, P. Elevated Bile Acid 3β,5α,6β-Trihydroxycholanoyl Glycine in a Subset of Adult Ataxias Including Niemann–Pick Type C. Antioxidants 2024, 13, 561. doi:10.3390/antiox13050561 

Patient No. 155 had a 3β,5α,6β-triOH-Gly of 159 nM. Analysis of the Frataxin gene (FXN) showed that the patient was compound heterozygous for two GAA expansions (length 75 and 101 bp), indicating a diagnosis of Friedreich’s ataxia (FRDA). This raises the question as to whether oxidation of cholesterol by ROS could play a role in the pathogenesis of FRDA, or at least, provide a marker of ROS damage.

Calcitriol Treatment Is Safe and Increases Frataxin Levels in Friedreich Ataxia Patients

Alemany-Perna, B., Tamarit, J., Cabiscol, E., Delaspre, F., Miguela, A., Huertas-Pons, J.M., Quiroga-Varela, A., Merchan Ruiz, M., López Domínguez, D., Ramió i Torrentà, L., Genís, D. and Ros, J. (2024), Calcitriol Treatment Is Safe and Increases Frataxin Levels in Friedreich Ataxia Patients. Mov Disord. doi:10.1002/mds.29808 

Although the patients did not experience any observable neurological improvement, there was a statistically significant increase in frataxin levels from initial values, 5.5 to 7.0 pg/μg after 12 months. Differences in frataxin levels referred to total protein levels were observed among sex- and age-matched controls (18.1 pg/μg), relative controls (10.1 pg/μg), and FRDA patients (5.7 pg/μg). The treatment was well tolerated by most patients, and only some of them experienced minor adverse effects at the beginning of the trial. 

Calcitriol dosage used (0.25 mcg/24 h) is safe for FRDA patients, and it increases frataxin levels. We cannot rule out that higher doses administered longer could yield neurological benefits.

Genetic Determined Iron Starvation Signature in Friedreich's Ataxia

Grander, M., Haschka, D., Indelicato, E., Kremser, C., Amprosi, M., Nachbauer, W., Henninger, B., Stefani, A., Högl, B., Fischer, C., Seifert, M., Kiechl, S., Weiss, G. and Boesch, S. (2024), Genetic Determined Iron Starvation Signature in Friedreich's Ataxia. Mov Disord. doi:10.1002/mds.29819

In conclusion, we collected multiple findings suggestive of a systemic and cellular iron starvation signature in FA whose severity is determined by the genotype. We provided for the first-time quantitative MRI data on iron storages and parenchyma state in liver, spleen, and pancreas in FA in vivo. Our findings argue against the use of surrogate measures of iron reduction as endpoints in clinical trials. They furthermore show that a stratification according to the genotype is necessary when addressing iron metabolism in FA. Overall, the present findings provide an indispensable clinical ground for the development of iron-targeting therapeutics in FA.

One-to-one Benefit provided by Antioxidants to cultured skin Fibroblasts from Friedreich Ataxia patients

One-to-one Benefit provided by Antioxidants to cultured skin Fibroblasts from Friedreich Ataxia patients, Paule Bénit, Malgorzata Rak, Pierre Rustin, bioRxiv 2024.04.25.591088; doi: 10.1101/2024.04.25.591088 

Under conditions that force the cells to rely on mitochondrial activity, we observed significant yet variable FRDA cell proliferation. These conditions were thereafter used to screen the effectiveness of a set of antioxidant molecules targeting different steps of the pro-oxidant cascade previously documented in FRDA, i.e. Uridine, Pyruvate, and Pioglitazone, to prevent or slow down cell mortality. We observed a surprising variability of response to antioxidant molecules even under the similar, controlled conditions used to culture patient’s fibroblasts. We conclude that the specific response of each individual already discernable at cellular level may well play an important role in the frequent difficulties encounter to reach firm conclusions when testing the capacity of antioxidants to counteract the consequences of frataxin depletion, including in clinical trials.

Astellas' Friedreich’s ataxia gene therapy cleared for clinical study after earlier version stumbled

April 25, 2024. Astellas' Friedreich’s ataxia gene therapy cleared for clinical study after earlier version stumbled. On Thursday, the Japanese drugmaker announced the FDA has cleared its IND for ASP2016.

Friedreich’s ataxia, a rare disease caused by the mutations in the gene for the protein frataxin, can cause both cardiac and neuromuscular complications, Wilson said. Addressing both in a single shot, as Astellas and several other companies had tried to do, turned out to be an “incredibly complicated problem” because of challenges in distribution, expression levels and therapeutic window, he said. 

 Frataxin, as Wilson put it, is “one of those Goldilocks proteins” — either having too much or too little would be dangerous. With ASP2016, which targets the cardiac complications of the condition, Astellas employed a mild promoter so that the AAV8-delivered gene therapy produces “just enough” protein in the target tissue.

“Our intention really has been to try and get as many cardiomyocytes transduced as we can, but not to produce such an overwhelming amount of frataxin protein that it would produce toxicity".

 The company is hoping to dose the first patient in the second half of 2024.

Alterity Therapeutics Presents New Data Demonstrating Potential of ATH434 to Treat Rare Neurodegenerative Disease Friedreich’s Ataxia

MELBOURNE, Australia and SAN FRANCISCO, April 29, 2024 (GLOBE NEWSWIRE) -- Alterity Therapeutics (ASX: ATH, NASDAQ: ATHE) (“Alterity” or “the Company”), a biotechnology company dedicated to developing disease modifying treatments for neurodegenerative diseases, today announced that important new data on its lead drug candidate ATH434 was presented at the World Orphan Drug Congress USA 2024 in Boston, MA. 

The poster, entitled, “Biophysical Characteristics of ATH434, a Unique Iron-Targeting Drug for Treating Friedreich’s Ataxia”, was presented by Ashley Pall, Department of Pharmaceutical Sciences at Wayne State University. The study evaluated the ability of ATH434 to target the toxic form of iron that drives the pathology of Friedreich’s Ataxia

Opinion: Larimar Could Compete with Biogen in Friedreich’s Ataxia

BioSpace. Published: Apr 29, 2024. n February 2024, Larimar Therapeutics released positive Phase II data for its injectable subcutaneous investigational agent nomlabofusp in treating Friedreich’s ataxia, a rare disease that causes neuromuscular degeneration. The data indicate that Larimar could go head-to-head in the market with Biogen's Skyclarys, the only disease-specific therapy for Friedreich’s ataxia to so far receive FDA approval.

Inherited metabolic disorders in Cyprus

Theodoros Georgiou, Petros P. Petrou, Anna Malekkou, Ioannis Ioannou, Marina Gavatha, Nicos Skordis, Paola Nicolaidou, Irini Savvidou, Emilia Athanasiou, Sofia Ourani, Elena Papamichael, Marios Vogazianos, Maria Dionysiou, Gabriella Mavrikiou, Olga Grafakou, George A. Tanteles, Violetta Anastasiadou, Anthi Drousiotou, Inherited metabolic disorders in Cyprus, Molecular Genetics and Metabolism Reports, Volume 39, 2024, 101083, ISSN 2214-4269, doi:10.1016/j.ymgmr.2024.101083. 

The Cypriot population has a unique genetic composition which differs significantly from that of its neighbours. This was the result of enrichment of the local genetic pool by the genes of numerous “visitors” to the island, whether as conquerors (Persians, Arabs, Franks, Venetians and Turks) or as immigrants (Maronites, Armenians). Founder effects have been described for many genetic disorders in addition to Sandhoff's and GM1 gangliosidosis: familial Mediterranean fever, cystic fibrosis, Friedreich's ataxia and 21-hydroxylase deficiency.

Mitochondria function in cytoplasmic FeS protein biogenesis

Andrew Dancis, Ashutosh K. Pandey, Debkumar Pain, Mitochondria function in cytoplasmic FeS protein biogenesis, Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Volume 1871, Issue 5, 2024, 119733, ISSN 0167-4889, doi:10.1016/j.bbamcr.2024.119733.