Omaveloxolone Driven NRF2 Activation as a Novel Therapeutic Strategy for Pulmonary Hypertension

Omaveloxolone Driven NRF2 Activation as a Novel Therapeutic Strategy for Pulmonary Hypertension. Huang, Chuangjia, Bai, June, Luo, Ang, Yang, Lei, Wang, Xingting, Dang, Linlin, Bao, Changlei, Zhu, Jinsheng, Chen, Zixuan, Wu, Bitao, Long, Jintao, Feng, Jieyi, Luo, Zinan, Xiao, Yingying, Sun, Hanliang, Liang, Shuxin, Zhang, Li, Hua, Jing, Gou, Demin, Desai, Ankit A., Li, Li, Zhang, Caojin, Chu, Aiai, Tang, Haiyangdoi:10.1161/HYPERTENSIONAHA.126.26711 Published Online: 2026-07-27 

 NRF2 expression and nuclear localization were reduced in PH lungs and hypoxia-exposed cells, whereas Omaveloxolone restored NRF2 activity and increased downstream antioxidant enzymes. In endothelial cells, Omaveloxolone reduced oxidative stress, suppressed inflammatory signaling, and inhibited endothelial-to-mesenchymal transition. In smooth muscle cells, it attenuated oxidative stress and normalized abnormal proliferation, migration, and apoptosis. Omaveloxolone reduced HIF (hypoxia-inducible factor)-2α accumulation in endothelial cells and inhibited HIF-1α stabilization in smooth muscle cells. NRF2 knockdown attenuated these effects, supporting pathway dependency. Omaveloxolone attenuated PH, reduced right ventricular hypertrophy and vascular remodeling, and improved right ventricular function across hypoxia, monocrotaline, and sugen/hypoxia models under both preventive and therapeutic regimens.

Larimar Therapeutics Reports Positive Open Label Data and Submission of First Module of Rolling BLA for Accelerated Approval of Nomlabofusp for Friedreich’s Ataxia

June 29, 2026. BALA CYNWYD, Pa., June 29, 2026 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (Larimar)  a clinical-stage biotechnology company focused on developing treatments for complex rare diseases, today announced it has submitted the first module of its rolling Biologics License Application (BLA) submission to the Food and Drug Administration (FDA) for accelerated approval of nomlabofusp. The OL study is evaluating the safety and tolerability, pharmacokinetics (PK), and frataxin (FXN) levels in skin and buccal cells, along with exploratory pharmacodynamic (PD) markers (lipid profiles and gene expression) and clinical outcomes following long-term subcutaneous administration of nomlabofusp. The OL study protocol has now been amended to include children 2-11 years of age, adolescents and adults who have not participated in a prior nomlabofusp study.

Characterizing Friedreich’s ataxia cardiomyopathy with serial cardiac magnetic resonance imagings

Cripe, L. H., Alvarado, C., Hayes, E. A., Krishnamurthy, R., Gunsaulus, M. E., Waldrop, M. A., & Nandi, D. (2026). Characterizing Friedreich’s ataxia cardiomyopathy with serial cardiac magnetic resonance imagings. Annals of Pediatric Cardiology, 19(4), 364–373. doi:10.4103/apc.apc_22_26 

In this exploratory study, CMR demonstrated patterns of septal hypertrophy, lateral wall fibrosis, and trends toward declining ventricular function. Findings were largely nonsignificant and should be considered hypothesis-generating. Larger, multicenter studies are needed to clarify the role of CMR in disease progression and clinical management.

Effects of Friedeich Ataxia on the Interrelations Between Left Ventricular Length and Long-Axis Systolic and Diastolic Excursions

R. Peverill, Effects of Friedeich Ataxia on the Interrelations Between Left Ventricular Length and Long-Axis Systolic and Diastolic Excursions, Heart, Lung and Circulation, Volume 35, Supplement 3, 2026, Page S142, doi:10.1016/j.hlc.2026.07.126. 

 Features of long-axis dysfunction in FRDA include: (i) a smaller contraction amplitude, which is partly attributable to a smaller LVEDL, and therefore has both structural and functional elements, (ii) smaller early diastolic excursion which is fully accounted for by smaller long-axis contraction, and (iii) lack of any compensatory increase in LA contraction, which is consistent with the presence of a concomitant LA myopathy.

Cardiomyocyte Dysfunction is Modulated by PCDHGA10 in Friedreich Ataxia,

J. Lees, H. Zhang, L. Jiao, A. Kong, R. Phang, L. Li, N. Su, A. Mukhtar, S. Bass-Stringer, A. Pébay, M. Dottori, L. Corben, M. Delatycki, R. Peverill, S. Wilcox, J. Choi, J. Pullin, D. McCarthy, J. Napierala, M. Napierala, S. Lim, Cardiomyocyte Dysfunction is Modulated by PCDHGA10 in Friedreich Ataxia, Heart, Lung and Circulation, Volume 35, Supplement 3, 2026, Pages S709-S710, doi:10.1016/j.hlc.2026.07.1148. 

Our human iPSC model captures early, clinically relevant features of FRDA cardiomyopathy and identifies PCDHGA10 as a disease-associated target within the γ-protocadherin family of calcium-dependent adhesion molecules. siRNA-mediated PCDHGA10 knockdown rescued cell survival, diastolic dysfunction, and mitochondrial ROS levels, implicating Ca2+-coupled and redox-linked phenotypes in cardiomyocyte dysfunction. These findings support further mechanistic study and therapeutic exploration of PCDHGA10

Design Therapeutics Provides RESTORE-FA Clinical Development Update and Reports Second Quarter 2026 Financial Results

CARLSBAD, Calif., Aug. 03, 2026 (GLOBE NEWSWIRE) -- Design Therapeutics, Inc..Positive 

RESTORE-FA Four-Week Data Support Advancement of DT-216P2. As reported in May 2026, DT-216P2 was generally well-tolerated and demonstrated dose-dependent increases in endogenous frataxin mRNA and protein levels, together with improvements across multiple clinical measures following four weeks of intravenous dosing in patients with Friedreich ataxia. 

Modifications to RESTORE-FA. Based on the four-week data, Design is modifying the ongoing cohorts in the RESTORE-FA trial to support the next stage of clinical development. The study will continue to evaluate 1 mpk as the planned go-forward dose, with the intention of enrolling 10 patients in the 12-week cohort. In addition, modifications include specifying endogenous blood FXN protein percent change from baseline as the primary efficacy endpoint and exploring a dose level above 1 mpk. 

Next Steps and Expected Milestones: Design expects to provide an update on its registrational plans in the fourth quarter of 2026, with data following 12 weeks of treatment expected in the first quarter of 2027.

Towards routine genetic testing of repeat expansions in neurogenetic diseases using multiplex CRISPR-Cas9-targeted long read sequencing

Fergelot, P., Boury, C., Penaud, B. et al. Towards routine genetic testing of repeat expansions in neurogenetic diseases using multiplex CRISPR-Cas9-targeted long read sequencing. Sci Rep (2026). doi:10.1038/s41598-026-64095-6 

 We simultaneously targeted nine loci involved in 10 repeat expansion disorders in a single capture panel, including FMR1, HTT, DMPK, CNBP/ZNF9, ATXN2, JPH3, FXN, C9ORF72 and RFC1, covering a broad range of repeat types, sizes and diagnostic needs. Results were compared with standard routine testing methods.

Clinical Challenges in Managing Diabetes Mellitus in Friedreich’s Ataxia

Aarya Naik, MBBS, Hooman Oktaei, MD, Clinical Challenges in Managing Diabetes Mellitus in Friedreich’s Ataxia, Endocrine Practice , 32, S66-S67. doi:10.1016/j.eprac.2026.01.168 

Friedreich’s ataxia (FRDA) is a multisystem disease, with ataxia being the most overt clinical feature. It can be complicated by diabetes mellitus. FRDA-related diabetes has been reported in 5% to 40% of children and adults. Despite the clinical relevance of FRDA-related diabetes mellitus, no evidence-based clinical practice guidelines for screening or management have been set.

CRISPR-Cas9-based therapies for Huntington's disease and Friedreich's ataxia: mechanisms, advances, and future perspectives

Mundada AR, Badikol AR, Mangu K. CRISPR-Cas9-based therapies for Huntington's disease and Friedreich's ataxia: mechanisms, advances, and future perspectives. Neurogenetics. 2026 Jul 13;27(1):49. doi: 10.1007/s10048-026-00921-3. PMID: 42439976. 

 This review examines current CRISPR therapeutic strategies for HD and FRDA, including allele-specific editing, transcriptional suppression, repeat excision, epigenetic reactivation, and emerging precision editing approaches such as base editing and prime editing. We compare the molecular rationale, preclinical outcomes, and translational limitations associated with each approach while highlighting how disease architecture influences therapeutic design. Although preclinical studies demonstrate promising restoration of cellular phenotypes and functional improvement, significant barriers remain. Efficient delivery to the central nervous system and cardiac tissue, control of editing duration, immune responses, off-target activity, and emerging concerns regarding on-target genomic instability continue to limit clinical translation. Recent advances in delivery engineering, non-viral systems, and programmable editing platforms suggest that future therapeutic success will depend on integrating disease-specific biology with increasingly precise and controllable genome engineering technologies. Ethical and regulatory concerns remain substantial, particularly regarding informed consent in the context of cognitive decline and the irreversibility of genomic modification.

Microglia from Friedreich Ataxia patients are intrinsically primed for neuroinflammation

La microglía de Friedreich Ataxia de los pacientes está intrínsecamente preparada para la neuroinflamación Ye Man Tang, Rita Lo, Louise Thiry, Michael Fiorini, Sali Farhan, Massimo Pandolfo, Stefano Stifani bioRxiv 2026.07.16.738960; doi:10.64898/2026.07.16.738960

Aquí, mostramos que la microglía generada a partir de iPSC derivadas de pacientes FRDA exhibe un fenotipo proinflamatorio autónomo de células en ausencia de estímulos inflamatorios exógenos. Este fenotipo se caracteriza por la activación coordinada de programas transcripcionales inmunes, la secreción desregulada de proteínas neuroinflamatorias, la función autofagia-lisosomal deteriorada y la activación de las vías de los inflamasomas que involucran NLRP2 y NLRP3. Estos hallazgos demuestran que la deficiencia de FXN es suficiente para inducir la activación microglial intrínseca e identificar vías moleculares que pueden representar objetivos atractivos para futuras terapias con FRDA.