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.