Monday, May 27, 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.

Sunday, May 26, 2024

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.

Thursday, May 23, 2024

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.

Tuesday, May 21, 2024

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.

Thursday, May 16, 2024

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.