Acceso a medicamentos huérfanos para el tratamiento de la atrofia muscular espinal en España

B. García-Parra, J.M. Guiu, P. Modamio, A. Martínez-Yélamos, E.L. Mariño-Hernández, M. Povedano[REV NEUROL 2022;75:261-267]PMID: 36285446DOI: doi:10.33588/rn.7509.2022298 

La atrofia muscular espinal (AME) es una enfermedad rara cuyo diagnóstico y tratamiento es complejo. En España hay dos medicamentos huérfanos financiados por el Sistema Nacional de Salud, nusinersén y onasemnogén abeparvovec, y un tercero, risdiplam, pendiente. El objetivo fue analizar el acceso a los fármacos modificadores de la AME y detectar posibles causas de inequidad. Materiales y método. Estudio descriptivo realizado en dos fases: revisión bibliográfica y entrevistas semiestructuradas a expertos clínicos en AME de las comunidades autónomas (CC. AA.) de Andalucía, Castilla-La Mancha, Cataluña y Murcia. El número de centros, servicios o unidades de referencia, la disponibilidad de planes autonómicos para enfermedades raras y los programas piloto de cribado neonatal pueden modular el acceso a los nuevos tratamientos farmacológicos. El número de nuevos pacientes diagnosticados al año se estimó entre uno y seis en cada una de las CC. AA. estudiadas. Dos de las cuatro CC. AA. estaban participando en ensayos clínicos. El tiempo desde la prescripción a la administración de nusinersén estaba entre siete y 60 días. Sólo Cataluña comunicó experiencia con onasemnogén abeparvovec a 30 de junio de 2022. Dos CC. AA. de las cuatro estudiadas disponen de plan autonómico para enfermedades raras; no obstante, se identificó como relevante para el tratamiento de la AME sólo en una de ellas.

Repositioning Drugs for Rare Diseases Based on Biological Features and Computational Approaches

Otero-Carrasco, B.; Prieto Santamaría, L.; Ugarte Carro, E.; Caraça-Valente Hernández, J.P.; Rodríguez-González, Healthcare 2022, 10, 1784. doi:10.3390/healthcare10091784 

Rare diseases are a group of uncommon diseases in the world population. To date, about 7000 rare diseases have been documented. However, most of them do not have a known treatment. As a result of the relatively low demand for their treatments caused by their scarce prevalence, the pharmaceutical industry has not sufficiently encouraged the research to develop drugs to treat them. This work aims to analyse potential drug-repositioning strategies for this kind of disease. Drug repositioning seeks to find new uses for existing drugs. In this context, it seeks to discover if rare diseases could be treated with medicines previously indicated to heal other diseases. Our approaches tackle the problem by employing computational methods that calculate similarities between rare and non-rare diseases, considering biological features such as genes, proteins, and symptoms. Drug candidates for repositioning will be checked against clinical trials found in the scientific literature. In this study, 13 different rare diseases have been selected for which potential drugs could be repositioned. By verifying these drugs in the scientific literature, successful cases were found for 75% of the rare diseases studied. The genetic associations and phenotypical features of the rare diseases were examined. In addition, the verified drugs were classified according to the anatomical therapeutic chemical (ATC) code to highlight the types with a higher predisposition to be repositioned. These promising results open the door for further research in this field of study.

Patient-Reported Impact of Symptoms in Friedreich Ataxia

Jamison Seabury, Danae Alexandrou, Nuran Dilek, Brittany Cohen, John Heatwole, Jane Larkindale, David R Lynch, Courtney Park, Spencer Rosero, Sub H Subramony, Anika Varma, Ellen Wagner, Susan Walther, Jennifer Weinstein, McKenzie Wells, Christine Zizzi, Chad Heatwole Neurology Nov 2022, 10.1212/WNL.0000000000201598; DOI: 10.1212/WNL.0000000000201598 

There are a wide variety of symptoms that affect the lives of individuals with FA. These symptoms, many underrecognized, have different levels of importance and occur at different rates in the FA population. The most common and life altering of these symptoms represent potential targets for future therapeutic interventions.

Efficacy of Omaveloxolone in Friedreich's Ataxia: Delayed-Start Analysis of the MOXIe Extension

Lynch, D.R., Chin, M.P., Boesch, S., Delatycki, M.B., Giunti, P., Goldsberry, A., Hoyle, J.C., Mariotti, C., Mathews, K.D., Nachbauer, W., O'Grady, M., Perlman, S., Subramony, S., Wilmot, G., Zesiewicz, T. and Meyer, C.J. (2022), . Mov Disord. doi:10.1002/mds.29286 

 The noninferiority testing demonstrated that the difference in mFARS between omaveloxolone and placebo observed at the end of placebo-controlled MOXIe part 2 (−2.17 ± 1.09 points) was preserved after 72 weeks in the extension (−2.91 ± 1.44 points). In addition, patients previously randomized to omaveloxolone in MOXIe part 2 continued to show no worsening in mFARS relative to their extension baseline through 144 weeks.

METTL17 is an Fe-S cluster checkpoint for mitochondrial translation

Ast T, Itoh Y, Sadre S, McCoy JG, Namkoong G, Chicherin I, Joshi PR, Kamenski P, Suess DLM, Amunts A, Mootha VK.; bioRxiv; 2022. DOI: 10.1101/2022.11.24.517765. 

Friedreich’s ataxia (FA) is the most common monogenic mitochondrial disease. FA is caused by a depletion of the mitochondrial protein frataxin (FXN), an iron-sulfur (Fe-S) cluster biogenesis factor. To better understand the cellular consequences of FA, we performed quantitative proteome profiling of human cells depleted for FXN. Nearly every known Fe-S cluster-containing protein was depleted in the absence of FXN, indicating that as a rule, cluster binding confers stability to Fe-S proteins. Proteomic and genetic interaction mapping identified impaired mitochondrial translation downstream of FXN loss, and specifically highlighted the methyltransferase-like protein METTL17 as a candidate effector. Using comparative sequence analysis, mutagenesis, biochemistry and cryogenic electron microscopy we show that METTL17 binds to the mitoribosomal small subunit during late assembly and harbors a previously unrecognized [Fe 4 S 4 ] 2+ cluster required for its stability on the mitoribosome. Notably, METTL17 overexpression rescued the mitochondrial translation and bioenergetic defects, but not the cellular growth, of FXN null cells. Our data suggest that METTL17 serves as an Fe-S cluster checkpoint: promoting the translation and assembly of Fe-S cluster rich OXPHOS proteins only when Fe-S cluster levels are replete.

Personal factors understood through the Ecological-Enactive Model of Disability and implications for rehabilitation research

Schwab SM, Spencer C, Carver NS, Andrade V, Dugan S, Greve K, Silva PL.; Front Rehabil Sci. 2022 Aug 12;3:954061. doi:10.3389/fresc.2022.954061. 

The International Classification of Functioning, Disability and Health (ICF) recognizes that disability arises from the interaction between an individual with a medical condition and the context in which they are embedded. Context in the ICF is comprised of environmental and personal factors. Personal factors, the background life and lifestyle of an individual, are poorly understood in rehabilitation. There is limited knowledge about how personal and environmental factors interact to shape the contextual conditions critical for explaining functioning and disability. In this paper, we explore how a newly proposed model of disability, the Ecological-Enactive Model of Disability, can enhance understanding of personal factors across multiple rehabilitation disciplines. We draw from a review of evidence and phenomenological interviews of individuals with Friedreich's Ataxia. We consider the practical impact of this understanding on disability and rehabilitation research and pathways for the future focusing on representative design.

Multimodal Analysis of the Visual Pathways in Friedreich's Ataxia Reveals Novel Biomarkers

Thomas-Black, G., Altmann, D.R., Crook, H., Solanky, N., Carrasco, F.P., Battiston, M., Grussu, F., Yiannakas, M.C., Kanber, B., Jolly, J.K., Brett, J., Downes, S.M., Moran, M., Chan, P.K., Adewunmi, E., Gandini Wheeler-Kingshott, C.A., Németh, A.H., Festenstien, R., Bremner, F. and Giunti, P. (2022), Mov Disord. doi:10.1002/mds.29277 

We demonstrate that frataxin level correlates with peripapillary retinal nerve fibre layer thickness and that retinal sectors differ in their degree of degeneration. We also shown that retinal nerve fibre layer is thinner in FRDA patients than controls and that this thinning is influenced by the AAO and GAA1. Furthermore we show that the ganglion cell and inner plexiform layers are affected in FRDA. Our MRI data indicate that there are borderline correlations between retinal layers and areas of the cortex involved in visual processing. 

Our study demonstrates the uneven distribution of the axonopathy in the retinal nerve fibre layer and highlight the relative sparing of the papillomacular bundle and temporal sectors. We show that thinning of the retinal nerve fibre layer is associated with frataxin levels, supporting the use the two biomarkers in future clinical trials design.

Design and Implementation of a Personalizable Alternative Mouse and Keyboard Interface for Individuals with Limited Upper Limb Mobility

Andreas, D.; Six, H.; Bliek, A.; Beckerle, P.; Multimodal Technol. Interact. 2022, 6, 104. doi:10.3390/mti6120104 

 People with neuromuscular diseases often experience limited upper limb mobility, which makes the handling of standard computer mice and keyboards difficult. Due to the importance of computers in private and professional life, this work aims at implementing an alternative mouse and keyboard interface that will allow for their efficient use by people with a neuromuscular disease. Due to the strongly differing symptoms of these diseases, personalization on the hardware and software levels is the focus of our work. The presented mouse alternative is based on a spectacle frame with an integrated motion sensor for head tracking, which enables the control of the mouse cursor position; the keyboard alternative consists of ten keys, which are used to generate word suggestions for the user input. The interface was tested in a user study involving three participants without disabilities, which showed the general functionality of the system and potential room for improvement. With an average throughput of 1.56 bits per second achieved by the alternative mouse and typing speeds of 8.44 words per minute obtained using the alternative keyboard, the proposed interface could be a promising input device for people with limited upper limb mobility.

A natural history study to track brain and spinal cord changes in individuals with Friedreich's ataxia: TRACK-FA study protocol

Georgiou-Karistianis N, Corben LA, Reetz K, Adanyeguh IM, Corti M, Deelchand DK, Delatycki MB, Dogan I, Evans R, Farmer J, França MC, Gaetz W, Harding IH, Harris KS, Hersch S, Joules R, Joers JJ, Krishnan ML, Lax M, Lock EF, Lynch D, Mareci T, Muthuhetti Gamage S, Pandolfo M, Papoutsi M, Rezende TJR, Roberts TPL, Rosenberg JT, Romanzetti S, Schulz JB, Schilling T, Schwarz AJ, Subramony S, Yao B, Zicha S, Lenglet C, Henry PG.; PLoS One. 2022 Nov 21;17(11):e0269649. doi: 10.1371/journal.pone.0269649. PMID: 36410013. 

 Prioritising immediate areas of need, TRACK-FA aims to deliver a set of sensitive, clinical trial-ready neuroimaging biomarkers to accelerate drug discovery efforts and better understand disease trajectory. Once validated, these potential pharmacodynamic biomarkers can be used to measure the efficacy of new therapeutics in forestalling disease progression.

Determinant of the Cerebellar cognitive affective syndrome in Friedreich Ataxia

destrebecq, comet, deveylder, alaerts, naeije.; Research Square; 2022. DOI: 10.21203/rs.3.rs-2279266/v1. 

CCAS is highly prevalent in adult individuals with FRDA. CCAS is predicted by ataxic motor symptoms severity. This finding supports common core cerebellar pathophysiology in both cognitive and motor symptoms in FRDA and warrants screening for CCAS, especially in patients with SARA > 20.

Harmonizing results of ataxia rating scales: mFARS, SARA, and ICARS

Rummey C, Harding IH, Delatycki MB, Tai G, Rezende T, Corben LA.; Ann Clin Transl Neurol. 2022 Nov 16. doi: 10.1002/acn3.51686. Epub ahead of print. PMID: 36394163. 

 The ever-increasing body of ataxia research provides opportunities for large-scale meta-analyses, systematic reviews, and data aggregation. Because multiple standardized scales are used to quantify ataxia severity, harmonization of these measures is necessary for quantitative data pooling. We applied the modified Friedreich Ataxia Rating Scale (mFARS), the Scale for the Assessment and Rating of Ataxia (SARA), and the International Cooperative Ataxia Rating Scale (ICARS) to a large cohort of people with Friedreich's ataxia. We provide regression coefficients for scale interconversion and discuss the reliability of this approach, together with insights into the differential sensitivities of mFARS and SARA to disease progression.

Cerebellar impulsivity–compulsivity assessment scale

Lin, C.-Y.R., Amokrane, N., Chen, S., Chen, T.X., Lai, R.-Y., Trinh, P., Minyetty, M.J., Emmerich, H., Pan, M.-K., Claassen, D.O. and Kuo, S.-H. (2022); Ann Clin Transl Neurol. doi.:10.1002/acn3.51698

Cerebellar ataxia cases with ICBs have threefold higher total preliminary CIA scores than those without ICBs (12.06 ± 5.96 vs. 4.68 ± 3.50, p = 0.038). Cronbach's alpha revealed good internal consistency across all items (α > 0.70). By performing the test–retest reliability and inter-rater reliability on the preliminary version of CIA, we excluded seven questions (r < 0.70) and generated the final version of CIA. Based on the ROC, a score of 8.0 in CIA was chosen as the cut-off for ICBs in individuals with cerebellar ataxia with 81% sensitivity and 81% specificity.

Safety and pharmacokinetics of a highly bioavailable resveratrol preparation (JOTROL TM)

Kemper C, Benham D, Brothers S, Wahlestedt C, Volmar CH, Bennett D, Hayward M.; AAPS Open. 2022;8(1):11. doi: 10.1186/s41120-022-00058-1. Epub 2022 Jun 30. PMID: 35789594; PMCID: PMC9243782. 

 Resveratrol exhibits a wide range of biological properties, including anti-glycation, antioxidant, anti-inflammation, neuroprotective (including against advanced dementia and Alzheimer's disease), anti-cancer, and anti-aging activity in experimental models (Galiniak et al., Acta Biochim Pol 66:13-21, 2019). Unfortunately, this compound exhibits low bioavailability and solubility (Galiniak et al., Acta Biochim Pol 66:13-21, 2019), requiring large doses that can cause nausea and GI distress. JOTROLTM is a micellar 10% resveratrol solubilization formulation that is thought to increase bioavailability of resveratrol via lymphatic system absorption. Jupiter Neurosciences (formerly Jupiter Orphan Therapeutics; "Jupiter") is pursuing the use of resveratrol in mucopolysaccharidosis type 1 (MPS 1), Friedreich's ataxia, and Alzheimer's disease/mild cognitive impairment.

Diagnostic delay in rare diseases: data from the Spanish rare diseases patient registry

Juan Benito-Lozano, Blanca López-Villalba, Greta Arias-Merino, Manuel Posada de la Paz & Verónica Alonso-Ferreira; Orphanet J Rare Dis 17, 418 (2022). doi:10.1186/s13023-022-02530-3 

This is the first study to quantify time to diagnosis of RDs in Spain, based on data from a national registry open to any RD. Since over half of all persons affected by RDs experience delay in diagnosis, new studies are needed to ascertain the factors associated with this delay and the implications this has on the lives of patients and their families.

Criterios de derivación a genética clínica desde Atención Primaria. Documento de consenso, Atención Primaria

Ismael Ejarque Doménech, Purificación Marín Reina, Sixto García-Miñaur Rica, Isabel Chirivella González, María Teresa Martínez Martínez, Ana María García Rodríguez, Sara Álvarez de Andrés, Juan José Tellería Orriols, Volume 54, Issue 12, 2022, 102501, doi:10.1016/j.aprim.2022.102501. La Atención Primaria (AP) es el primer contacto entre el paciente y el médico, por lo que es fundamental tener claro los criterios de sospecha de una enfermedad genética y dónde se debe remitir para su estudio. s Cuatro sociedades científicas: la Sociedad Española de Medicina Familiar y Comunitaria (semFYC), la Asociación Española de Genética Humana (AEGH), la Asociación Española de Pediatría (AEP) y la Sociedad Española de Oncología Médica (SEOM), han revisado los criterios de derivación a los servicios de genética clínica de las diferentes guías publicadas, con el objetivo de elaborar unas recomendaciones para AP.

De acuerdo con las recomendaciones internacionales, y teniendo siempre como objetivo fundamental la protección de los derechos del menor, se desaconseja el estudio genético de portadores (sanos) y de enfermedades de inicio en la edad adulta (sin posibilidad de intervención preventiva) en pacientes menores de edad. 

Glucagon-like Peptide-1 (GLP-1) Receptor Agonists and Neuroinflammation: Implications for Neurodegenerative Disease Treatment

Katherine O. Kopp, Elliot J. Glotfelty, Yazhou Li, Nigel H. Greig; Pharmacological Research, 2022, 106550, DOI:10.1016/j.phrs.2022.106550. Abstract: Chronic, excessive neuroinflammation is a key feature of neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). However, neuroinflammatory pathways have yet to be effectively targeted in clinical treatments for such diseases. Interestingly, increased inflammation and neurodegenerative disease risk have been associated with type 2 diabetes mellitus (T2DM) and insulin resistance (IR), suggesting that treatments that mitigate T2DM pathology may be successful in treating neuroinflammatory and neurodegenerative pathology as well. Glucagon-like peptide-1 (GLP-1) is an incretin hormone that promotes healthy insulin signaling, regulates blood sugar levels, and suppresses appetite. Consequently, numerous GLP-1 receptor (GLP-1R) stimulating drugs have been developed and approved by the US Food and Drug Administration (FDA) and related global regulatory authorities for the treatment of T2DM. Furthermore, GLP-1R stimulating drugs have been associated with anti-inflammatory, neurotrophic, and neuroprotective properties in neurodegenerative disorder preclinical models, and hence hold promise for repurposing as a treatment for neurodegenerative diseases. In this review, we discuss incretin signaling, neuroinflammatory pathways, and the intersections between neuroinflammation, brain IR, and neurodegenerative diseases, with a focus on AD and PD. We additionally overview current FDA-approved incretin receptor stimulating drugs and agents in development, including unimolecular single, dual, and triple receptor agonists, and highlight those in clinical trials for neurodegenerative disease treatment. We propose that repurposing already-approved GLP-1R agonists for the treatment of neurodegenerative diseases may be a safe, efficacious, and cost-effective strategy for ameliorating AD and PD pathology by quelling neuroinflammation. 

 FRDA is a heritable neurodegenerative movement disorder fueled and exacerbated by neuroinflammation 290, 291, 292, which could make it a candidate for GLP-1R agonist treatment. Exenatide treatment was found to re-elevate reduced levels of frataxin, a critical mitochondrial protein, in FRDA patients, which can enhance mitochondrial health and function and could, by extension, reduce neuroinflammation and neurodegeneration characteristic of the disease [293]—again, providing a potentially fruitful area of future basic and clinical research. Similarly, studies by Meissner and colleagues [178] demonstrated the presence of impaired insulin/IGF-1 and IR in vulnerable brain regions of multiple system atrophy patients and a related transgenic mouse model, and their mitigation in the latter by exendin-4, likewise suggesting a promising area of future research.

Decreased mitochondrial respiration in cardiac fibers isolated from a mouse model of Friedreich’s ataxia

Peter Vitiello, Paul Pierce, Shirley/Xiu Wang, Alec Cooper, Aristides Rivera, Jared Ailts, Holly Van Remmen, Jacob Brown; Free Radical Biology and Medicine,Volume 192, Supplement 1, 2022, Page 75, doi:10.1016/j.freeradbiomed.2022.10.308.

Characterization of human mitochondrial aconitase and its interaction with frataxin

Santiago Mansilla, Verónica Tórtora, Florencia Pignataro, Santiago Sastre, Ignacio Castro, María Laura Chiribao, Carlos Robello, Ari Zeida, Javier Santos, Laura Castro; Free Radical Biology and Medicine, Volume 192, Supplement 1, 2022, Pages 86-87, doi:10.1016/j.freeradbiomed.2022.10.151.

RNA as a Major-Groove Ligand: RNA-RNA and RNA-DNA Triplexes Formed by GAA and UUC or TTC Sequences

Zhang J, Fakharzadeh A, Roland C, Sagui C.; ACS Omega. 2022 Nov;7(43):38728-38743. DOI: 10.1021/acsomega.2c04358. PMID: 36340174; PMCID: PMC9631886. 

 Friedreich's ataxia is associated with noncanonical nucleic acid structures that emerge when GAA:TTC repeats in the first intron of the FXN gene expand beyond a critical number of repeats. Specifically, the noncanonical repeats are associated with both triplexes and R-loops. Here, we present an in silico investigation of all possible triplexes that form by attaching a third RNA strand to an RNA:RNA or DNA:DNA duplex, complementing previous DNA-based triplex studies. For both new triplexes results are similar. For a pyridimine UUC+ third strand, the parallel orientation is stable while its antiparallel counterpart is unstable. For a neutral GAA third strand, the parallel conformation is stable. A protonated GA+A third strand is stable in both parallel and antiparallel orientations. We have also investigated Na+ and Mg2+ ion distributions around the triplexes. The presence of Mg2+ ions helps stabilize neutral, antiparallel GAA triplexes. These results (along with previous DNA-based studies) allow for the emergence of a complete picture of the stability and structural characteristics of triplexes based on the GAA and TTC/UUC sequences, thereby contributing to the field of trinucleotide repeats and the associated unusual structures that trigger expansion.

Phenotype and management of neurologic intronic repeat disorders (NIRDs)

Finsterer J.; Rev Neurol (Paris). 2022 Nov 9:S0035-3787(22)00793-7. doi: 10.1016/j.neurol.2022.09.004. Epub ahead of print. PMID: 36371266. 

During recent years an increasing number of neurologic disorders due to expanded tri-, tetra-, penta-, or hexa-nucleotide repeat motifs in introns of various genes have been described (neurologic intronic repeat disorders (NIRDs)). The repeat may be pathogenic in the heterozygous or homozygous form. Repeat lengths vary considerably and can be stable or unstable during transmission to the next generation. The most well-known NIRDs are Friedreich ataxia, spinocerebellar ataxia types-10, -31, and -36, CANVAS, C9Orf72 familial amyotrophic lateral sclerosis (fALS), and myotonic dystrophy-2 (MD2). Phenotypically, NIRDs manifest as mono-organ (e.g. spinocerebellar ataxia type 31) or multi-organ disease (e.g. Friedreich ataxia, myotonic dystrophy-2). A number of other more rare NIRDs have been recently detected. This review aims at summarising and discussing previous findings and recent advances concerning the etiology, pathophysiology, clinical presentation, and therapeutic management of the most common NIRDs.

Blood Transcript Biomarkers Selected by Machine Learning Algorithm Classify Neurodegenerative Diseases including Alzheimer’s Disease

Huseby, C.J.; Delvaux, E.; Brokaw, D.L.; Coleman, P.D.; Biomolecules 2022, 12, 1592. doi:10.3390/biom12111592 

A blood-based screen to distinguish and classify neurodegenerative diseases is especially interesting having low cost, minimal invasiveness, and accessibility to almost any world clinic. In this study, we set out to discover a small set of blood transcripts that can be used to distinguish healthy individuals from those with Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, Friedreich’s ataxia, or frontotemporal dementia. Using existing public datasets, we developed a machine learning algorithm for application on transcripts present in blood and discovered small sets of transcripts that distinguish a number of neurodegenerative diseases with high sensitivity and specificity. We validated the usefulness of blood RNA transcriptomics for the classification of neurodegenerative diseases. Information about features selected for the classification can direct the development of possible treatment strategies.

Prediction of the disease course in Friedreich ataxia

Christian Hohenfeld, Ulrich Terstiege, Imis Dogan, Paola Giunti, Michael H. Parkinson, Caterina Mariotti, Lorenzo Nanetti, Mario Fichera, Alexandra Durr, Claire Ewenczyk, Sylvia Boesch, Wolfgang Nachbauer, Thomas Klopstock, Claudia Stendel, Francisco Javier Rodríguez de Rivera Garrido, Ludger Schöls, Stefanie N. Hayer, Thomas Klockgether, Ilaria Giordano, Claire Didszun, Myriam Rai, Massimo Pandolfo, Holger Rauhut, Jörg B. Schulz & Kathrin Reetz. Sci Rep 12, 19173 (2022). doi:10.1038/s41598-022-23666-z 

 We explored whether disease severity of Friedreich ataxia can be predicted using data from clinical examinations. From the database of the European Friedreich Ataxia Consortium for Translational Studies (EFACTS) data from up to five examinations of 602 patients with genetically confirmed FRDA was included. Clinical instruments and important symptoms of FRDA were identified as targets for prediction, while variables such as genetics, age of disease onset and first symptom of the disease were used as predictors. We used modelling techniques including generalised linear models, support-vector-machines and decision trees. The scale for rating and assessment of ataxia (SARA) and the activities of daily living (ADL) could be predicted with predictive errors quantified by root-mean-squared-errors (RMSE) of 6.49 and 5.83, respectively. Also, we were able to achieve reasonable performance for loss of ambulation (ROC-AUC score of 0.83). However, predictions for the SCA functional assessment (SCAFI) and presence of cardiological symptoms were difficult. In conclusion, we demonstrate that some clinical features of FRDA can be predicted with reasonable error; being a first step towards future clinical applications of predictive modelling. In contrast, targets where predictions were difficult raise the question whether there are yet unknown variables driving the clinical phenotype of FRDA.

C-Path and EFACTS Announce Data Sharing Agreement Making RDCA-DAP the Largest Worldwide Database for Friedreich’s Ataxia

TUCSON, Ariz., Nov. 10, 2022 — Critical Path Institute (C-Path) and the European Friedreich’s Ataxia Consortium for Translational Studies (EFACTS) today announced a data sharing agreement to incorporate patient data into C-Path’s Rare Disease Cures Accelerator-Data and Analytics Platform (RDCA-DAP®) solidifying RDCA-DAP as the largest worldwide database for Friedreich’s ataxia. 

 “The Friedreich’s Ataxia Research Alliance (FARA) partnered with C-Path to create a database that could integrate data from natural history studies and clinical trials, FA Integrated Clinical Database (FA-ICD), and we are really excited that this data is now part of RDCA-DAP and that our EFACTS partners are also contributing such informative data,” said FARA CEO Jennifer Farmer, M.S. “The collaboration with EFACTS goes beyond the contribution of this important data as EFACTS concomitantly joins the steering committee of the C-Path’s taskforce for FA and will inform new research. We look forward to the new insights and clinical trial tools that will be derived from having such a robust database shared with the research community.”

Frataxin deficiency alters gene expression in Friedreich ataxia derived IPSC-neurons and cardiomyocytes

Angulo, M. B., Bertalovitz, A., Argenziano, M. A., Yang, J., Patel, A., Zesiewicz, T., & McDonald, T. V. (2022). Molecular Genetics & Genomic Medicine, 00, e2093. doi:10.1002/mgg3.2093 

 RNA-seq and differential gene expression enrichment analyses demonstrated that frataxin deficiency affected the expression of glycolytic pathway genes in neurons and extracellular matrix pathway genes in cardiomyocytes. Genes in these pathways were differentially expressed when compared to a control and restored to control levels when FRDA cells were supplemented with frataxin.

Clinical management guidelines for Friedreich ataxia: best practice in rare diseases

Corben, L.A., Collins, V., Milne, S. et al. Orphanet J Rare Dis 17, 415 (2022). doi:10.1186/s13023-022-02568-3 

Individuals with Friedreich ataxia (FRDA) can find it difficult to access specialized clinical care. To facilitate best practice in delivering healthcare for FRDA, clinical management guidelines (CMGs) were developed in 2014. However, the lack of high-certainty evidence and the inadequacy of accepted metrics to measure health status continues to present challenges in FRDA and other rare diseases. To overcome these challenges, the Grading of Recommendations Assessment and Evaluation (GRADE) framework for rare diseases developed by the RARE-Bestpractices Working Group was adopted to update the clinical guidelines for FRDA. This approach incorporates additional strategies to the GRADE framework to support the strength of recommendations, such as review of literature in similar conditions, the systematic collection of expert opinion and patient perceptions, and use of natural history data.

Clinical Management Guidelines for Friedreich Ataxia (FRDA)

In 2020, an executive guidelines panel comprising seven international clinicians was commissioned to provide oversight of the guidelines development process and endorse the final recommendations. The guidelines panel invited international expert clinicians and researchers (the authors) to write background chapter content and develop recommendations for topics that were assigned according to their particular expertise.

REATA PHARMACEUTICALS INC Management's Discussion and Analysis of Financial Condition and Results of Operations

11/08/2022​.

REATA PHARMACEUTICALS INC Management's Discussion and Analysis of Financial Condition and Results of Operations (form 10-Q)

Evolution of an Iron-Detoxifying Protein: Eukaryotic and Rickettsia Frataxins Contain a Conserved Site Which Is Not Present in Their Bacterial Homologues

Alves, R.; Pazos-Gil, M.; Medina-Carbonero, M.; Sanz-Alcázar, A.; Delaspre, F.; Tamarit, J., Int. J. Mol. Sci. 2022, 23, 13151. doi:10.3390/ijms232113151

 Friedreich’s ataxia is a neurodegenerative disease caused by mutations in the frataxin gene. Frataxin homologues, including bacterial CyaY proteins, can be found in most species and play a fundamental role in mitochondrial iron homeostasis, either promoting iron assembly into metaloproteins or contributing to iron detoxification. While several lines of evidence suggest that eukaryotic frataxins are more effective than bacterial ones in iron detoxification, the residues involved in this gain of function are unknown. In this work, we analyze conservation of amino acid sequence and protein structure among frataxins and CyaY proteins to identify four highly conserved residue clusters and group them into potential functional clusters.

Design Therapeutics Highlights Pipeline Progress and Upcoming Milestones and Reports Third Quarter 2022 Financial Results

CARLSBAD, Calif., Nov. 03, 2022 (GLOBE NEWSWIRE) -- Design Therapeutics, Inc. (Nasdaq: DSGN), a clinical-stage biotechnology company developing treatments for serious degenerative genetic diseases, today highlighted recent progress and anticipated upcoming milestones across its clinical and research-stage pipeline of novel GeneTAC™ small molecules and reported third quarter 2022 financial results.

Design is evaluating DT-216 in a Phase 1 single-ascending dose (SAD) clinical trial in adult patients with FA, and plans to report initial SAD data, including safety, tolerability, pharmacokinetics and FXN levels in December 2022.

Design plans to complete the MAD trial in mid-2023.

Efficacy and Safety of Leriglitazone in Patients With Friedreich Ataxia, A Phase 2 Double-Blind, Randomized Controlled Trial (FRAMES)

Massimo Pandolfo, Kathrin Reetz, Alejandra Darling, Francisco Javier Rodriguez de Rivera, Pierre-Gilles Henry, James Joers, Christophe Lenglet, Isaac Adanyeguh, Dinesh Deelchand, Fanny Mochel, Françoise Pousset, Sílvia Pascual, Delphine Van den Eede, Itziar Martin-Ugarte, Anna Vilà-Brau, Adriana Mantilla, María Pascual, Marc Martinell, Uwe Meya, Alexandra Durr Neurol Genet Dec 2022, 8 (6) e200034; DOI: 10.1212/NXG.0000000000200034 

 The primary endpoint of change in spinal cord area was not met. Secondary endpoints provide evidence supporting proof of concept for leriglitazone mode of action and, with acceptable safety data, support larger studies in patients with FRDA.