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.