Plasma and red blood cell membrane accretion and pharmacokinetics of RT001 (bis-allylic 11,11-D2-linoleic acid ethyl ester) during long term dosing in patients

J. Thomas Brenna, Genevieve James, Mark Midei, Frederic Heerinckx, Paldeep Atwal, Peter Milner, Karsten Schmidt, Lex van der Ploeg, Robert Fielding, Mikhail S. Shchepinov, Journal of Pharmaceutical Sciences, 2020, doi:10.1016/j.xphs.2020.08.019.

RT001 is the di-deutero isotopologue of linoleic acid ethyl ester (D2-LA). Resistance to oxidative damage at the carbon-deuterium bond depends upon the concentration of D2-LA as a percentage of total LA. We report here on the plasma and red cell (RBC) pharmacokinetics (PK) of D2-LA, and its metabolite 13,13-D2-arachidonic acid (D2-AA), in patients with multiple neurodegenerative diseases (total of 59 participants). In Friedreich’s ataxia patients, D2-LA was absorbed and transported similarly to dietary LA, peaking at about 6 h after oral dosing. Plasma D2-LA concentrations approached steady state after 28 days of dosing. After 6 months of daily dosing in subjects with other disorders, D2-LA and D2-AA levels were at or above the 20% of total (D2-LA/ total LA, or D2-AA/ total AA) therapeutic targets for most subjects. We conclude that chronic dosing of RT001 and associated dietary guidance can be maintained over many months to achieve target plasma and RBC levels, forming a basis for therapeutic dosing across a broad range of conditions. RT001 has been safe and well-tolerated in 59 different participants treated across 10 different neurodegenerative diseases in multiple clinical trials for up to 36 months with no significant drug related adverse events limiting use.

Friedreich Ataxia: current state-of-the-art, and future prospects for mitochondrial-focused therapies

Federico V. Pallardó, Giovanni Pagano, Laura R. Rodríguez, Pilar Gonzalez-Cabo, Alex Lyakhovich, Marco Trifuoggi; Translational Research,
2020, doi:10.1016/j.trsl.2020.08.009.

The present mini review is aimed at evaluating the basic and clinical reports on the roles and the use of a set of iron chelators, antioxidants and some cofactors involved in the key mitochondrial functions. Extensive literature has focused on the protective roles of iron chelators, coenzyme Q10 and analogs, and vitamin E, altogether with varying outcomes in clinical studies. Other studies have suggested mitoprotective roles for other mitochondrial cofactors, involved in Krebs cycle, such as alpha-lipoic acid and carnitine, involved in acyl transport across the mitochondrial membrane.

Frataxin gene editing rescues Friedreich’s ataxia pathology in dorsal root ganglia organoid-derived sensory neurons

Pietro Giuseppe Mazzara, Sharon Muggeo, Mirko Luoni, Luca Massimino, Mattia Zaghi, Parisa Tajalli-Tehrani Valverde, Simone Brusco, Matteo Jacopo Marzi, Cecilia Palma, Gaia Colasante, Angelo Iannielli, Marianna Paulis, Chiara Cordiglieri, Serena Gea Giannelli, Paola Podini, Cinzia Gellera, Franco Taroni, Francesco Nicassio, Marco Rasponi & Vania Broccoli; Nat Commun 11, 4178 (2020). doi:10.1038/s41467-020-17954-3

These results strongly suggest that removal of the repressed chromatin flanking the GAA tract might contribute to rescue FXN total expression and fully revert the pathological hallmarks of FRDA DRG neurons.

Atypical structures of GAA/TTC trinucleotide repeats underlying Friedreich’s ataxia: DNA triplexes and RNA/DNA hybrids

Jiahui Zhang, Ashkan Fakharzadeh, Feng Pan, Christopher Roland, Celeste Sagui; Nucleic Acids Research, gkaa665, doi:10.1093/nar/gkaa665

The authors intended the study to provide a ‘rationale for the discovery and characterization of the non-B DNA regulatory structures involved in the formation of the RNA:DNA interactome’. However, experimental data with molecular resolution for these non-B DNA structures is noticeably scarce. We believe that structural studies such as ours can meaningfully contribute in the creation of such a roadmap.

Clinical presentation and survival of childhood hypertrophic cardiomyopathy: a retrospective study in United Kingdom

Gabrielle Norrish, Ella Field, Karen Mcleod, Maria Ilina, Graham Stuart, Vinay Bhole, Orhan Uzun, Elspeth Brown, Piers E F Daubeney, Amrit Lota, Katie Linter, Sujeev Mathur, Tara Bharucha, Khoon Li Kok, Satish Adwani, Caroline B Jones, Zdenka Reinhardt, Juan Pablo Kaski; European Heart Journal, Volume 40, Issue 12, 21 March 2019, Pages 986–993, doi:10.1093/eurheartj/ehy798

This study describes the clinical characteristics and outcomes of childhood HCM over four decades in a well-characterized United Kingdom cohort.
Aetiology was: non-syndromic (n = 433, 63%), RASopathy (n = 126, 18.3%), Friedreich’s ataxia (n = 59, 8.6%) or inborn errors of metabolism (IEM) (n = 64, 9%). In infants (n = 159, 23%) underlying aetiology was more commonly a RASopathy (42% vs. 11.2%, P < 0.0001) or IEM (18.9% vs. 6.4% P < 0.0001)

Multiple Ascending Dose Study of CTI-1601 Versus Placebo in Subjects With Friedreich's Ataxia

ClinicalTrials.gov Identifier: NCT04519567 Responsible Party: Larimar Therapeutics, Inc. First Posted: August 19, 2020

A Phase 1 Multiple Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Subcutaneous CTI-1601 Versus Placebo in Subjects With Friedreich's Ataxia

Actual Study Start Date: July 31, 2020
Estimated Primary Completion Date: June 30, 2021
Estimated Study Completion Date: June 30, 2021

Validation of low-cost system for gait assessment in children with ataxia

S. Summa, G. Tartarisco, M. Favetta, A. Buzachis, A. Romano, G.M. Bernava, A. Sancesario, G. Vasco, G. Pioggia, M. Petrarca, E. Castelli, E. Bertini, T. Schirinzi; Computer Methods and Programs in Biomedicine, 2020, 105705, Doi:10.1016/j.cmpb.2020.105705.

This study aims to test the usability of the Kinect system for assessing ataxia severity, exploring the potentiality of clustering algorithms and validating this system with a standard motion capture system.
The spatio-temporal parameters measured by Kinect cannot be used interchangeably with those parameters acquired with standard motion capture system in clinical practice but can still provide fundamental information. Specifically, these results might bring to the development of a novel system to perform easy and quick evaluation of gait in young patients with ataxia, useful for patients stratification in terms of clinical severity and diagnosis.

LARIMAR THERAPEUTICS : Management's Discussion and Analysis of Financial Condition and Results of Operations (form 10-Q) share with twitter share with LinkedIn share with facebook

MarketScreener; 08/14/2020.
CTI-1601 is currently being evaluated in Phase 1 clinical trials in patients with Friedreich's Ataxia. We have received orphan drug status, fast track designation and rare pediatric disease designation, from the U.S. Food and Drug Administration (the "FDA"), for CTI­1601. In addition, the European Medicines Agency ("EMA") Committee for Orphan Medicinal Products ("COMP") issued a positive opinion on the Company's application for orphan drug designation for CTI-1601. The receipt of such designations or positive opinions may not result in a faster development process, review or approval compared to products considered for approval under conventional FDA or EMA procedures and does not assure ultimate approval by the FDA or EMA.

Larimar Therapeutics (LRMR) Investor Presentation - Slideshow

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About CTI-1601

Identification of a Novel Oleic Acid Analog with Protective Effects in Multiple Cellular Models of Friedreich Ataxia

M Grazia Cotticelli, Roberto Forestieri, Shujuan Xia, Sipak Joyasawal, Taehee Lee, Kexin Xu, Amos B Smith Iii, Donna M Huryn, Robert B Wilson; ACS Chem Neurosci. 2020 Aug 11. doi: 10.1021/acschemneuro.0c00323. Online ahead of print.

Friedreich ataxia (FRDA) is an inherited neurodegenerative disorder for which there is no cure or approved treatment. It is characterized by the loss or impaired activity of frataxin protein, which is involved in the biogenesis of iron-sulfur clusters. Our previous studies suggested that cell death in FRDA may involve ferroptosis, an iron-dependent form of cell death requiring lipid peroxidation. Based on reports that oleic acid acts as a ferroptosis inhibitor, we evaluated whether it, other fatty acids, and fatty acid derivatives could rescue viability in cellular models of FRDA. We identified a trifluoromethyl alcohol analog of oleic acid that was significantly more potent than oleic acid itself. Further evaluation indicated that the effects were stereoselective, although a specific molecular target has not yet been identified. This work provides a potential starting point for therapeutics to treat FRDA, as well as a valuable probe molecule to interrogate FRDA pathophysiology.

Test–retest reliability of the Friedreich’s ataxia rating scale

Christian Rummey Theresa A. Zesiewicz Santiago Perez‐Lloret Jennifer M. Farmer Massimo Pandolfo David R. Lynch; Ann Clin Transl Neurol. doi:10.1002/acn3.51118

The modified Friedreich Ataxia Rating Scale (mFARS) is a disease specific, exam‐based neurological rating scale commonly used as a outcome measure in clinical trials. While extensive clinimetric testing indicates it’s validity in measuring disease progression, formal test–retest reliability was lacking. To fill this gap, we acquired results from screening and baseline visits of several large clinical trials and calculated intraclass correlation coefficients, coefficients of variance, standard error, and the minimally detectable changes. This study demonstrated excellent test–retest reliability of the mFARS, and it’s upright stability subscore.

UPDATED: Reata suggests Friedreich's ataxia program could be delayed, sending stock plunging

August 10, 2020 05:07 PM EDT; Reata Pharmaceuticals $RETA made waves last October when its drug omaveloxolone produced positive trial results in treating a rare neurological disorder, but the candidate’s path forward became much murkier Monday.
In a report of quarterly earnings, the biotech divulged that the FDA is considering delaying omaveloxolone’s NDA pending completion of a second trial. That could push back approval by at least a year given that the target population, individuals with Friedreich’s ataxia, is limited and progression of the hard-to-treat illness is notoriously slow. The Covid-19 pandemic would also hinder Reata’s ability to complete an additional trial.

FDA 'not convinced' MOXIe data sufficient

Onset features and time to diagnosis in Friedreich’s Ataxia

Elisabetta Indelicato, Wolfgang Nachbauer, Andreas Eigentler, Matthias Amprosi, Raffaella Matteucci Gothe, Paola Giunti, Caterina Mariotti, Javier Arpa, Alexandra Durr, Thomas Klopstock, Ludger Schöls, Ilaria Giordano, Katrin Bürk, Massimo Pandolfo, Claire Didszdun, Jörg B. Schulz, Sylvia Boesch & on behalf of the EFACTS (European Friedreich’s Ataxia Consortium for Translational Studies); Orphanet J Rare Dis 15, 198 (2020). doi:10.1186/s13023-020-01475-9

Six hundred eleven genetically confirmed FRDA patients were recruited within a multicentric natural history study conducted by the EFACTS (European FRDA Consortium for Translational Studies, ClinicalTrials.gov-Identifier NCT02069509). Age at first symptoms as well as age at first suspicion of FRDA by a physician were collected retrospectively at the baseline visit.
In the genetic era, presentation with non-neurological features or in the adulthood still leads to a significant diagnostic delay in FRDA. Well-known correlations between GAA1 repeat length and disease milestones are not valid in case of atypical presentations or positive family history.

A Drosophila model of Friedreich Ataxia with CRISPR/Cas9 insertion of GAA repeats in the frataxin gene reveals in vivo protection by N-acetyl cysteine

Maria Russi, Elodie Martin, Benoit D’Autréaux, Laura Tixier, Hervé Tricoire, Véronique Monnier; Human Molecular Genetics, ddaa170, doi:10.1093/hmg/ddaa170 

 Friedreich Ataxia (FA) is caused by GAA repeat expansions in the first intron of FXN, the gene encoding frataxin, which results in decreased gene expression. Thanks to the high degree of frataxin conservation, the Drosophila melanogaster fruitfly appears as an adequate animal model to study this disease and to evaluate therapeutic interventions. Here, we generated a Drosophila model of FA with CRISPR/Cas9 insertion of approximately 200 GAA in the intron of the fly frataxin gene fh. These flies exhibit a developmental delay and lethality associated with decreased frataxin expression. We were able to by-pass preadult lethality using genetic tools to overexpress frataxin only during the developmental period. These frataxin-deficient adults are short-lived and present strong locomotor defects. RNA-Seq analysis identified deregulation of genes involved in amino-acid metabolism and transcriptomic signatures of oxidative stress. In particular, we observed a progressive increase of Tspo expression, fully rescued by adult frataxin expression. Thus, Tspo expression constitutes a molecular marker of the disease progression in our fly model and might be of interest in other animal models or in patients. Finally, in a candidate drug screening, we observed that N-acetyl cysteine improved the survival, locomotor function, resistance to oxidative stress and aconitase activity of frataxin-deficient flies. Therefore, our model provides the opportunity to elucidate in vivo the protective mechanisms of this molecule of therapeutic potential. This study also highlights the strength of the CRISPR/Cas9 technology to introduce human mutations in endogenous orthologous genes, leading to Drosophila models of human diseases with improved physiological relevance.

Toward quantitative neuroimaging biomarkers for Friedreich's ataxia at 7 Tesla: Susceptibility mapping, diffusion imaging, R2 and R1 relaxometry

Sina Straub Stephanie Mangesius Julian Emmerich Elisabetta Indelicato Wolfgang Nachbauer Katja S. Degenhardt Mark E. Ladd Sylvia Boesch Elke R. Gizewski; J Neurosci Res. 2020; 00: 1– 13. doi:10.1002/jnr.24701


VBM revealed significant white matter atrophy within regions of the brainstem, and the cerebellum. These regions overlapped partially with brain regions for which significant differences between healthy controls and patients were found in the VOI‐based quantitative MRI evaluation. It was shown that two independent analyses provided overlapping results. Moreover, positive results on correlations with disease characteristics were found, indicating that these quantitative MRI parameters could provide more detailed information and assist the search for effective treatments. Positive results on correlations with disease characteristics were found, indicating that these quantitative MRI parameters could provide more detailed information and assist the search for effective treatments.

Antioxidant Defense Mechanisms and its Dysfunctional Regulation in the Mitochondrial Disease, Friedreich’s Ataxia

S. Chiang, M.L.H. Huang, K.C. Park, D.R. Richardson, Free Radical Biology and Medicine, 2020, doi.org/10.1016/j.freeradbiomed.2020.07.019.

 Considering FA, which is due to the decreased expression of the mitochondrial protein, frataxin, this iron accumulation does not occur within protective storage proteins such as mitochondrial ferritin. Instead, it forms unbound biomineral aggregates composed of high spin iron(III), phosphorous and sulfur, which probably contributes to the observed redox stress. There is also a dysregulated response to the ensuing redox assault, as the master regulator of oxidative stress, nuclear factor erythroid 2-related factor-2 (Nrf2), demonstrates marked down-regulation. The dysfunctional response of Nrf2 in FA is due to multiple mechanisms including: (1) up-regulation of Keap1 that is involved in Nrf2 degradation; (2) activation of the nuclear Nrf2 export/degradation machinery via glycogen synthase kinase-3β (Gsk3β) signaling; and (3) inhibited nuclear translocation of Nrf2. More recently, increased microRNA (miRNA) 144 expression has been demonstrated to down-regulate Nrf2 in several disease states, including an animal model of FA. Other miRNAs have also demonstrated to be dysregulated upon frataxin depletion in vivo in humans and animal models of FA. Collectively, frataxin depletion results in multiple, complex responses that lead to detrimental redox effects that could contribute to the mechanisms involved in the pathogenesis of FA.