Mitochondrial Calcium Homeostasis in the Pathology and Therapeutic Application in Friedreich's Ataxia

Hongting Zhao, Zhuoyuan Li, Yutong Liu, Meng Zhang & Kuanyu Li. Neurosci. Bull. (2022). doi:10.1007/s12264-022-01007-4

Gambling associated risk-taking decision in cerebellar ataxia

Ruo-Yah Lai Natasha A. Desai Christian J. Amlang Chi-Ying R. Lin Tiffany X. Chen Michael J. Minyetty Nadia Amokrane Sheng-Han Kuo;  Parkinsonism & Related Disorders, Volume 0, Issue 0, 105252,  doi:10.1016/j.parkreldis.2022.105252 

People with cerebellar ataxia (CA) can develop impulsive and compulsive behaviors that significantly affect their and their family's quality of life. To further assess the decision-making process associated with these behaviors, we used the Iowa Gambling Task (IGT) to study people with CA.

CA cases obtained significantly lower IGT total scores than controls (−5.30 ± 37.53 vs. 21.30 ± 37.37, p = 0.004). In addition, those with CA made riskier decisions throughout the task compared to controls. Although both CA and controls learned to make decisions with more favorable outcomes over the course of completing the IGT, CA participants never matched the controls' performance. IGT performance did not correlate with ataxia severity or depressive symptoms.

SHAREHOLDER ALERT: Pomerantz Law Firm Investigates Claims On Behalf of Investors of Design Therapeutics, Inc.

NEW YORK, Dec. 26, 2022 /PRNewswire/ -- Pomerantz LLP is investigating claims on behalf of investors of Design Therapeutics, Inc. ("Design" or the "Company") (NASDAQ: DSGN). 

On or around March 24, 2021, Design conducted its initial public offering ("IPO"), selling 12 million shares of stock priced at $20.00 per share. Then, on December 7, 2022, Design reported initial data from a Phase 1 trial of DT-216 in patients with Friedreich ataxia. Among other results, Design said 16 patients on DT-216 and eight on placebo reported at least one treatment-emergent adverse event. On this news, Design's stock price fell sharply during intraday trading on December 8, 2022.

The psychosocial situation of families caring for children with rare diseases during the COVID-19 pandemic: results of a cross-sectional online survey

Lydia Rihm, Mareike Dreier, Farhad Rezvani, Silke Wiegand-Grefe & Jörg Dirmaier; Orphanet J Rare Dis 17, 449 (2022). doi:10.1186/s13023-022-02595-0 

 This study indicates a high psychosocial burden on family caregivers of children with RDs during the early COVID-19 pandemic, characterized by high distress levels and wide-ranging everyday problems, unmet psychosocial information needs, and reduced caregiver-reported HRQoL in children with RDs. The findings highlight the ongoing need for target group-specific, low-threshold support services (e.g., websites) during and after the pandemic.

Social concepts and the cerebellum: behavioural and functional connectivity signatures in cerebellar ataxic patients

Lopes da Cunha Pamela, Fittipaldi Sol, González Campo Cecilia, Kauffman Marcelo, Rodríguez-Quiroga Sergio, Yacovino Darío Andrés, Ibáñez Agustín, Birba Agustina and García Adolfo M. 2023; Phil. Trans. R. Soc., B3782021036420210364, doi:10.1098/rstb.2021.0364 

We compared behavioural outcomes between groups and examined their association with cerebellar connectivity. CA patients showed deficits in social text comprehension and normal scores in the non-social text. Also, social text outcomes in controls selectively correlated with connectivity between the cerebellum and key regions subserving multi-modal semantics and social cognition, including the superior and medial temporal gyri, the temporal pole and the insula. Conversely, brain-behaviour associations involving the cerebellum were abolished in the patients. Thus, cerebellar structures and connections seem involved in processing social concepts evoked by naturalistic discourse. Such findings invite new theoretical and translational developments integrating social neuroscience with embodied semantics.

Protection of dystrophic muscle cells using Idebenone correlates with the interplay between calcium, oxidative stress and inflammation

Amanda Harduim Valduga, Daniela Sayuri Mizobuti, Fernanda dos Santos Rapucci Moraes, Rafael Dias Mâncio, Luis Henrique Rapucci Moraes, Túlio de Almeida Hermes, Aline Barbosa Macedo, Elaine Minatel; Int J Exp Path. 2022; 00: 1- 9. doi:10.1111/iep.12463 

The Idebenone treatment was able to reduce the levels of oxidative stress markers, such as H2O2 and 4-HNE, as well as decreasing intracellular calcium influx in the dystrophic muscle cells. Regarding Idebenone effects on the anti-oxidant defence system, an up-regulation of catalase levels, glutathione reductase (GR), glutathione peroxidase (GPx) and superoxide dismutase (SOD) activity was observed in the dystrophic muscle cells. In addition, the Idebenone treatment was also associated with reduction in inflammatory molecules, such as nuclear factor kappa-B (NF-κB) and tumour necrosis factor (TNF) in mdx muscle cells.

Astrocytic mitochondrial frataxin—A promising target for ischemic brain injury

Hazra, R, Novelli, EM, Hu, X.; CNS Neurosci Ther. 2022; 00: 1- 6. doi:10.1111/cns.14068 

In the ischemic brain, hypoxia leads to mitochondrial dysfunction, insufficient energy production, and astrocyte activation. Yet, most studies investigating mitochondrial dysfunction in cerebral ischemia have focused exclusively on neurons. This review will highlight the importance of the morphological, molecular, and functional heterogeneity of astrocytes in their role in brain injuries and explore how activated astrocytes exhibit calcium imbalance, reactive oxygen species overproduction, and apoptosis. In addition, special focus will be given to the role of the mitochondrial protein frataxin in activated astrocytes during ischemia and its putative role in the pharmacological management of cerebral ischemia.

Study traces shared and unique cellular hallmarks found in 6 neurodegenerative diseases

ScienceDaily, 21 December 2022. Arizona State University. 

In a study appearing in the current issue of Alzheimer's & Dementia: The Journal of the Alzheimer' Association, corresponding author Carol Huseby of Arizona State University and her colleagues look at cellular alterations in six distinct neurodegenerative diseases: amyotrophic lateral sclerosis or Lou Gehrig's disease, Alzheimer's disease, Friedreich's ataxia, frontotemporal dementia, Huntington's disease and Parkinson's disease. The selected RNA transcripts reveal eight common themes across the six neurodegenerative diseases: transcription regulation, degranulation (a process involved in inflammation), immune response, protein synthesis, cell death or apoptosis, cytoskeletal components, ubiquitylation/proteasome (involved in protein degradation) and mitochondrial complexes (which oversee energy usage in cells). The eight cellular dysfunctions uncovered are associated with identifiable pathologies in the brain characteristic of each disease.

Blood RNA transcripts reveal similar and differential alterations in fundamental cellular processes in Alzheimer's disease and other neurodegenerative diseases

Carol J. Huseby, Elaine Delvaux, Danielle L. Brokaw, Paul D. Coleman; Alzheimer's & Dementia, 2022; DOI: 10.1002/alz.12880 

 We report that transcripts of the blood transcriptome selected for each of the neurodegenerative diseases represent fundamental biological cell processes including transcription regulation, degranulation, immune response, protein synthesis, apoptosis, cytoskeletal components, ubiquitylation/proteasome, and mitochondrial complexes that are also affected in the brain and reveal common themes across six neurodegenerative diseases.

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

Pandolfo M, Reetz K, Darling A, Rodriguez de Rivera FJ, Henry PG, Joers J, Lenglet C, Adanyeguh I, Deelchand D, Mochel F, Pousset F, Pascual S, Van den Eede D, Martin-Ugarte I, Vilà-Brau A, Mantilla A, Pascual M, Martinell M, Meya U, Durr A.; Neurol Genet. 2022 Nov 1;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.

Design and Delivery of SINEUP: A New Modular Tool to Increase Protein Translation

Arnoldi M, Zarantonello G, Espinoza S, Gustincich S, Di Leva F, Biagioli M.; Methods Mol Biol. 2022;2434:63-87. doi: 10.1007/978-1-0716-2010-6_4. 

Synthetic SINEUP is thus a novel molecular tool that potentially may be used for any industrial or biomedical application to enhance protein production, also as possible therapeutic strategy in haploinsufficiency-driven disorders.Here, we describe a detailed protocol to (1) design a specific BD directed to a gene of interest and (2) assemble and clone it with the ED to obtain a functional SINEUP molecule. Then, we provide guidelines to efficiently deliver SINEUP into mammalian cells and evaluate its ability to effectively upregulate target protein translation.

Recurrent repeat expansions in human cancer genomes

Erwin, G.S., Gürsoy, G., Al-Abri, R. et al.; Nature (2022). doi:10.1038/s41586-022-05515-1 

Expansions of tandem DNA repeats (TRs) are known to cause more than 50 devastating human diseases, including Huntington’s disease and fragile X syndrome1,2. TR tracts that cause human disease are typically large (more than 100 bp)1. However, identifying large TRs with short-read DNA sequencing methods is difficult because the repeat sequences are ubiquitous in the genome and many are too large—larger than the typical sequencing read length—to uniquely map to the reference genome9. Thus, many large TRs go undetected with current genomic technologies, and, despite their importance to monogenic disease, the frequency and function of recurrent repeat expansions (rREs) are unknown in complex human genetic diseases such as cancer.

Researchers may have found a new path for halting cancer cell production

Stanford Medicine; December 14, 2022; 

The project began not with cancer, but with a rare, neurodegenerative disease without a cure, Friedreich ataxia. Five years ago, Erwin, then a graduate student at the University of Wisconsin-Madison, was exploring the genetic underpinnings of Friedreich ataxia in hopes of filling the therapeutic void. Erwin knew that DNA mutations called repeat expansions cause Friedreich ataxia, along with dozens of other serious conditions, many neurological. 

Repeat expansions are stretches of DNA that erroneously repeat themselves dozens to thousands of times in the genome. 

 Testing the molecule in cells from a Friedreich ataxia patient, Erwin saw that Syn-TEF1 successfully targeted the repeat expansion, helping RNA polymerase move through it to transcribe the FXN gene, bringing frataxin to normal levels. Due to its success in cells, researchers are now testing the safety and dosage of a version of Syn-TEF1 in Friedreich ataxia patients.

Kaleibe launched by Replay to target genetic brain disorders with gene therapy

14-12-2022​. Replay, a genome writing company reprogramming biology by writing and delivering big DNA, has announced the launch of Kaleibe, a herpes simplex virus (HSV) gene therapy company targeting genetic brain disorders. It is the third product company to launch since Replay’s formation in July and will leverage its high payload capacity HSV delivery vector, synHSVTM, to target genetic brain disorders. 

The initial development programs will focus on genetic Parkinson’s disease (PD) and Friedreich’s ataxia (FRDA). These diseases have a high unmet medical need and known genetic causes. The target genes, 33kb and 135kb, respectively, far exceed the 5kb payload capacity of adeno-associated virus (AAV) vectors.

G-rich motifs within phosphorothioate-based antisense oligonucleotides (ASOs) drive activation of FXN expression through indirect effects

Feng Wang, Ezequiel Calvo-Roitberg, Julia M Rembetsy-Brown, Minggang Fang, Jacquelyn Sousa, Zachary J Kartje, Pranathi Meda Krishnamurthy, Jonathan Lee, Michael R Green, Athma A Pai, Jonathan K Watts; Nucleic Acids Research, 2022;, gkac1108, doi:10.1093/nar/gkac1108 

The phosphorodiamidate morpholino oligomer analogs of our ASOs did not activate FXN, pointing to a PS-backbone-mediated effect. Our study demonstrates the importance of multiple, detailed control experiments and target validation in oligonucleotide studies employing novel mechanisms such as gene activation.

Retinal and Visual Pathways Involvement in Carriers of Friedreich’s Ataxia

Ziccardi, L.; Barbano, L.; Antonelli, G.; Cioffi, E.; Di Renzo, A.; Gioiosa, V.; Marcotulli, C.; Grzybowski, A.; Casali, C.; Parisi, V. ; Diagnostics 2022, 12, 3135. doi:10.3390/diagnostics12123135 

Therefore, our data suggest that, in C-FRDA, a dysfunction of retinal elements without morphological macular impairment may occur. In addition, a morphological impairment of RNFL associated with an abnormal neural conduction along the visual pathways can be also detected.

Double blind trial of a deuterated form of linoleic acid (RT001) in Friedreich ataxia

David R. Lynch, Katherine D. Mathews, Susan Perlman, Theresa Zesiewicz, Sub Subramony, Omid Omidvar, Adam P. Vogel, Ana Krtolica, Nadia Litterman, Lex van der Ploeg, Frederic Heerinckx, Peter Milner & Mark Midei; J Neurol (2022). doi:10.1007/s00415-022-11501-4 

The results of this study provide no evidence for a significant benefit of RT001 at the dosages tested in this Friedreich ataxia patient population.

Ataxia Rating Scales: Content Analysis by Linking to the International Classification of Functioning, Disability and Health

Etoom, M.; Jahan, A.M.; Alghwiri, A.; Lena, F.; Modugno, N.; Healthcare 2022, 10, 2459. doi:10.3390/healthcare10122459

The content analysis of ataxia rating scales would help clinicians and researchers select the most appropriate scale and understand ataxic symptoms and their impact on function. It seems that SARA is the optimal scale for rapid assessment of ataxia or in busy clinical settings. UMSARS or FARS are more appropriate for the investigating the impact of ataxia on overall health, and monitoring ataxia progression and disability.

Clinical Drug-Drug Interaction Between Vatiquinone, a 15-Lipoxygenase Inhibitor, and Rosuvastatin, a Breast Cancer Resistance Protein Substrate

Lee, L., Murase, K., Ma, J. and Thoolen, M. (2022); Clin Pharmacol Drug Dev. doi:10.1002/cpdd.1199

These results demonstrate that vatiquinone has no clinically relevant effect on the pharmacokinetics of rosuvastatin.

Ataxia Rating Scales Reflect Patient Experience: an Examination of the Relationship Between Clinician Assessments of Cerebellar Ataxia and Patient-Reported Outcomes

Michele H. Potashman, Miranda L. Mize, Melissa W. Beiner, Samantha Pierce, Vladimir Coric & Jeremy D. Schmahmann; Cerebellum (2022). doi:10.1007/s12311-022-01494-1 

Ataxia rating scales are observer administered clinical outcome assessments (COAs) of the cerebellar motor syndrome. It is not known whether these COAs mirror patient experience of their disease. Here we test the hypothesis that ataxia COAs are related to and reflect patient reported symptoms and impact of illness.

CIRM grant $4.8m to fund gene therapy for rare disease

6 December 2022. CIRM grant will fund novel gene therapy that aims for single lifelong treatment of Friedreich’s ataxia, a progressive neuromuscular disorder; a second CIRM grant will advance efforts to leverage UC San Diego research on another rare disease. 

I n 2020, Cherqui and her team, in a new study, found that specifically described how CRISPR-Cas9 gene editing of hematopoietic stem cells from patients with FA could work. Hematopoietic stem cells are capable of developing into all types of blood cells. CRISPR-Cas9 is a technology that allows scientists to edit parts of the genome by removing, adding or altering sections of the DNA sequence. 

 In November 2022, the California Institute for Regenerative Medicine (CIRM) awarded Cherqui and the team a grant of $4.8 million, to move this approach closer to clinical trials. The funding will be used to develop a therapy based on gene-edited hematopoietic stem and progenitor cells derived from FA patients, which would be re-infused as a one-time, lifelong treatment.

Form S-1/A JUPITER NEUROSCIENCES,

December 7, 2022; UNITED STATES SECURITIES AND EXCHANGE COMMISSION. REGISTRATION STATEMENT UNDER THE SECURITIES ACT OF 1933. 

JOTROL™ was developed together with our technology partner Aquanova AG, Darmstadt, Germany. JOTROL™ is formulated with a unique patented micellar technology that is projected to increase the bioavailability profile of resveratrol. Manufacturing technology transfers were completed in 2017 and manufacturing procedures and clinical trial supply manufacturing has been completed at Catalent Pharmaceutical Services, Inc., St Petersburg, Florida. JOTROL™ is a micellar non-aqueous solution of resveratrol delivered in a softgel capsule. Each capsule includes 100mg of resveratrol. Pre-clinical trials in mice and rats were conducted comparing JOTROL™ to micronized resveratrol, labeled to have the highest bioavailability in the nutritional market, to demonstrate that we could achieve a significantly higher bioavailability. Summary details of these studies are included in the section “Description of Business”. A Phase I dose finding pharmacokinetic (“PK”) study in healthy volunteers was completed during the first half of 2021. The study results met our targeted goals. The results from this study will be used as a cross-reference for all indications where JOTROL™ will be used in Phase II and Phase III clinical trials. The Phase I results and the FDA guidance of cross-referencing is further described in the section “Description of Business”. The Company has not discussed the use of cross-referencing in this manner with the FDA or other comparable regulatory authorities.

Design Therapeutics Reports Positive Data from Single-Ascending Dose Trial of DT-216 for the Treatment of Friedreich Ataxia and Portfolio Progress

CARLSBAD, Calif., Dec. 07, 2022 (GLOBE NEWSWIRE) -- Design Therapeutics, Inc. (Nasdaq: DSGN), a clinical-stage biotechnology company developing treatments for serious degenerative genetic diseases, today reported progress across its portfolio of novel GeneTAC™ small molecules. Today’s updates include initial results on DT-216 from the company’s single-ascending dose (SAD) Phase 1 clinical trial in patients with Friedreich ataxia (FA). The results show that DT-216 was generally well-tolerated and able to overcome the frataxin (FXN) transcription impairment that causes FA, with a greater than two-fold increase in FXN mRNA in the cohort with the highest response. These data support the continued advancement of DT-216 in the ongoing multiple-ascending dose (MAD) Phase 1 trial and the anticipated Phase 2 clinical trial in FA patients, which is on track to begin in 2023.

FDA: B-NMN Can No Longer Be Sold as a Dietary Supplement in the US

December 06, 2022. Recently, the US Food and Drug Administration (FDA) said that beta-nicotinamide mononucleotide (Β-NMN) — a popular longevity supplement ingredient — is under investigation as a potential new drug. Therefore, companies can no longer market it as a dietary supplement. This decision has sparked concern among those who use NMN and the dietary supplement industry.

Ataxia Rating Scales: Content Analysis by Linking to the International Classification of Functioning, Disability and Health

Etoom, M.; Jahan, A.M.; Alghwiri, A.; Lena, F.; Modugno, N. . Healthcare 2022, 10, 2459. doi:10.3390/healthcare10122459 

 The content analysis of ataxia rating scales would help clinicians and researchers select the most appropriate scale and understand ataxic symptoms and their impact on function. It seems that SARA is the optimal scale for rapid assessment of ataxia or in busy clinical settings. UMSARS or FARS are more appropriate for the investigating the impact of ataxia on overall health, and monitoring ataxia progression and disability.

Solid Biosciences Announces Closing of Acquisition of AavantiBio and Concurrent $75 Million Private Placement

CHARLESTOWN, Mass., Dec. 05, 2022 (GLOBE NEWSWIRE) -- Solid Biosciences Inc. (Nasdaq: SLDB), a life sciences company focused on advancing meaningful therapies for Duchenne muscular dystrophy (Duchenne), today announced the closing of its acquisition of AavantiBio, a privately held gene therapy company focused on transforming the lives of patients with Friedreich’s ataxia and rare cardiomyopathies, including its pipeline assets and net cash. The combined company will focus on advancing a portfolio of neuromuscular and cardiac programs, including SGT-003, a differentiated gene transfer candidate, for the treatment of Duchenne, AVB-202, a gene transfer candidate for the treatment of Friedreich’s ataxia, AVB-401 for BAG3 mediated dilated cardiomyopathy, and additional assets for the treatment of undisclosed cardiac diseases.

The French Friedreich's Ataxia Association awards a grant of 28,000 € to the IRBLleida to understand the early stages of this rare disease

Monday, December 5, 2022 

 The French Friedreich's Ataxia Association (AFAF) has awarded a €28,000 grant to the Biochemistry of Oxidative Stress research group at the Institute for Research in Biomedicine of Lleida (IRBLleida) and the University of Lleida (UdL) to better understand the early stages of the disease. This is the third time that the AFAF has financed a Lleida project and on this occasion, it will be used for a comparative study of mice of the I151F model to discern the early stages of the pathogenesis of Friedreich's ataxia.

Tele-Exercise During COVID-19: Effectiveness of an Adaptive Seated Intervention for Adults With Chronic Neurological Impairments

Devina Kumar, Amy Bialek, Ayushi Divecha, Rachel Garn, Kathleen Friel, Talita Campos; Archives of Physical Medicine and Rehabilitation, Volume 103, Issue 12, e54 - e55, doi:10.1016/j.apmr.2022.08.566

The COVID pandemic has influenced in-person physical, social, and emotional engagement for all populations across the lifespan. Individuals with CNI who require regular exercise and physical activity may demonstrate benefits from guided virtual exercise programs that foster social interaction, personal engagement and physical well-being.

Double blind trial of a deuterated form of linoleic acid (RT001) in Friedreich ataxia

David R. Lynch, Katherine D. Mathews, Susan Perlman, Theresa Zesiewicz, Sub Subramony, Omid Omidvar, Adam P. Vogel, Ana Krtolica, Nadia Litterman, Lex van der Ploeg, Frederic Heerinckx, Peter Milner & Mark Midei; J Neurol (2022). doi:10.1007/s00415-022-11501-4

The results of this study provide no evidence for a significant benefit of RT001 at the dosages tested in this Friedreich ataxia patient population.

Clinical evidence of interventions assessed in Friedreich ataxia: a systematic review

Jain P, Badgujar L, Spoorendonk J, Buesch K.; Therapeutic Advances in Rare Disease. 2022;3. doi:10.1177/26330040221139872

 Identified literature showed a considerable unmet need for therapeutic interventions that halt or slow the deteriorating nature of FA. Novel efficacious drugs should be investigated that aim to improve symptoms or slow disease progression.

Friedreich’s ataxia: major trial readouts and regulatory events to watch in 2023

www.clinicaltrialsarena.com; Analysis. November 30, 2022 

The FDA could approve the first treatment for Friedreich’s ataxia, and at least three other major trials have readouts expected by year end. All signs indicate 2023 will prove a pivotal year in Friedreich’s ataxia drug development. Reata’s omaveloxolone, which met its primary endpoint in a Phase II trial, is up for FDA approval on February 28. Meanwhile, a Phase II/III trial of PTC’s vatiquinone, a Phase I/II trial of Stealth Bio’s elamipretide, and a Phase II study of Larimar’s CI-1601 all have key results expected in 2023.