PTC Therapeutics Announces Topline Results from Vatiquinone MOVE-FA Registration-Directed Trial Twitter Facebook LinkedIn GooglePlus Pinterest

SOUTH PLAINFIELD, N.J. , May 23, 2023 /PRNewswire/ -- PTC Therapeutics, Inc. (NASDAQ: PTCT) today reported topline results from the MOVE-FA trial of vatiquinone in patients with Friedreich ataxia. The study did not meet its primary endpoint of statistically significant change in mFARS score at 72 weeks in the primary analysis population. However, vatiquinone treatment did demonstrate significant benefit on key disease subscales and secondary endpoints. In addition, in the population of subjects that completed the study protocol, significance was reached in the mFARS endpoint and several secondary endpoints.

Large-scale expansions of Friedreich's ataxia GAA•TTC repeats in an experimental human system: role of DNA replication and prevention by LNA-DNA oligonucleotides and PNA oligomers

Anastasia Rastokina, Jorge Cebrián, Negin Mozafari, Nicholas H Mandel, C I Edvard Smith, Massimo Lopes, Rula Zain, Sergei M Mirkin, Large-scale expansions of Friedreich's ataxia GAA•TTC repeats in an experimental human system: role of DNA replication and prevention by LNA-DNA oligonucleotides and PNA oligomers, Nucleic Acids Research, 2023;, gkad441, doi:10.1093/nar/gkad441 

 In summary, we developed a first of a kind, genetically tractable experimental system to study large-scale expansions of FRDA GAA•TTC repeats in cultured human cells. Our candidate gene analysis implicates fork reversal and restoration in the process. We believe that this system could be a valuable tool for elucidating the mechanisms of large-scale expansions in humans and for evaluating the efficiency of perspective FRDA drugs targeting the instability of GAA•TTC repeats. Finally, we have showed that LNA-modified oligonucleotides and PNA oligomers targeting the GAA•TTC repeats prevent their expansion holding a promise to be developed as future therapeutics for the treatment of FRDA.

The Loss of Frataxin Impairs Microglia Homeostatic Functions in Friedreich’s Ataxia

Ferrara G. Abstracts of the Fifth Brainstorming Research Assembly for Young Neuroscientists (BraYn), Italy, 28-30 September 2022. Neurology International. 2023 Mar;15(1):415-496. DOI: 10.3390/neurolint15010028. PMID: 36976671; PMCID: PMC10056600. 

Martina Milani, Ilaria Della Valle, Riccardo Turchi, Flavia Tortolici, Daniele Lettieri Barbato, Katia Aquilano, Savina Apolloni and Nadia D’Ambrosi. These data suggest that microglia targeting could play a valuable role in ameliorating neuronal circuits in FRDA-affected CNS regions, consistent with other neurodegenerative conditions, where the modulation of microglia represents one of the most promising therapeutic strategies.

Neuropsychiatric symptoms in spinocerebellar ataxias and Friedreich ataxia

Karamazovova S, Matuskova V, Ismail Z, Vyhnalek M. Neuropsychiatric symptoms in spinocerebellar ataxias and Friedreich ataxia. Neuroscience and Biobehavioral Reviews. 2023 May;150:105205. DOI: 10.1016/j.neubiorev.2023.105205. PMID: 37137435. 

 Apart from its role in motor coordination, the importance of the cerebellum in cognitive and affective processes has been recognized in the past few decades. Spinocerebellar ataxias (SCA) and Friedreich ataxia (FRDA) are rare neurodegenerative diseases of the cerebellum presenting mainly with a progressive loss of gait and limb coordination, dysarthria, and other motor disturbances, but also a range of cognitive and neuropsychiatric symptoms.

Patient-Derived iPSC-Neurons and Microglia for Modeling Friedreich’s Ataxia Disease

1694 Patient-Derived iPSC-Neurons and Microglia for Modeling Friedreich’s Ataxia Disease; Priyanka Mishra, Anusha Sivakumar, Avalon Johnson, Emily Hansen, Jacqueline Nguyen, Nicole Coufal, Stephanie Cherqui. May 01, 2023 Volume 31 Issue 4 Supplement 1 S1-794 26th Annual Meeting of the American Society of Gene & Cell Therapy.

Utilising these two models, to understand the role of microglia in the neurodegeneration in FRDA, and its rescue by the gene corrected microglia.

Safety of Ascending Doses of AAVrh.10hFXN to Treat the Cardiac Manifestations of Friedreich’s Ataxia

1656 Safety of Ascending Doses of AAVrh.10hFXN to Treat the Cardiac Manifestations of Friedreich’s Ataxia; Jonathan B. Rosenberg, Alessandria Greco, Carlos Munoz Zuluaga, Monica La Russa Gertz, Melissa Yost-Bido, Nicholas C. Gorman, Alvin Chen, Vikrum Kooner, Bishnu P. De, Stephen M. Kaminsky, Rodolfo J. Ricart Arbona, Heather R. Martin, Sebastien Monette, Richie Khanna, Ronald G. Crystal, Dolan Sondhi. 

 On average, the increase in cardiac FXN expression after AAVrh.10hFXN administration with 5.7x1011 and 1.8x1012 gc/kg doses was 6.5 and 37%, respectively, over the PBS-treated controls. Together, these data identify the safe doses of AAVrh.10hFXN relevant for the treatment of the cardiac manifestations of FA.

Novel AAV Capsid Identification and Characterization for Neuromuscular and Cardiac Indications

1549 Novel AAV Capsid Identification and Characterization for Neuromuscular and Cardiac Indications; Jennifer C. G. Green, Jessica F. Boehler, Meghan S. Soustek, Jamie L. Marshall, Tiffany Willacy, Prushti Bhavsar, Kristy J. Brown, Sharon McGonigle, Carl Morris (Solid Biosciences). May 01, 2023 Volume 31Issue 4Supplement 1S1-794 26th Annual Meeting of the American Society of Gene & Cell Therapy.

 Adeno-associated virus (AAV) mediated gene therapy continues to be a promising therapeutic path for various diseases, including monogenic neuromuscular and cardiac indications such as Duchenne muscular dystrophy (DMD) and Friedreich’s ataxia (FA). However, the high systemic doses currently required to achieve widespread therapeutic benefit can pose potential safety risks. These risks could be decreased or eliminated if therapeuticbenefit could be achieved using lower doses through a more targeted and efficacious vector.

Comparison of Cardiac Specific Promoters to Liver-Specific miRNA Targets to Maximize Cardiac vs Liver Expression Following Intravenous AAVrh.10-Mediated Cardiac Gene Therapy

1518 Comparison of Cardiac Specific Promoters to Liver-Specific miRNA Targets to Maximize Cardiac vs Liver Expression Following Intravenous AAVrh.10-Mediated Cardiac Gene Therapy; Abhishek Bose, Neil R. Hackett, Nadir Khan-Yusufzai, Katie M. Stiles, Ronald G. Crystal. May 01, 2023 Volume 31Issue 4Supplement 1S1-794 26th Annual Meeting of the American Society of Gene & Cell Therapy. 

 Intravenous (IV) administration of a cardiotropic AAV vector is the simplest and most effective strategy to deliver a gene to the myocardium for the treatment of hereditary cardiac disease. The challenge in using the IV route is that a substantial proportion of AAV vectors distribute to the liver, resulting in high liver expression with risks of liver toxicity.

CRISPR/Cas9 Edited Hematopoietic Stem and Progenitor Cells for Friedreich’s Ataxia

1354 CRISPR/Cas9 Edited Hematopoietic Stem and Progenitor Cells for Friedreich’s Ataxia; Anusha Sivakumar, Rafael Andres Badell-Grau, Rita Wan, Veenita Khare, Stephanie Cherqui. May 01, 2023 Volume 31Issue 4Supplement 1S1-794 26th Annual Meeting of the American Society of Gene & Cell Therapy.

Preliminary data suggest decreased pathological cardiac hypertrophy, improved mitochondrial biogenesis, reduced inflammation, and oxidativedamage in mice receiving gene-edited cells compared to mock. Altogether, the preliminary data from the in vivo studies demonstrate that single infusion of FXN gene corrected HSPCs engraft in the bone marrow niche to become a reservoir of healthy cells that can integrate into the injured organs for local and systemic delivery of frataxin protein.

Reversal of Cardiac Phenotype in a Mouse Model of Friedreich’s Ataxia Following Administration of AAV Gene Therapy

1184 Reversal of Cardiac Phenotype in a Mouse Model of Friedreich’s Ataxia Following Administration of AAV Gene Therapy; Joshua C. Chang, Whitney Blankenberger, Su Liu, Marie Stark, Jacqueline A. Brassard, Tianbi Zhang, Fria Bolan, Samuel D. Sutton, Mario Guerrero, José A. Corleto, Nakyo Heo, Dwaipayan Sen, Mark A. Champe, Fabrizia Urbinati, Bala Medicherla, Carlos Fonck (Astellas Gene Therapies); May 01, 2023 Volume 31Issue 4Supplement 1S1-794 26th Annual Meeting of the American Society of Gene & Cell Therapy 

The livers of KO mice treated with AAV-PGK-hFXN displayed Kupffer cell hypertrophy and minimal hepatocyte necrosis. These liver changes are commonly associated with AAV gene therapies, are likely related to gene expression, and are considered non-adverse given the low incidence of observations. Overall, dose-dependent efficacy was observed in AAV-PGK-hFXN-treated KO mice compared with vehicle-treated mice based on survival, cardiac function, cardiac injury biomarkers, and histology. These data support the use AAV-based gene transfer as a promising approach to treat patients with FA cardiomyopathy.