A Gene-Edited Cell Therapy for an Incurable Disease: Researchers Receive USD 4.8M Grant to Treat Friedreich’s Ataxia

By: Rebecca Roberts - Jan. 23, 2023. Professor Stephanie Cherqui of University of California San Diego’s School of Medicine recently received a prestigious grant from the Californian Institute of Regenerative Medicine, which will allow her and her team to bring her novel CRISPR therapy for the fatal neurodegenerative disease Friedreich’s ataxia to the clinic. Cherqui’s novel treatment for FRDA is an ex vivo gene-edited autologous cell therapy. The process begins with extracting haematopoietic stem and progenitor cells (HSPCs) from the peripheral blood of patients before excising the trinucleotide repeat hyperexpansion in intron 1 of the FXN gene from the cells. This edit involves delivering a ribonucleoprotein (RNP) complex consisting of Cas9 and two sgRNAs – one guide for either end of the trinucleotide expansion. In their original proof-of-concept study, the team were able to achieve editing efficiencies of more than 50% in the HSPCs of FRDA patients. Edited HSPCs display restored expression of frataxin and mitochondrial function, and can be transplanted back to patients as a one-time, curative therapy. »Because this mutation is located within an intron in the FXN gene, it is a good target for gene correction by removing this expansion using CRISPR-Cas9. In addition, this approach would be valid for all FRDA patients, because they all carry a trinucleotide expansion mutation,« Cherqui elaborates. Edited HSPCs are currently used for the treatment of blood disorders such as sickle cell disease and β-thalassemia. However, Cherqui’s work is novel because it offers proof that these cells can be used to treat conditions like FRDA. Edited HSPCs are able to proliferate and differentiate into macrophages and microglia in vivo in mice, and traffic to the necessary tissues throughout the body and brain of FRDA patients. The early data shows that transplantation of the corrected HSPCs in mice prevents disease progression. The therapy will be aimed at the treatment of babies and children in whom the disease has not yet caused significant damage, however, Cherqui says they may also be able to halt disease progression in adult patients.

A Gene-Edited Cell Therapy for an Incurable Disease: Researchers Receive USD 4.8M Grant to Treat Friedreich’s Ataxia

Protoporphyrin IX Binds to Iron(II)-Loaded and to Zinc-Loaded Human Frataxin

Bernardo-Seisdedos G, Schedlbauer A, Pereira-Ortuzar T, Mato JM, Millet O.; Life (Basel). 2023 Jan 12;13(1):222. doi: 10.3390/life13010222. PMID: 36676171. 

We demonstrate that frataxin also binds Zn2+ in a structurally similar way to Fe2+, but with lower affinity. In turn, both Fe2+-loaded and Zn2+-loaded frataxins specifically associate to protoporphyrin IX with micromolar affinity, while apo-frataxin does not bind to the porphyrin. Protoporphyrin IX association to metal-loaded frataxin shares the binding epitope with ferrochelatase.

Small-molecule inhibitors of proteasome increase CjCas9 protein stability

Yaméogo P, Majeau N, Mbakam CH, Tremblay JP (2023) . PLoS ONE 18(1): e0280353. doi:10.1371/journal.pone.0280353 

We observed that the CjCas9 protein expressed in HEK293T cells after transfection of this transgene under a CMV promoter was much lower than the SpCas9 protein in the same conditions. We thus evaluated the effect of proteasome inhibitors on CjCas9 protein stability and its efficiency on FXN gene editing. Western blotting showed that the addition of MG132 or bortezomib, significantly increased CjCas9 protein levels in HEK293T and HeLa cells. Moreover, bortezomib increased the level of CjCas9 protein expressed under promoters weaker than CMV such as CBH or EFS but which are specific for certain tissues. Finally, ddPCR quantification showed that bortezomib treatment enhanced CjCas9 efficiency to delete GAA repeat region of FXN gene in HEK293T cells. The improvement of CjCas9 protein stability would facilitate its used in CRISPR/Cas system.

A wearable motion capture suit and machine learning predict disease progression in Friedreich’s ataxia

Balasundaram Kadirvelu, Constantinos Gavriel, Sathiji Nageshwaran, Jackson Ping Kei Chan, Suran Nethisinghe, Stavros Athanasopoulos, Valeria Ricotti, Thomas Voit, Paola Giunti, Richard Festenstein & A. Aldo Faisal; Nat Med (2023). doi:10.1038/s41591-022-02159-6

Our work demonstrates how data-derived wearable biomarkers can track personal disease trajectories and indicates the potential of such biomarkers for substantially reducing the duration or size of clinical trials testing disease-modifying therapies and for enabling behavioral transcriptomics.

Proprioceptors-enriched neuronal cultures from induced pluripotent stem cells from Friedreich ataxia patients show altered transcriptomic and proteomic profiles, abnormal neurite extension, and impaired electrophysiological properties

Chiara Dionisi, Marine Chazalon, Myriam Rai, Céline Keime, Virginie Imbault, David Communi, Hélène Puccio, Serge N Schiffmann, Massimo Pandolfo; Brain Communications, 2023;, fcad007, doi:10.1093/braincomms/fcad007 

 Our study suggests the existence of abnormalities affecting proprioceptors in Friedreich ataxia, particularly their ability to extend towards their targets and transmit proper synaptic signals. It also highlights the need for further investigations to better understand the mechanistic link between FXN silencing and proprioceptive degeneration in Friedreich ataxia.

Form S-1/A JUPITER NEUROSCIENCES

As filed with the U.S. Securities and Exchange Commission on January 17, 2023. 

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.

Neurobehavioral deficits of mice expressing a low level of G127V mutant frataxin

Daniel Fil, Robbie L. Conley, Aamir R. Zuberi, Cathleen M. Lutz, Terry Gemelli, Marek Napierala, Jill S. Napierala; Neurobiology of Disease, Volume 177, 2023, 105996, ISSN 0969-9961, doi:10.1016/j.nbd.2023.105996. 

 Results of these studies provide insight into the unique pathogenic mechanism of the FXN G130V mechanism and the tolerable limit of Fxn/FXN expression in vivo.

Quantitative Oculomotor Assessment in Hereditary Ataxia: Discriminatory Power, Correlation with Severity Measures, and Recommended Parameters for Specific Genotypes

Pilar Garces, Chrystalina A. Antoniades, Anna Sobanska, Norbert Kovacs, Sarah H. Ying, Anoopum S. Gupta, Susan Perlman, David J. Szmulewicz, Chiara Pane, Andrea H. Németh, Laura B. Jardim, Giulia Coarelli, Michaela Dankova, Andreas Traschütz & Alexander A. Tarnutzer; Cerebellum (2023). doi:10.1007/s12311-023-01514-8 

Recommendation of other paradigms was limited by the scarcity of cross-validating correlations, except saccadic intrusions (FRDA), pursuit eye movements (SCA17), and quantitative head-impulse testing (SCA3/6). This work aids in understanding the current knowledge of quantitative oculomotor parameters in hereditary ataxias, and identifies gaps for validation as potential trial outcome measures in specific ataxia genotypes.

Ketolysis is Required for the Proper Development and Function of the Somatosensory Nervous System

Jonathan Enders, Jarrid Jack, Sarah Thomas, Paige Lynch, Sarah Lasnier, Xin Cao, M Taylor Swanson, Janelle M Ryals, John P Thyfault, Patrycja Puchalska, Peter A Crawford, Douglas E Wright; bioRxiv 2023.01.11.523492; doi:10.1101/2023.01.11.523492 

We conclude that ketone metabolism is essential for the development of the somatosensory nervous system. These findings also suggest that decreased ketone oxidation in the somatosensory nervous system may explain the neurological symptoms of Friedreich's ataxia.

FXN gene methylation determines carrier status in Friedreich ataxia

Lam C, Gilliam KM, Rodden LN, Schadt KA, Lynch DR, Bidichandani S.; J Med Genet. 2023 Jan 12:jmedgenet-2022-108742. doi: 10.1136/jmg-2022-108742. Epub ahead of print. PMID: 36635061. 

 FXN DNA methylation reliably detects the GAA-TRE in the heterozygous state and offers a robust alternative strategy to diagnose FRDA due to compound heterozygosity and to identify asymptomatic heterozygous carriers of the GAA-TRE.