Anti-gene oligonucleotides targeting Friedreich’s ataxia expanded GAA•TTC repeats increase Frataxin expression

Negin Mozafari, Salomé Milagres, Tea Umek, Cristina S.J. Rocha, Claudia Marina Vargiu, Fiona Freyberger, Osama Saher, Marek Napierala, Jill S. Napierala, Pontus Blomberg, Per T. Jørgensen, Tanel Punga, C. I. Edvard Smith, Jesper Wengel, Rula Zain, Anti-gene oligonucleotides targeting Friedreich’s ataxia expanded GAA•TTC repeats increase Frataxin expression, Molecular Therapy Nucleic Acids, 2025, 102541, doi:10.1016/j.omtn.2025.102541. 

Friedreich’s ataxia is a progressive, autosomal recessive ataxia caused, in most cases, by homozygous expansion of GAA•TTC triplet-repeats in the first intron of the frataxin gene. GAA•TTC repeat expansion results in the formation of a non-B DNA intramolecular triplex as well as changes in the epigenetic landscape at the frataxin locus. Expansion of intronic GAA•TTC repeats is associated with reduced levels of frataxin mRNA and protein, resulting in disease development. In our previous study, we demonstrated that DNA-binding anti-gene oligonucleotides specifically targeting the GAA•TTC repeat expansion effectively disrupted the formation of intramolecular triplex structures. In this study, we extend these findings by showing that targeting repeat-expanded chromosomal DNA with anti-gene oligonucleotides leads to an increase in frataxin mRNA and protein levels in cells derived from Friedreich’s ataxia patients. We examined numerous anti-gene oligonucleotides and found that the design, length, and their locked nucleic acid composition have a high impact on the effectiveness of the treatment. Collectively, our results demonstrate the unique capability of specifically designed oligonucleotides targeting the GAA•TTC DNA repeats to upregulate frataxin gene expression.

Hepatic Manifestations Following Gene Therapy

Akash Roy, Shalini Bansal, Anand Kulkarni, K. Rajender Reddy, Hepatic Manifestations Following Gene Therapy, Gastro Hep Advances, 2025, 100681, ISSN 2772-5723, doi:10.1016/j.gastha.2025.100681.

 Abstract: Gene therapy (GT) involves the introduction of genetic materials, most commonly using viral vectors, to alter gene expression to ameliorate or cure disease symptoms and with minimal adverse events. While interest in GT has been on the increase, concerns have arisen about the potential for hepatotoxicity, which arises from diverse mechanisms. While viral vectors can produce dose-dependent hepatotoxicity secondary to integration, immune responses appear to be the primary driving mechanism. A mild increase in aminotransferases is the most common hepatic manifestation, occurring variably in 20-80%, while there has been rare progress to acute liver failure. The occurrence of hepatotoxicity is unpredictable and can vary depending on patient comorbidities, vector dose, vector type, and degree of immune activation. Pre-treatment screening for underlying chronic liver disease and exclusion of advanced fibrosis or cirrhosis using non-invasive tests is essential. Literature on liver biopsy pre and post-therapy is limited, but small studies show safety in the long term. Immunosuppression, most commonly using corticosteroids, is the first-line modality in management. Approaches vary between prophylactic and reactive strategies, and there remains an absence of consensus on the most appropriate strategies. First-line therapy for a variable duration and dose settles most cases of hepatoxicity. In selected difficult-to-treat cases, second-line agents (sirolimus, mycophenolate mofetil, calcineurin inhibitors) are required, while there is no current consensus on the ideal second-line strategy. Intense short-term and extended long-term hepatic monitoring is recommended. Variabilities in presentation and challenges in management strategies mandate a multidisciplinary collaboration with the active involvement of hepatologists/gastroenterologists to optimize liver health