Ella Mathews

All Publications

• Selective targeting of mutant <i>huntingtin</i> intron 1 improves rescue provided by antisense oligonucleotides in Huntington's disease mice SCIENCE TRANSLATIONAL MEDICINE Bragg, R. M., Landles, C., Smith, E. J., Osborne, G. F., Mathews, E. W., Cantle, J. P., Bates, G. P., Carroll, J. B. 2026; 18 (841): eadv0702

  Abstract

  Huntington's disease (HD) arises from the toxic gain of function caused by a CAG expansion in the coding region of the huntingtin (HTT) gene. HD is increasingly appreciated to emerge from multiple pathogenic processes, including somatic instability in mutant HTT's (mHTT) CAG repeat tract, which leads to diverse deleterious consequences. These include the alternative processing of HTT pre-mRNA to generate the HTT1a transcript that encodes the very toxic mHTT isoform referred to as HTT1a. We set out to compare the efficacy and safety of allele-selective lowering of mHTT with those of non-allele-selective lowering using antisense oligonucleotides (ASOs) in heterozygous HttQ111 (Q111) mice. We developed a mutant-specific ASO (MutASO) targeting Htt intron 1 that selectively reduced mutant full-length HTT, as well as HTT1a, in the brains of Q111 mice. Compared with the rescue provided by a panallele-targeting ASO (PanASO) that lowers wild-type HTT and full-length mHTT (sparing HTT1a), the MutASO essentially eliminated aggregate formation and provided marked protection from transcriptional dysregulation in HD knockin mice. Thus, by targeting the ASO to the region upstream of the cryptic polyadenylation sites required to generate the HTT1a transcript, our allele-selective MutASO potently reduced HTT1a transcript and protein levels. Our findings suggest that HTT1a may have a disproportionate impact on aggregate formation and transcriptional dysregulation and that lowering the levels of HTT1a could provide benefit when designing HTT-lowering-based therapeutic strategies for HD.

  View details for DOI 10.1126/scitranslmed.adv0702

  View details for Web of Science ID 001717138100006

  View details for PubMedID 41849580

• Suppression of Huntington's Disease Somatic Instability by Transcriptional Repression and Direct CAG Repeat Binding NATURE COMMUNICATIONS Mathews, E. W., Coffey, S. R., Gartner, A., Belgrad, J., Bragg, R. M., O'Reilly, D., Cantle, J. P., McHugh, C., Summers, A., Fentz, J., Schwagarus, T., Cornelius, A., Lingos, I., Burch, Z., Kovalenko, M., Andrew, M. A., Bennett, C., Kordasiewicz, H. B., Marchionini, D. M., Wilkinson, H., Vogt, T. F., Beuzer, P., Pinto, R. M., Khvorova, A., Howland, D., Wheeler, V. C., Carroll, J. B. 2025; 16 (1): 10009

  Abstract

  Huntington's disease arises from a CAG expansion in the huntingtin gene beyond a critical threshold. Current therapeutics primarily aim to reduce toxicity by lowering levels of mutant HTT mRNA and protein. Genetic data support a role for somatic instability in HTT's CAG repeat as a driver of age of motor dysfunction onset, but currently, the relationship between instability and HTT lowering remains unexplored. Here, we investigate various HTT-lowering modalities to establish the relationship between HTT lowering and instability in Huntington's disease knock-in mice. We find that repressing transcription of mutant Htt reduces instability, using genetic and pharmacological approaches. Remarkably, zinc finger proteins that target CAG repeats, but lack a repressive domain, protect from somatic instability despite not reducing HTT mRNA or protein levels. These results suggest that DNA-targeted HTT-lowering treatments may have advantages compared to other HTT-lowering approaches, and that steric blockage of CAG repeats may reduce instability while sparing HTT expression.

  View details for DOI 10.1038/s41467-025-64936-4

  View details for Web of Science ID 001616374600003

  View details for PubMedID 41238535

  View details for PubMedCentralID PMC12618468

• Global huntingtin knockout in adult mice leads to fatal neurodegeneration that spares the pancreas LIFE SCIENCE ALLIANCE Bragg, R. M., Mathews, E. W., Grindeland, A., Cantle, J. P., Howland, D., Vogt, T., Carroll, J. B. 2024; 7 (9)

  Abstract

  Huntington's disease (HD) is a fatal neurodegenerative disorder caused by an expanded CAG tract in the huntingtin (HTT) gene, leading to toxic gains of function. HTT-lowering treatments are in clinical trials, but the risks imposed are unclear. Recent studies have reported on the consequences of widespread HTT loss in mice, where one group described early HTT loss leading to fatal pancreatitis, but later loss as benign. Another group reported no pancreatitis but found widespread neurological phenotypes including subcortical calcification. To better understand the liabilities of widespread HTT loss, we knocked out Htt with two separate tamoxifen-inducible Cre lines. We find that loss of HTT at 2 mo of age leads to progressive tremors and severe subcortical calcification at examination at 14 mo of age but does not result in acute pancreatitis or histological changes in the pancreas. We, in addition, report that HTT loss is followed by sustained induction of circulating neurofilament light chain. These results confirm that global loss of HTT in mice is associated with pronounced risks, including progressive subcortical calcification and neurodegeneration.

  View details for DOI 10.26508/lsa.202402571

  View details for Web of Science ID 001288443200001

  View details for PubMedID 39054288

  View details for PubMedCentralID PMC11272958

• Di-valent siRNA-mediated silencing of MSH3 blocks somatic repeat expansion in mouse models of Huntington's disease MOLECULAR THERAPY O 'Reilly, D., Belgrad, J., Ferguson, C., Summers, A., Sapp, E., McHugh, C., Mathews, E., Boudi, A., Buchwald, J., Ly, S., Moreno, D., Furgal, R., Luu, E., Kennedy, Z., Hariharan, V., Monopoli, K., Yang, W., Carroll, J., DiFiglia, M., Aronin, N., Khvorova, A. 2023; 31 (6): 1661-1674

  Abstract

  Huntington's disease (HD) is a severe neurodegenerative disorder caused by the expansion of the CAG trinucleotide repeat tract in the huntingtin gene. Inheritance of expanded CAG repeats is needed for HD manifestation, but further somatic expansion of the repeat tract in non-dividing cells, particularly striatal neurons, hastens disease onset. Called somatic repeat expansion, this process is mediated by the mismatch repair (MMR) pathway. Among MMR components identified as modifiers of HD onset, MutS homolog 3 (MSH3) has emerged as a potentially safe and effective target for therapeutic intervention. Here, we identify a fully chemically modified short interfering RNA (siRNA) that robustly silences Msh3 in vitro and in vivo. When synthesized in a di-valent scaffold, siRNA-mediated silencing of Msh3 effectively blocked CAG-repeat expansion in the striatum of two HD mouse models without affecting tumor-associated microsatellite instability or mRNA expression of other MMR genes. Our findings establish a promising treatment approach for patients with HD and other repeat expansion diseases.

  View details for DOI 10.1016/j.ymthe.2023.05.006

  View details for Web of Science ID 001018941500001

  View details for PubMedID 37177784

  View details for PubMedCentralID PMC10277892