Desminopathies are a therapeutic challenge as there are over 130 different mutations in the human desmin gene resulting in myopathy and/or cardiomyopathy. In this issue, a gene therapeutic approach is validated in two different models of autosomal-recessive desminopathy. This image shows successful AAV-mediated reconstitution of myocardial desmin filaments in desmin deficient mice (left to right: wildtype mice; desmin deficient control mice; AAV-treated desmin deficient mice). See paper by Ruppert et al. in this issue of Gene Therapy.

Cover legend: Living on the edge. Left image: The transcription factor Oct4 (green) and cell surface marker SSEA4 (red) are classic markers of human induced pluripotent stem cells shown here at the edge of a colony, with DAPI showing both the nuclei of the stem cells as well as surrounding inactivated MEF feeder layer. Right image: Closer inspection reveals rapid cell division in these colonies as indicated by the frequent identification of condensed chromosomes undergoing mitosis and the temporary absence of the stem cell transcription factor. Images acquired by Dr Janine Scholefield, Bioengineering and Integrated Genomics, NextGen Health, CSIR, South Africa.

Cover legend: Viral mediated CRISPR-Cas9 activation in adult murine inner ear. Associated-adenovirus (AAV) infects murine cochlea efficiently and safely, but it is unable to package SpCas9 and guide RNA into the same AAV. By inner ear microinjection, AAV activates Cas9 expression in diverse cochleae cell types of neonatal and adult Cas9 knock-in mice, with high efficiency and non-ototoxicity. See paper by Kang et al. in this issue of Gene Therapy.

Cover legend: The Twisted Reality of Biology - The essence of biology is summarised by the relationship of cellular organisms and the life molecule deoxyribonucleotide, and from this twisted symbiosis of chemicals and host form all that we know to live. The image is a collage work of various images of cells stained for visualisation using fluorescence microscopy shaped to the structure of the DNA helix. Brian Kariithi.

Cover credit: Detection of Streptococcus pyogenes Cas9 (SpCas9) nucleases in HeLa cells by immunofluorescence microscopy. Delivering RNA-guided nucleases into target cell nuclei, the cellular compartment where they must operate, remains a major challenge for advancing genome editing technologies. In this issue of Gene Therapy, Maggio et al. endow a high-specificity SpCas9 nuclease with extra nuclear localizations signals (NLSs) and report its enhanced nuclear uptake by using single-cell quantitative immunofluorescence microscopy analysis. The authors further report that the enhanced high-specificity SpCas9 nuclease is compatible with guide RNAs harboring optimized scaffolds and, once introduced into human cells by adenoviral vectors, yield frequencies of target DNA cleavage that are higher than those achieved by its unmodified high-specificity counterpart. The image shows the cellular distribution of a standard SpCas9 (Cas9), a high-specificity Cas9 with 2 NLSs (eCas9.2NLS) and its engineered derivate with 4NLSs (eCas9.4NLS). See paper by Maggio et al. in this issue of Gene Therapy.

AAV-Cas9-based gene editing strategy could efficiently prevent motor neuron death by excising the SOD1 gene locus. The image shows the double staining of SaCas9 and mutant SOD1 was observed by confocal microscopy at the end stage of ALS animal model and the SaCas9-positive and SOD1-negative motor neurons are preserved in the spinal cord. See paper by Weisong Duan et al. in this issue of Gene Therapy.

Spotlight on South America. Research in regenerative medicine is thriving across the world, and América del Sur is no exception. This special issue of Gene Therapy, coordinated by South America Associate Editor Ursula da Silveira Matte and Guest Editor Hugo Peluffo Zavala, is devoted to work submitted by authors located in many South American countries, with topics including cancer, cardiovascular, Parkinson and inherited diseases. The papers report use of multiple gene and cell therapy technologies, spanning viral and non-viral vectors, genome editing, DNA vaccines, chimeric antigen receptor T-cells (CAR-T), induced pluripotent stem cells (iPSC), and adipose-tissue-derived stem cells. See Editorial by Matte and Peluffo in this issue of Gene Therapy.