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In vivo genetic engineering has recently shown remarkable potential as a novel effective treatment for an ever-growing number of diseases, as also witnessed by the recent marketing authorization of several in vivo gene therapy products. In vivo genetic engineering comprises both viral vector-mediated gene transfer and the more recently developed genome/epigenome editing strategies, as long as they are directly administered to patients. Here we first review the most advanced in vivo gene therapies that are commercially available or in clinical development. We then highlight the major challenges to be overcome to fully and broadly exploit in vivo gene therapies as novel medicines, discussing some of the approaches that are being taken to address them, with a focus on the nervous system and liver taken as paradigmatic examples., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cantore, Fraldi, Meneghini and Gritti.)

Glial cells (astrocytes, oligodendrocytes, and microglia) are emerging as key players in several physiological and pathological processes of the central nervous system (CNS). Astrocytes and oligodendrocytes are not only supportive cells that release trophic factors or regulate energy metabolism, but they also actively modulate critical neuronal processes and functions in the tripartite synapse. Microglia are defined as CNS-resident cells that provide immune surveillance; however, they also actively contribute to shaping the neuronal microenvironment by scavenging cell debris or regulating synaptogenesis and pruning. Given the many interconnected processes coordinated by glial cells, it is not surprising that both acute and chronic CNS insults not only cause neuronal damage but also trigger complex multifaceted responses, including neuroinflammation, which can critically contribute to the disease progression and worsening of symptoms in several neurodegenerative diseases. Overall, this makes glial cells excellent candidates for targeted therapies to treat CNS disorders. In recent years, the application of gene editing technologies has redefined therapeutic strategies to treat genetic and age-related neurological diseases. In this review, we discuss the advantages and limitations of clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-based gene editing in the treatment of neurodegenerative disorders, focusing on the development of viral- and nanoparticle-based delivery methods for in vivo glial cell targeting., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Meneghini, Peviani, Luciani, Zambonini and Gritti.)

Lysosomal storage diseases (LSDs) are a group of rare genetic conditions. The absence or deficiency of lysosomal proteins leads to excessive storage of undigested materials and drives secondary pathological mechanisms including autophagy, calcium homeostasis, ER stress, and mitochondrial abnormalities. A large number of LSDs display mild to severe central nervous system (CNS) involvement. Animal disease models and post-mortem tissues partially recapitulate the disease or represent the final stage of CNS pathology, respectively. In the last decades, human models based on induced pluripotent stem cells (hiPSCs) have been extensively applied to investigate LSD pathology in several tissues and organs, including the CNS. Neural stem/progenitor cells (NSCs) derived from patient-specific hiPSCs (hiPS-NSCs) are a promising tool to define the effects of the pathological storage on neurodevelopment, survival and function of neurons and glial cells in neurodegenerative LSDs. Additionally, the development of novel 2D co-culture systems and 3D hiPSC-based models is fostering the investigation of neuron-glia functional and dysfunctional interactions, also contributing to define the role of neurodevelopment and neuroinflammation in the onset and progression of the disease, with important implications in terms of timing and efficacy of treatments. Here, we discuss the advantages and limits of the application of hiPS-NSC-based models in the study and treatment of CNS pathology in different LSDs. Additionally, we review the state-of-the-art and the prospective applications of NSC-based therapy, highlighting the potential exploitation of hiPS-NSCs for gene and cell therapy approaches in the treatment of neurodegenerative LSDs., (Copyright © 2020 Luciani, Gritti and Meneghini.)