The 5q Spinal Muscular Atrophy (SMA) is a hereditary autosomal recessive disease caused by defects in the survival motor neuron (SMN1) gene encoding survival motor neuron (SMN) protein. Currently, it is the leading cause of infantile mortality worldwide. SMA is a progressive neurodegenerative disease with “continuum of clinical severity”, which can be modulated by genetic and epigenetic factors known as disease modifiers (DMs). Individuals (even siblings) with the same defects in SMN1 gene might have strikingly different types of SMA, supposedly due to the impact of DMs. There are several therapeutic options for SMA, all of them focusing on the restoration of the SMN protein levels to normal. Determining DMs and the pathways in which they are involved might aid in enhancing existing curative approaches. Furthermore, DMs might become novel therapeutic targets or prognostic biomarkers of the disease. This narrative review provides a brief overview of the genetics and pathobiology of SMA, and its bona fide modifiers. We describe novel, emerging DMs, approaches and tools used to identify them, as well as their potential mechanisms of action and impact on disease severity. We also propose several disease-modifying molecular mechanisms which could provide a partial explanation of the staggering variability of SMA phenotypes.

The brain-derived neurotrophic factor (BDNF) is a key modulator of neurogenesis, synaptogenesis, neuroregeneration, and cell differentiation in the nervous system. Impaired BDNF functioning is a characteristic of various neurological diseases, such as Alzheimer’s disease, multiple sclerosis, and depressive disorders. There is recent evidence that patients with COVID-19 have reduced BDNF levels in the blood plasma. Furthermore, exogenous BDNF and its mimetics have demonstrated therapeutic potential. In this review, we systematized data of the BDNF gene structure, epigenetic and microRNA-mediated regulation of its expression, transcriptional variants of BDNF, and the effects of BDNF on neuronal and oligodendroglial differentiation. Further, we point out the gaps in the current knowledge about BDNF and propose experiments that can expand such knowledge and the range of possibilities for using BDNF in biomedicine. These include determining the expression pattern of all BDNF gene transcripts at different stages of differentiation and in different cell subpopulations and studying the role of receptor-independent BDNF signaling, circadian fluctuations in BDNF levels, and their role in physiological and pathophysiological conditions. Finally, for translational medicine, evaluating the effect of BDNF mimetics (including those immobilized on three-dimensional scaffolds for tissue engineering) on neuronal and oligodendroglial differentiation of pluripotent and polypotent cells and identifying molecular regulators of BDNF transcription, including small molecules and microRNAs capable of regulating BDNF gene expression, are crucial.

Glioblastoma (GBM) is the most common malignancy of the central nervous system in adults. GBM has high levels of therapy failure and its prognosis is usually dismal. The phenotypic heterogeneity of the tumor cells, dynamic complexity of non-tumor cell populations within the GBM tumor microenvironment (TME), and their bi-directional cross-talk contribute to the challenges of current therapeutic approaches. Herein, we discuss the etiology of GBM, and describe several major types of non-tumor cells within its TME, their impact on GBM pathogenesis, and molecular mechanisms of such an impact. We also discuss their value as potential therapeutic targets or prognostic biomarkers, with reference to the most recent works on this subject. We conclude that unless all “key player” populations of non-tumor cells within the TME are considered, no breakthrough in developing treatment for GBM can be achieved.

This review examines the safety and clinical efficacy of mesenchymal stem/stromal cells (MSCs)-based therapies in patients with spinal cord injury (SCI). The analysis covers 26 clinical studies conducted on patients with varying degrees of the post-SCI neurological deficit. The review highlights the methodology of trials, the source of MSCs, the dosage of cells administered, transplantation methods, patient inclusion criteria, and the methods of evaluating the effectiveness of the therapy. MSC transplantation in SCI was safe and feasible in all the studies summarized in our review. All studies conducted have demonstrated varying degrees of patient improvement and reduction in the severity of neurological deficits. However, further controlled randomized studies on larger numbers of patients are needed to better evaluate the therapeutic efficacy of MS transplantation. The prospects of the enhancement of the efficacy of the SCI cell therapy with MSCs, including their transplantation with other types of stem cells, administration of MSC-derived exosomes, genetic modification of MSCs, use of the MSC- and other-stem-cell-based tissue-engineered scaffolds, and combination of cell therapy with neuromodulation, are discussed.

Spinal cord injury (SCI) is a medical condition affecting ~2.5–4 million people worldwide. The conventional therapy for SCI fails to restore the lost spinal cord functions; thus, novel therapies are needed. Recent breakthroughs in stem cell biology and cell reprogramming revolutionized the field. Of them, the use of neural progenitor cells (NPCs) directly reprogrammed from non-neuronal somatic cells without transitioning through a pluripotent state is a particularly attractive strategy. This allows to “scale up” NPCs in vitro and, via their transplantation to the lesion area, partially compensate for the limited regenerative plasticity of the adult spinal cord in humans. As recently demonstrated in non-human primates, implanted NPCs contribute to the functional improvement of the spinal cord after injury, and works in other animal models of SCI also confirm their therapeutic value. However, direct reprogramming still remains a challenge in many aspects; one of them is low efficiency, which prevents it from finding its place in clinics yet. In this review, we describe new insights that recent works brought to the field, such as novel targets (mitochondria, nucleoli, G-quadruplexes, and others), tools, and approaches (mechanotransduction and electrical stimulation) for direct pro-neural reprogramming, including potential ones yet to be tested.

Schimke immuno-osseous dysplasia (SIOD) is a hereditary autosomal-recessive multi-system disorder with early mortality. It has variable clinical presentations, mainly characterised by disproportional short stature, steroid-resistant nephrotic syndrome, spondyloepiphyseal dysplasia, and T-cell immunodeficiency. In the majority of cases, SIOD is caused by pathogenic sequence variants (PSVs) in the SMARCAL1 gene that encodes protein involved in chromatin remodelling. SIOD is an ultra-rare condition, with an incidence of ~1 per 1–3 million live births; data on its genetic and clinical features are scarce. We conducted a retrospective study of 21 paediatric patients with SIOD diagnosed in our centre during the years 2003–2023. The most common extra-renal clinical features were short stature, osseous dysplasia, multiple stigmas, and leukopenia. Proteinuria of varying severity was observed in 16 cases. The five-year overall survival rate (OS) was 89% (95% CI 77–100%), and the ten-year OS was 10%. Next-generation sequencing (NGS) revealed the following PSVs in SMARCAL1 in 19 patients: c.355_500del, c.2542G>T, c.2290C>T, c.2562del, c.2533_2534del, c.1582A>C, c.1933C>T, c.1010T>C, c.1736C>T, c.2070dup, c.2551A>T, c.2149_2150dup, c.939delC, and c.1451T>A; the most common was c.2542G>T, resulting in premature translation termination (p.E848*), and it was found in 14 patients either in a homozygous (four patients) or compound-heterozygous (10 patients) state. According to microsatellite analysis, it is a “founder mutation” in Russia.