Biology subjects

Astord, S.

Publications and source records attributed to Astord, S..

4 recordsLinked to original sources

bioRxiv2025

Pre-clinical evaluation of a gene therapy candidate for SOD1-ALS shows improved survival and signs of inflammation in the CNS of treated mice.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor neurons loss (MN). In 15-20% of familial ALS cases, mutations in the superoxide dismutase 1 (SOD1) gene are the underlying cause. Targeting human SOD1 (hSOD1) toxicity has emerged as a promising approach to treat SOD1-ALS. We previously demonstrated the efficacy of an exon-skipping strategy using a self-complementary AAVrh10-U7-hSOD1 vector in SOD1G93A mice achieving significant hSOD1 silencing. In this study, we optimized the therapeutic protocol by conducting a dose-finding and biodistribution study of scAAVrh10-U7-hSOD1 following a single intracerebroventricular injection in adult SOD1G93A mice. Our findings demonstrate a dose-dependent reduction in mutant hSOD1 levels in the cortex, spinal cord, and peripheral tissues, sustained for up to 60 days post-injection. In vivo, some adverse effects were noted mostly at the highest dose, with inflammation early post-injection and persistent microglial activation in the brain observed around the injection site. Importantly, the medium-dose treatment extended mean survival by up to 27% with a much milder early toxicity, which will provide a great possibility for future applications. Additionally, no major off-target effects were observed in human cell models, highlighting the targeting specificity of this approach and the potential safety for translation. These findings confirm and extend the therapeutic potential of scAAVrh10-U7-hSOD1 gene therapy while emphasizing the need for further technological development to minimize adverse effects and maximize potential clinical benefit.

pharmacology and toxicology↗

bioRxiv2025

Systemic Factors Affect Bone Health in SMA Type II Patients and a Mouse Model of SMA

Spinal muscular atrophy (SMA) is a rare developmental disorder affecting multiple tissues. Among the non-central nervous system tissues implicated in SMA is the skeletal system, including bone and cartilage. Low bone mineral density, increased numbers of fractures of the long bones and vertebra, hip pain, and scoliosis have been reported across the spectrum of SMA patients. While lack of ambulation likely contributes significantly to bone pathology, SMA patients have markedly lower bone density compared to other non-ambulatory patients with debilitating diseases such as Duchenne muscular dystrophy, suggesting that there is a cell-intrinsic contribution of SMN to bone homeostasis and function. Mouse models of SMA have also confirmed the presence of bone and cartilage phenotypes. These alterations frequently persist post-treatment. Recent advancements in therapeutic strategies, approved by both the FDA and the EMA, have represented a leap forward in the management of SMA. However, treatment gaps remain. Post-treatment, patients frequently face continued challenges with scoliosis, bone fractures, and persistent muscle weakness--conditions that underscore the urgent need for more comprehensive therapeutic strategies with combination therapies that can support skeletal health. To date, no molecular map exists of the changes that occur in SMA patient bone and cartilage, impeding the ability of finding targeted therapies. To address this clinical need, we profiled the transcriptome of the vertebral bone and cartilage in a cohort of 11 Type II SMA patients who were undergoing surgery for scoliosis correction and compared them to 7 idiopathic scoliosis and 2 DMD controls. Additionally, we characterized the skeletal health of a mouse model of type I SMA. We find that multisystemic factors including liver and muscle health affect the underlying SMA bone pathology. Specifically, we detect alterations in the balance between osteoclasts and osteoblasts, changes in PPAR{gamma} signaling, mitochondrial oxidative phosphorylation and fatty acid beta-oxidation, and alterations in the muscle-derived factor Irisin that play a role in overall SMA bone pathology.

genomics↗

bioRxiv2024

Targeted-SMN insufficiency in Skeletal Muscle Stem Cells mediates non-cell autonomous loss of motor neurons at long term

Spinal Muscular Atrophy (SMA) is due to a deficit in SMN protein encoded by the SMN1 gene. SMN-targeted disease modifying treatments have greatly improved the clinical outcomes of this neuromuscular disease. However, uncertainties remain regarding their long-term efficacy and non-neuronal tissue involvement in disease progression. We found that SMA type II patient muscles display a reduced number of quiescent PAX7+ Muscle Stem Cells (MuSC). In SMA mice, we showed that SMN is an important regulator of myogenic progenitor fate during early postnatal growth. In Pax7 Cre-driven conditional knockout mouse models, we demonstrated that high levels of SMN are required to ensure the maintenance of the quiescent MuSC pool in adult muscle. We further established that depletion of SMN-deficient MuSC yielded neuromuscular junctions remodeling followed by a non-cell autonomous loss of motor neurons in the long term. Overall, our findings demonstrate that MuSC are a crucial therapeutic target for SMA treatment. HIGHLIGHTSO_LISMN regulates myogenic lineage progression and quiescent MuSC pool establishment during postnatal growth C_LIO_LIBoth Smn alleles are necessary for the survival of quiescent MuSC in adult muscle C_LIO_LIDepletion of SMN-deficient MuSC leads to NMJ remodeling and non-cell autonomous loss of MN C_LI

pathology↗

bioRxiv2024

SMA Type II Skeletal Muscle Treated with Nusinersen shows SMN Restoration but Mitochondrial Deficiency.

Spinal muscular atrophy (SMA) is a rare autosomal recessive developmental disorder caused by the genetic loss or mutation of the gene SMN1 (Survival of Spinal Motor Neuron 1). SMA is classically characterized by neuromuscular symptoms, including muscular atrophy, weakness of the proximal muscles, especially those of the lower extremities, and hypotonia. Although originally thought of as a purely motor neuron disease, current research has shown that most, if not all, tissues are affected, including the muscle. Until recently, muscle problems in SMA were predominantly considered a consequence of denervation due to the motor neuron death. However, recent work using muscle-specific mouse models of SMN loss, as well as skeletal stem cell specific models have shown that there are tissue specific problems in muscle due to SMN deficiency. Several years ago, SMA treatment underwent a radical transformation, with the approval of three different SMN-dependent disease modifying therapies. This includes two SMN2 splicing therapies - Risdiplam and Nusinersen, which can be administered by Type II patients that have symptom onset later in age. One main challenge for Type II SMA patients treated with Risdiplam and Nusinersen is ongoing muscle fatigue, limited mobility, and other skeletal problems, including hip dysplasia and scoliosis. To date, few molecular studies have been conducted on SMA-patient derived tissues after treatment, limiting our understanding how different organ systems react to the therapies, and what additional combination therapies may be beneficial. With this goal in mind, we collected paravertebral muscle from the surgical discard in a cohort of 8 SMA Type II patients undergoing spinal surgery for scoliosis, as well as 7 non-SMA controls with scoliosis and used RNA-sequencing to characterize their molecular profiles. We observed that despite a restoration of the SMN mRNA and protein levels in these patients - at levels at or above the controls - a subset of patients continued to have alterations in mitochondrial metabolism and other markers of cellular stress.

genetics↗