Biology subjects

Gidaja, E.

Publications and source records attributed to Gidaja, E..

2 recordsLinked to original sources

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

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↗