Biology subjects

Sadiq, S. A.

Publications and source records attributed to Sadiq, S. A..

3 recordsLinked to original sources

bioRxiv2025

AAV-Delivered Anti-PC-OxPL Antibody Fragments: A NovelTherapeutic Approach to Target ALS

Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of motor neurons and premature death. The limited understanding of the mechanisms underlying selective motor neuron death has significantly hindered the development of disease-modifying treatments. Ferroptosis, a form of cell death dependent on iron accumulation, has been implicated in the selective degeneration of motor neurons in ALS. Oxidized phosphatidylcholines (PC-OxPL) have been identified as key effectors in the pathophysiological processes associated with this pathway. Preclinical observations revealed a distinct PC-OxPL profile in the cerebrospinal fluid (CSF) of sporadic ALS (sALS) patients and identified apolipoprotein E (APOE) particles as the primary carriers of PC-OxPL in the CSF. Furthermore, in ALS brain and spinal cord tissue sections, PC-OxPL was found to be predominantly associated with motor neurons. Exposure of iPSC-derived motor neurons to PC-OxPL led to transcriptomic changes in genes known to be linked to ALS, as well as the induction of significant TDP-43 pathology and motor neuron death. To counter this, we developed a single-chain antibody fragment (scFv) encoded by an AAV-delivered DNA construct that specifically targets PC-OxPL neoepitopes (PC-OxPL-VecTab(R)). PC-OxPL-VecTab(R) effectively neutralized PC-OxPL-induced neurotoxicity and TDP-43 aggregation in motor neurons, while preventing motor neuron death and deficits in a sALS CSF mouse model. When administered intrathecally to minipigs, PC-OxPL-VecTab(R) was distributed to both upper and lower motor neurons and expressed at levels predicted to be therapeutically effective. Our work identifies PC- OxPL as a critical pathological factor and a key inducer of TDP-43 pathology in ALS, providing the foundation for a novel therapeutic intervention modality for patients with sALS. Furthermore, it offers the exciting potential to be expanded to diseases characterized by PC-OxPL neurotoxicity.

neuroscience↗

bioRxiv2025

Impaired Myelination in Multiple Sclerosis Organoids: p21 Links Oligodendrocyte Dysfunction to Disease Subtype

Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system. The cause of the disease is unknown but both genetic and environmental factors are strongly implicated in its pathogenesis. We derived cerebral and spinal cord organoids from induced pluripotent stem cells (iPSC) from healthy controls as well as from primary progressive MS (PPMS), secondary progressive MS (SPMS) and relapsing-remitting MS (RRMS) patients to investigate and compare oligodendrocyte differentiation and myelination capacity in healthy subjects and MS subtypes. In MS organoids, particularly in PPMS, we observed a decrease in p21 expression associated with a dysregulation of PAK1 and E2F1 expression. In parallel, a decrease in oligodendrocyte maturation was detected in long-term cultured cerebral and spinal cord organoids, especially in PPMS, leading to a reduced myelination capacity. Disruption of astrocyte and neuronal populations was also observed. Our findings demonstrate that in MS, inherent deficits in the p21 pathway may alter glial and neuronal cell populations and may contribute to the disease pathogenesis by reducing the capacity for myelin repair. Summary StatementUsing cerebral and spinal cord organoids derived from multiple sclerosis patients, we found an innate disruption of oligodendrocyte differentiation and myelination capacity as well as excitotoxicity, associated with PAK1 and E2F1-induced p21 dysregulation.

neuroscience↗

bioRxiv2022

Cerebral Organoids In Primary Progressive Multiple Sclerosis Reveal Stem Cell Disruption And Failure To Produce Oligodendrocytes

Multiple sclerosis (MS) is an auto-immune inflammatory disorder affecting the central nervous system. The cause of the disease is unknown but both genetic and environmental factors are implicated in the pathogenesis. We derived cerebral organoids from induced pluripotent stem cells (iPSC) of healthy control subjects as well as from primary progressive MS (PPMS), secondary progressive MS (SPMS) and relapsing remitting MS (RRMS) patients to better understand the pathologic basis of the varied clinical phenotypic expressions of MS. In MS organoids, most notably in PPMS, we observed a decrease of proliferation marker Ki67 and a reduction of the SOX2+ stem cell pool associated with an increased expression of neuronal markers CTIP2 and TBR1. This dysregulation of the stem cell pool is associated with a decreased expression of the cell cycle inhibitor p21. Our findings show that the genetic background of a patient can directly alter stem cell function. This study also provides new insights on the innate cellular dysregulation in MS and identifies p21 pathway as a new potential target for therapeutic strategies in MS. Summary StatementUsing cerebral organoids derived from patients with multiple sclerosis we detected that p21 decrease may induce a disruption of the stem cell cycle leading to a defect of oligodendrocyte differentiation

neuroscience↗