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. 2025 Jul 8:19:1620181.
doi: 10.3389/fnins.2025.1620181. eCollection 2025.

Targeting oxidized phosphatidylcholines in SOD1-associated ALS: therapeutic potential of PC-OxPL-VecTab®

Andreia Gomes-Duarte  1 , Sofia Pascoal #  1 , Rob Haselberg #  1 , Marina Sogorb-Gonzalez  1 , Sander van Deventer  1
Affiliations

Targeting oxidized phosphatidylcholines in SOD1-associated ALS: therapeutic potential of PC-OxPL-VecTab®

Andreia Gomes-Duarte et al. Front Neurosci. .

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive motor neuron degeneration. Mutations in the superoxide dismutase 1 (SOD1) gene account for a significant fraction of familial ALS (fALS) cases. Oxidative stress and oxidized phosphatidylcholines (PC-OxPL) contribute to neuroinflammation and neuronal damage, and to motor neuron degeneration in ALS. We previously demonstrated the therapeutic efficacy of an AAV-delivered anti-PC-OxPL single-chain variable fragment (PC-OxPL-VecTab®) in neutralizing PC-OxPL toxicity in the periphery and central nervous system (CNS), but the therapeutic potential of PC-OxPL-VecTab® has not been investigated in the context of fALS and SOD1-associated ALS. We report that PC-OxPL accumulation contributes to the pathological phenotypes associated with SOD1G93A iPSC-derived motor neurons and the corresponding mouse model. The current findings further demonstrate that PC-OxPL-VecTab® is efficacious in neutralizing the downstream effects of SOD1-associated PC-OxPL accumulation, such as altered gene expression and axonal health in SOD1 motor neurons, as well as a pathological lipid profile in the SOD1G93A mouse model. Collectively, the present study underscores the significance of PC-OxPL dysfunction in the context of SOD1 genotypes and sheds light on the potential of PC-OxPL-VecTab® for therapeutically targeting ALS.

Keywords: adeno-associated viruses; amyotrophic lateral sclerosis; gene therapy; oxidized phosphatidylcholines; superoxide dismutase 1.

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Conflict of interest statement

The authors declare that a patent application has been filed to protect the technology described in this study, in which AG-D and SVD are stated as inventors. AG-D, RH, MS-G and SVD are employees of VectorY and may own stock and/or stock options. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from VectorY Therapeutics. The funder had the following involvement in the study: writing of this article, and the decision to submit it to publication.

Figures

Figure 1
Figure 1
(A) Left panel: PC-OxPL expression in SOD1G93A motor neurons (% of PC-OxPL+ cells). Values are expressed as means (wt = 1.000; SOD1G93A = 1.239) ± SD. Unpaired two-tailed t-test; **p = 0.0024. Three independent experiments, n = 2–4 replicates each. Right panel: Representative images show increased % of PC-OxPL+ cells in SOD1G93A in comparison to wt motor neurons. Scale bar = 20 μM (PC-OxPL, Cy5). (B) Venn diagram depicting overlapping DE transcripts between SOD1G93A and wt motor neurons exposed to PC-OxPL (PONPC). Both NanoString neuropathology and neuroinflammation gene expression panels were considered in the analysis. (C) Functional enrichment analysis of transcriptomic changes following AAV5.2-PC-OxPL-VecTab® transduction of SOD1G93A motor neurons. Only the five most enriched terms of each category are graphically represented (GO, Gene Ontology; padj, adjusted p-value; MF, molecular function; BP, biological process; CC, cellular component). (D) Heatmap representation of SOD1G93A transcriptome normalization following AAV5.2-PC-OxPL-VecTab®. Cell values represent the mean FC in relation to wt levels (FC, fold-change). (E) Axonal pathology in SOD1G93A motor neurons exposed to PC-OxPL is mitigated by PC-OxPL-VecTab®. Upper panel: Values are expressed as means ± SD and normalized to the 25 μM PSPC condition. The number of axons was counted on the distal compartment as per TuJ-1 detection, used as a neuronal marker; n = 2 independent experiments. Lower panel: Representative panel of the distal compartment depicting PC-OxPL toxicity and neutralization by PC-OxPL-VecTab® in SOD1G93A motor neurons.
Figure 2
Figure 2
(A) Study design and treatment groups in wt and SOD1G93A mice. (B) Vector DNA levels (gc/μg DNA) in cervical and lumbar spinal cord, brain cortex, and liver in PC-OxPL-VecTab®-treated SOD1G93A at day 70 of age (3 weeks post-injection). vDNA levels were determined by qPCR analysis and quantified based on a plasmid standard curve. Columns represent mean ± SD. (C) PC-OxPL-VecTab® mRNA expression levels in cervical and lumbar spinal cord, brain cortex, and liver in PC-OxPL-VecTab®-treated SOD1G93A at day 70 of age (3 weeks post-injection). Transgene mRNA levels were measured by RT-qPCR and quantified as FC to the housekeeping (HKG) gene mHPRT1. Columns represent mean ± SD. One of the animals with low levels of vDNA (< 3×103 gc/μg DNA) showed undetectable levels of PC-OxPL-VecTab® mRNA. (D) Plasma PC-OxPL concentrations (in ng/mL) determined in wt and SOD1G93A mice over time (killed at days 45, 70, and 90 of age). Values are expressed as means ± SD. Unpaired t-test with Welch correction; ****p < 0.0001; ***p < 0.001; **p < 0.01; *p < 0.05, n = 4–6 depending on lipid and time point. (E) Log2(FC) converted the effect of PC-OxPL-VecTab®-treated SOD1G93A mice vs. vehicle-SOD1G93A mice for the 19 detected PC-OxPL species. A negative value represents a decrease in a specific PC-OxPL upon treatment with AAV5.2-PC-OxPL-VecTab®. Two-way ANOVA; ****p < 0.0001; ***p < 0.001; **p < 0.01; *p < 0.05. n = 9–12, depending on lipid and treatment.
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