Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 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.

PubMed Disclaimer

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.
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Abel O., Powell J. F., Andersen P. M., Al-Chalabi A. (2012). ALSoD: a user-friendly online bioinformatics tool for amyotrophic lateral sclerosis genetics. Hum. Mutat. 33, 1345–1351. doi: 10.1002/humu.22157, PMID: - DOI - PubMed
    1. Binder C. J., Papac-Milicevic N., Witztum J. L. (2016). Innate sensing of oxidation-specific epitopes in health and disease. Nat. Rev. Immunol. 16, 485–497. doi: 10.1038/nri.2016.63, PMID: - DOI - PMC - PubMed
    1. D’Erchia A. M., Gallo A., Manzari C., Raho S., Horner D. S., Chiara M., et al. (2017). Massive transcriptome sequencing of human spinal cord tissues provides new insights into motor neuron degeneration in ALS. Sci. Rep. 7:10046. doi: 10.1038/s41598-017-10488-7, PMID: - DOI - PMC - PubMed
    1. Dong Y., D’Mello C., Pinsky W., Lozinski B. M., Kaushik D. K., Ghorbani S., et al. (2021). Oxidized phosphatidylcholines found in multiple sclerosis lesions mediate neurodegeneration and are neutralized by microglia. Nat. Neurosci. 24, 489–503. doi: 10.1038/s41593-021-00801-z, PMID: - DOI - PubMed
    1. Dong Y., Yong V. W. (2022). Oxidized phospholipids as novel mediators of neurodegeneration. Trends Neurosci. 45, 419–429. doi: 10.1016/j.tins.2022.03.002, PMID: - DOI - PubMed

LinkOut - more resources