Anti-SOD1 Nanobodies That Stabilize Misfolded SOD1 Proteins Also Promote Neurite Outgrowth in Mutant SOD1 Human Neurons

Kumar, Meenakshi Sundaram; Fowler-Magaw, Megan E; Kulick, Daniel; Boopathy, Sivakumar; Gadd, Del Hayden; Rotunno, Melissa; Douthwright, Catherine; Golebiowski, Diane; Yusuf, Issa; Xu, Zuoshang; Brown, Robert H.; Sena‐Esteves, Miguel; O’Neil, Alison; Bosco, Daryl A.

doi:10.3390/ijms232416013

Cited by 3 publications

(2 citation statements)

References 66 publications

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“…Early studies (since 2003) with RNAi targeting mRNA of mutated SOD1 using small interfering RNAs (siRNAs) and short hairpin RNAs were performed on models with A5V, G86R or G94A mutation [169][170][171][172][173][174][175]. To achieve higher permeability of the blood-brain barrier, adeno-associated virus (AAV) such as AAV6 and AAV9 have been used as viral vectors for packaging [176][177][178][179][180]. Chemically modified siRNAs are also showing promise [181].…”

Section: Current Therapeutic Strategies Targeting Sod1mentioning

confidence: 99%

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Variability in SOD1-associated amyotrophic lateral sclerosis: geographic patterns, clinical heterogeneity, molecular alterations, and therapeutic implications

Huang,

Liu,

Yao

et al. 2024

Transl Neurodegener

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons, resulting in global health burden and limited post-diagnosis life expectancy. Although primarily sporadic, familial ALS (fALS) cases suggest a genetic basis. This review focuses on SOD1, the first gene found to be associated with fALS, which has been more recently confirmed by genome sequencing. While informative, databases such as ALSoD and STRENGTH exhibit regional biases. Through a systematic global examination of SOD1 mutations from 1993 to 2023, we found different geographic distributions and clinical presentations. Even though different SOD1 variants are expressed at different protein levels and have different half-lives and dismutase activities, these alterations lead to loss of function that is not consistently correlated with disease severity. Gain of function of toxic aggregates of SOD1 resulting from mutated SOD1 has emerged as one of the key contributors to ALS. Therapeutic interventions specifically targeting toxic gain of function of mutant SOD1, including RNA interference and antibodies, show promise, but a cure remains elusive. This review provides a comprehensive perspective on SOD1-associated ALS and describes molecular features and the complex genetic landscape of SOD1, highlighting its importance in determining diverse clinical manifestations observed in ALS patients and emphasizing the need for personalized therapeutic strategies.

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Section: Current Therapeutic Strategies Targeting Sod1mentioning

confidence: 99%

“…A preclinical study has been conducted on anti-SOD1 nanobodies [180]. An epitope of Derlin-1, which selectively binds pathogenic SOD1, showed potentials to direct lysosomal degradation of the misfolded SOD1 protein in both cellular and mouse models [182].…”

Section: Current Therapeutic Strategies Targeting Sod1mentioning

confidence: 99%

Variability in SOD1-associated amyotrophic lateral sclerosis: geographic patterns, clinical heterogeneity, molecular alterations, and therapeutic implications

Huang,

Liu,

Yao

et al. 2024

Transl Neurodegener

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Design and investigation of celastrol‐peptide nanoassemblies and their binding interactions with superoxide dismutase 1 and its mutants

Goncalves,

Phan,

Biggs

et al. 2024

Nano Select

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The misfolding and aggregation of superoxide dismutase 1 (SOD1) and its mutants has been implicated in amyotrophic lateral sclerosis (ALS). In this study, we have created three peptide conjugates with the antioxidant pentacyclic terpene celastrol and examined their interactions with SOD1 and its mutants A4V and G93A. The peptides YYIVS, MPDAHL, and GSGGL are derived from natural sources and are known for their inherent antioxidant properties. Docking studies revealed that most conjugates showed strong binding with the metal binding and electrostatic loops as well as the β1, β5, and β6 hydrophobic core of SOD1. The conjugates were synthesized and self‐assembled into nanoassemblies. Surface plasmon resonance studies further confirmed the binding interactions of the nanoassemblies with the SOD1 proteins. The nanoassemblies were found to internalize into HEK293T cells. The HEK 293T cells were then transfected with GFP fused WT (Wild Type), A4V and G93A SOD1 mutants. Flow cytometry revealed that treatment with celastrol‐peptide nanoassemblies, affected the fluorescence of the SOD1 protein, implying their role in modulating SOD1, particularly for the mutants. N–Acetyl–Leu–Leu–Norleucinal (ALLN) induced SOD1 aggregation was also affected upon treatment with the nanoassemblies. These results suggest that the nanoassemblies may potentially modulate the activity and structure of SOD1.

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Discovery of nanobodies: a comprehensive review of their applications and potential over the past five years

Alexander,

Leong

2024

J Nanobiotechnol

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Nanobodies (Nbs) are antibody fragments derived from heavy-chain-only IgG antibodies found in the Camelidae family as well as cartilaginous fish. Their unique structural and functional properties, such as their small size, the ability to be engineered for high antigen-binding affinity, stability under extreme conditions, and ease of production, have made them promising tools for diagnostics and therapeutics. This potential was realized in 2018 with the approval of caplacizumab, the world’s first Nb-based drug. Currently, Nbs are being investigated in clinical trials for a broad range of treatments, including targeted therapies against PDL1 and Epidermal Growth Factor Receptor (EGFR), cardiovascular diseases, inflammatory conditions, and neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. They are also being studied for their potential for detecting and imaging autoimmune conditions and infectious diseases such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A variety of methods are now available to generate target-specific Nbs quickly and efficiently at low costs, increasing their accessibility. This article examines these diverse applications of Nbs and their promising roles. Only the most recent articles published in the last five years have been used to summarize the most advanced developments in the field. Graphical Abstract

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Anti-SOD1 Nanobodies That Stabilize Misfolded SOD1 Proteins Also Promote Neurite Outgrowth in Mutant SOD1 Human Neurons

Cited by 3 publications

References 66 publications

Variability in SOD1-associated amyotrophic lateral sclerosis: geographic patterns, clinical heterogeneity, molecular alterations, and therapeutic implications

Variability in SOD1-associated amyotrophic lateral sclerosis: geographic patterns, clinical heterogeneity, molecular alterations, and therapeutic implications

Design and investigation of celastrol‐peptide nanoassemblies and their binding interactions with superoxide dismutase 1 and its mutants

Discovery of nanobodies: a comprehensive review of their applications and potential over the past five years

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