ArticleMolecular therapy : the journal of the American Society of Gene Therapy2014
Chaperone nanobodies protect gelsolin against MT1-MMP degradation and alleviate amyloid burden in the gelsolin amyloidosis mouse model.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers, 1 of them a synthesis that pooled it.
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Who cites it
15 citing papers in PubMed, 1 synthesis or guideline pooled it, 33 citations in OpenAlex.
- Research Progress and Applications of Multivalent, Multispecific and Modified Nanobodies for Disease Treatment.Frontiers in immunology · 2021Pooled it
- A molecular perspective of gelsolin amyloidosis: An old foe with new faces.Cellular and molecular life sciences : CMLS · 2026Review
- The Impact of Nanobodies on G Protein-Coupled Receptor Structural Biology and Their Potential as Therapeutic Agents.Molecular pharmacology · 2024Review
- Rational Design of a Peptidomimetic Inhibitor of Gelsolin Amyloid Aggregation.International journal of molecular sciences · 2022Article
- Review
- Exploring cellular biochemistry with nanobodies.The Journal of biological chemistry · 2020Review
- Long-term live-cell microscopy with labeled nanobodies delivered by laser-induced photoporation.Nano research · 2020Article
- Intracellular displacement of p53 using transactivation domain (p53 TAD) specific nanobodies.mAbs · 2018Article
- Atypical Presentation of Gelsolin Amyloidosis in a Man of African Descent with a Novel Mutation in the Gelsolin Gene.The American journal of case reports · 2018Article
- Common origin of the gelsolin gene variant in 62 Finnish AGel amyloidosis families.European journal of human genetics : EJHG · 2018Article
- Gelsolin pathogenic Gly167Arg mutation promotes domain-swap dimerization of the protein.Human molecular genetics · 2018Article
- Nanobody Technology: A Versatile Toolkit for Microscopic Imaging, Protein-Protein Interaction Analysis, and Protein Function Exploration.Frontiers in immunology · 2017Review
- Non-Invasive Imaging of Amyloid Deposits in a Mouse Model of AGel UsingMolecular imaging and biology · 2016Article
- Fascin Rigidity and L-plastin Flexibility Cooperate in Cancer Cell Invadopodia and Filopodia.The Journal of biological chemistry · 2016Article
- A nanobody modulates the p53 transcriptional program without perturbing its functional architecture.Nucleic acids research · 2014Article
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Gelsolin amyloidosis is an autosomal dominant incurable disease caused by a point mutation in the GSN gene (G654A/T), specifically affecting secreted plasma gelsolin. Incorrect folding of the mutant (D187N/Y) second gelsolin domain leads to a pathological proteolytic cascade. D187N/Y gelsolin is first cleaved by furin in the trans-Golgi network, generating a 68 kDa fragment (C68). Upon secretion, C68 is cleaved by MT1-MMP-like proteases in the extracellular matrix, releasing 8 kDa and 5 kDa amyloidogenic peptides which aggregate in multiple tissues and cause disease-associated symptoms. We developed nanobodies that recognize the C68 fragment, but not native wild type gelsolin, and used these as molecular chaperones to mitigate gelsolin amyloid buildup in a mouse model that recapitulates the proteolytic cascade. We identified gelsolin nanobodies that potently reduce C68 proteolysis by MT1-MMP in vitro. Converting these nanobodies into an albumin-binding format drastically increased their serum half-life in mice, rendering them suitable for intraperitoneal injection. A 12-week treatment schedule of heterozygote D187N gelsolin transgenic mice with recombinant bispecific gelsolin-albumin nanobody significantly decreased gelsolin buildup in the endomysium and concomitantly improved muscle contractile properties. These findings demonstrate that nanobodies may be of considerable value in the treatment of gelsolin amyloidosis and related diseases.
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