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Publication : Comprehensive evaluation of human-derived anti-poly-GA antibodies in cellular and animal models of C9orf72 disease.

First Author	Jambeau M	Year	2022
Journal	Proc Natl Acad Sci U S A	Volume	119
Issue	49	Pages	e2123487119
PubMed ID	36454749	Mgi Jnum	J:352174
Mgi Id	MGI:7437389	Doi	10.1073/pnas.2123487119
Citation	Jambeau M, et al. (2022) Comprehensive evaluation of human-derived anti-poly-GA antibodies in cellular and animal models of C9orf72 disease. Proc Natl Acad Sci U S A 119(49):e2123487119

abstractText

Hexanucleotide G(4)C(2) repeat expansions in the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Dipeptide repeat proteins (DPRs) generated by translation of repeat-containing RNAs show toxic effects in vivo as well as in vitro and are key targets for therapeutic intervention. We generated human antibodies that bind DPRs with high affinity and specificity. Anti-GA antibodies engaged extra- and intra-cellular poly-GA and reduced aggregate formation in a poly-GA overexpressing human cell line. However, antibody treatment in human neuronal cultures synthesizing exogenous poly-GA resulted in the formation of large extracellular immune complexes and did not affect accumulation of intracellular poly-GA aggregates. Treatment with antibodies was also shown to directly alter the morphological and biochemical properties of poly-GA and to shift poly-GA/antibody complexes to more rapidly sedimenting ones. These alterations were not observed with poly-GP and have important implications for accurate measurement of poly-GA levels including the need to evaluate all centrifugation fractions and disrupt the interaction between treatment antibodies and poly-GA by denaturation. Targeting poly-GA and poly-GP in two mouse models expressing G(4)C(2) repeats by systemic antibody delivery for up to 16 mo was well-tolerated and led to measurable brain penetration of antibodies. Long-term treatment with anti-GA antibodies produced improvement in an open-field movement test in aged C9orf72(450) mice. However, chronic administration of anti-GA antibodies in AAV-(G(4)C(2))(149) mice was associated with increased levels of poly-GA detected by immunoassay and did not significantly reduce poly-GA aggregates or alleviate disease progression in this model.

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