Single chain variable fragment antibodies block aggregation and toxicity induced by familial ALS-linked mutant forms of SOD1

NEUROBIOLOGY OF DISEASE

卷:56

Article

Ghadge, Ghanashyam D.¹  Pavlovic, John D.²  Koduvayur, Sujatha P.²  Kay, Brian K.²  Roos, Raymond P.¹ 

[1] Univ Chicago, Med Ctr, Dept Neurol, Chicago, IL 60637 USA

[2] Univ Illinois, Dept Biol Sci, Chicago, IL 60607 USA

关键词: Familial amyotrophic lateral sclerosis;    Mutant superoxide dismutase type 1;    Amyotrophic lateral sclerosis;    ALS;    Single chain fragments of variable region antibodies;    scFvs;    Motor neuron disease;   

DOI  :  10.1016/j.nbd.2013.04.007

来源: Elsevier

【 摘 要 】

Approximately 10% of amyotrophic lateral sclerosis (ALS) cases are familial (known as FALS) with an autosomal dominant inheritance pattern, and similar to 25% of FALS cases are caused by mutations in Cu/Zn superoxide dismutase (SOD1). There is convincing evidence that mutant SOD1 (mtSOD1) kills motor neurons (MNs) because of a gain-of-function toxicity, most likely related to aggregation of mtSOD1. A number of recent reports have suggested that antibodies can be used to treat mtSOD1-induced FALS. To follow up on the use of antibodies as potential therapeutics, we generated single chain fragments of variable region antibodies (scFvs) against SOD1, and then expressed them as 'intrabodies' within a motor neuron cell line. In the present study, we describe isolation of human scFvs that interfere with mtSOD1 in vitro aggregation and toxicity. These scFvs may have therapeutic potential in sporadic ALS, as well as FALS, given that sporadic ALS may also involve abnormalities in the SOD1 protein or activity. (c) 2013 Elsevier Inc. All rights reserved.

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