Central Nervous System Delivery and Biodistribution Analysis of an Antibody-Enzyme Fusion for the Treatment of Lafora Disease

Grant L. Austin, Zoe R. Simmons, Jack E. Klier, Alberto Rondon, Brad L. Hodges, Robert Shaffer, Nadine M. Aziz, Tracy R. McKnight, James R. Pauly, Dustin D. Armstrong, Craig W. Vander Kooi, Matthew S. Gentry

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


Lafora disease (LD) is a fatal juvenile epilepsy characterized by the accumulation of aberrant glucan aggregates called Lafora bodies (LBs). Delivery of protein-based therapeutics to the central nervous system (CNS) for the clearance of LBs remains a unique challenge in the field. Recently, a humanized antigen-binding fragment (hFab) derived from a murine systemic lupus erythematosus DNA autoantibody (3E10) has been shown to mediate cell penetration and proposed as a broadly applicable carrier to mediate cellular targeting and uptake. We report studies on the efficacy and CNS delivery of VAL-0417, an antibody-enzyme fusion composed of the 3E10 hFab and human pancreatic α-amylase, in a mouse model of LD. An enzyme-linked immunosorbent assay has been developed to detect VAL-0417 post-treatment as a measure of delivery efficacy. We demonstrate the robust and sensitive detection of the fusion protein in multiple tissue types. Using this method, we measured biodistribution in different methods of delivery. We found that intracerebroventricular administration provided robust CNS delivery when compared to intrathecal administration. These data define critical steps in the translational pipeline of VAL-0417 for the treatment of LD.

Original languageEnglish
Pages (from-to)3791-3801
Number of pages11
JournalMolecular Pharmaceutics
Issue number9
StatePublished - Sep 3 2019

Bibliographical note

Publisher Copyright:
Copyright © 2019 American Chemical Society.


  • 3E10
  • CNS delivery
  • Lafora bodies
  • Lafora disease
  • VAL-0417
  • amylase
  • antibody therapy
  • autoantibody
  • glycogen storage disease

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery


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