作者: Brandon, Jason A ; DePaoli-Roach, Anna ; Sun, Ramon C ; Zeller, Jill ; Gentry, Matthew S ; Segvich, Dyann M ; Simmons, Zoe R ; McKnight, Tracy R ; Zhou, Zhengqiu ; Roach, Peter J ; Brewer, M Kathryn ; Armstrong, Dustin D ; Hodges, Bradley L ; Aziz, Nadine M ; Uittenbogaard, Annette ; Austin, Grant L ; Young, Lyndsay E A ; Pauly, James R ; McCarthy, John J

Lafora disease (LD) is a fatal childhood epilepsy caused by recessive mutations in either the EPM2A or EPM2B gene. A hallmark of LD is the intracellular accumulation of insoluble polysaccharide deposits known as Lafora bodies (LBs) in the brain and other tissues. In LD mouse models, genetic reduction of glycogen synthesis eliminates LB formation and rescues the neurological phenotype. Therefore, LBs have become a therapeutic target for ameliorating LD. Herein, we demonstrate that human pancreatic α-amylase degrades LBs. We fused this amylase to a cell-penetrating antibody fragment, and this antibody-enzyme fusion (VAL-0417) degrades LBs in vitro and dramatically reduces LB loads in vivo in Epm2a^-/- mice. Using metabolomics and multivariate analysis, we demonstrate that VAL-0417 treatment of Epm2a^-/- mice reverses the metabolic phenotype to a wild-type profile. VAL-0417 is a promising drug for the treatment of LD and a putative precision therapy platform for intractable epilepsy.

2019-09-03·Molecular pharmaceutics2区 · 医学

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

2区 · 医学

Article

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

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.

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