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

Abstract

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 has been 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 (ELISA) 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 intracerebroventricular administration (ICV) provided robust CNS delivery when compared to intrathecal administration (IT). These data define critical steps in the translational pipeline of VAL-0417 for the treatment of LD.

An empirical pipeline for personalized diagnosis of Lafora disease mutations

“…Preclinical studies of LD therapeutics are currently underway with multiple lines of treatment in development ( Brewer and Gentry, 2018 ; Brewer et al., 2019a ; Gentry et al., 2020 ). The first published therapeutic strategy uses an antibody-enzyme fusion that degrades LBs, the toxic carbohydrate aggregates that cause LD ( Austin et al., 2019 ; Brewer et al., 2019b ; Zhou et al., 2019 ). This drug is administered directly into the central nervous system, eliminating brain LBs and correcting the cerebral metabolic phenotype in LD mouse models.…”

“…Moving forward, new mutations can be quickly classified using our empirical pipeline and distinguished from benign polymorphisms. Our results showed that this system can be used to guide patient-specific clinical care and the deployment of therapeutics, which is needed to maximize the benefit from emerging LD therapeutics (Austin et al, 2019;Brewer and Gentry, 2018;Brewer et al, 2019aBrewer et al, , 2019bGentry et al, 2020;Zhou et al, 2019).…”

An empirical pipeline for personalized diagnosis of Lafora disease mutations

“…Excitingly, preclinical studies of LD therapeutics are currently underway with multiple lines of treatment in development [34][35][36] . The first published therapeutic strategy utilizes an antibodyenzyme fusion that degrades LBs, the toxic carbohydrate aggregates that cause LD [37][38][39] . This drug is administered directly into the CNS, eliminating brain LBs and correcting the cerebral metabolic phenotype in LD mouse models.…”

“…Moving forward, novel mutations can be quickly classified using our empirical pipeline and distinguished from benign polymorphisms. This system can be used to guide patient-specific clinical care and the deployment of therapeutics, which is needed to maximize the benefit from emerging novel LD therapeutics that are being developed [34][35][36][37][38][39] .…”

The 5th International Lafora Epilepsy Workshop: Basic science elucidating therapeutic options and preparing for therapies in the clinic

“…He then focused on recent work from his laboratory performed in collaboration with Valerion Therapeutics. They developed a novel antibody-enzyme fusion (AEF) that employs an antibody fragment with cell penetrating properties fused to an amylase that can degrade LBs [21][22][23]. Gentry showed that the AEF, termed VAL-0417, robustly degrades LBs in vitro releasing glucose and maltose.…”