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

2019 ◽  
Author(s):  
Grant L. Austin ◽  
Zoe R. Simmons ◽  
Jack E. Klier ◽  
Brad L. Hodges ◽  
Robert Shaffer ◽  
...  
Keyword(s):  
Lupus Erythematosus ◽  
Intrathecal Administration ◽  
Lafora Disease ◽  
Cell Penetration ◽  
Unique Challenge ◽  
Cellular Targeting ◽  
Lafora Bodies ◽  
Murine Systemic Lupus Erythematosus ◽  
Mediate Cell ◽  
Enzyme Fusion

AbstractLafora disease is a fatal juvenile epilepsy, characterized by the malignant accumulation of aberrant glucan inclusions called Lafora Bodies (LBs). Cerebral delivery of protein-based therapeutics for the clearance of Lafora Bodies remain 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 been proposed as a broadly applicable carrier to mediate cellular targeting and uptake. We report studies on cerebral delivery of VAL-0417, an antibody-enzyme fusion composed of the 3E10 hFab and human pancreatic α-amylase for the clearance of LBs in a mouse model of lafora disease. Herein, we report development of an enzyme-linked immunosorbant-based bioassay 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 our method, we measured biodistribution in different methods of delivery. We found intracerebroventricular administration provided the most robust delivery, while intrathecal administration only showed modest biodistribution. These data define critical steps in the translational pipeline of VAL-0417for the treatment of Lafora disease.

scholarly journals Targeting pathogenic Lafora bodies in Lafora disease using an antibody-enzyme fusion

2019 ◽  
Author(s):  
M. Kathryn Brewer ◽  
Annette Uittenbogaard ◽  
Grant Austin ◽  
John J. McCarthy ◽  
Dyann M. Segvich ◽  
...  
Keyword(s):  
Glycogen Synthesis ◽  
Intractable Epilepsy ◽  
Antibody Fragment ◽  
Glycogen Storage ◽  
Childhood Epilepsy ◽  
Lafora Disease ◽  
Polyglucosan Bodies ◽  
Lafora Bodies ◽  
Enzyme Fusion

AbstractLafora disease (LD) is a fatal childhood epilepsy and a non-classical glycogen storage disorder with no effective therapy or cure. LD is caused by recessive mutations in theEPM2AorEPM2Bgenes that encode the glycogen phosphatase laforin and an E3 ubiquitin ligase malin, respectively. A hallmark of LD is the intracellular accumulation of abnormal and insoluble α-linked polysaccharide deposits known as Lafora bodies (LBs) in several tissues, including most regions of the brain. In mouse models of LD, genetic reduction of glycogen synthesis eliminates LB formation and rescues the neurological phenotype. Since multiple groups have confirmed that neurodegeneration and epilepsy result from LB accumulation, a major focus in the field has shifted toward the development of therapies that reduce glycogen synthesis or target LBs for degradation with the goal of treating LD. Herein, we identify the optimal enzymes for degrading LBs, and we develop a novel therapeutic agent by fusing human pancreatic α-amylase to a cellpenetrating antibody fragment. This antibody-enzyme fusion (VAL-0417) degrades LBsin vitro, shows robust cellular uptake, and significantly reduces the LB loadin vivoinEpm2a-/- mice. VAL-0417 is a promising therapeutic for the treatment of LD and a putative precision therapy for an intractable epilepsy. Antibody-enzyme fusions represent a new class of antibody-based drugs that could be utilized to treat glycogen storage disorders and other diseases.One Sentence SummaryAn antibody-enzyme fusion delivering an amylase degrades the toxic polyglucosan bodies that cause Lafora disease, a fatal childhood epilepsy.

scholarly journals Targeting Pathogenic Lafora Bodies in Lafora Disease Using an Antibody-Enzyme Fusion

2019 ◽  
Vol 30 (4) ◽  
pp. 689-705.e6 ◽  
Author(s):  
M. Kathryn Brewer ◽  
Annette Uittenbogaard ◽  
Grant L. Austin ◽  
Dyann M. Segvich ◽  
Anna DePaoli-Roach ◽  
...  
Keyword(s):  
Lafora Disease ◽  
Lafora Bodies ◽  
Enzyme Fusion

scholarly journals The Yaa Locus and IFN-α Fine-Tune Germinal Center B Cell Selection in Murine Systemic Lupus Erythematosus

2012 ◽  
Vol 189 (9) ◽  
pp. 4305-4312 ◽  
Author(s):  
Ioana Moisini ◽  
Weiqing Huang ◽  
Ramalingam Bethunaickan ◽  
Ranjit Sahu ◽  
Peta-Gay Ricketts ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Germinal Center ◽  
Cell Selection ◽  
Systemic Lupus ◽  
Germinal Center B Cell ◽  
Murine Systemic Lupus Erythematosus ◽  
Fine Tune

scholarly journals Ketogenic diet reduces Lafora bodies in murine Lafora disease

2020 ◽  
Vol 6 (6) ◽  
pp. e533
Author(s):  
Lori Israelian ◽  
Peixiang Wang ◽  
Shoghig Gabrielian ◽  
Xiaochu Zhao ◽  
Berge A. Minassian
Keyword(s):  
Ketogenic Diet ◽  
Lafora Disease ◽  
Lafora Bodies

Modulation of disease activity in murine systemic lupus erythematosus by cytokine gene delivery

Lupus ◽  
1995 ◽  
Vol 4 (4) ◽  
pp. 286-292 ◽  
Author(s):  
E. Raz ◽  
J. Dudler ◽  
M. Lotz ◽  
S.M. Baird ◽  
C.C. Berry ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Gene Delivery ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Cytokine Gene ◽  
Systemic Lupus ◽  
Murine Systemic Lupus Erythematosus

scholarly journals Sequestration of chaperones and proteasome into Lafora bodies and proteasomal dysfunction induced by Lafora disease-associated mutations of malin

2010 ◽  
Vol 19 (23) ◽  
pp. 4726-4734 ◽  
Author(s):  
Sudheendra N.R. Rao ◽  
Ranjan Maity ◽  
Jaiprakash Sharma ◽  
Parthanarayan Dey ◽  
Susarla Krishna Shankar ◽  
...  
Keyword(s):  
Lafora Disease ◽  
Lafora Bodies
Sign in / Sign up

Export Citation Format

Share Document