PT  - JOURNAL ARTICLE
AU  - Hilla Vaknin
AU  - Kumudesh Mishra
AU  - Jeevitha D’Souza
AU  - Monzer Marisat
AU  - Uri Sprecher
AU  - Shane Wald-Altman
AU  - Anna Dukhovny
AU  - Yuval Raviv
AU  - Benny Da’adoosh
AU  - Hamutal Engel
AU  - Sandrine Benhamron
AU  - Keren Nitzan
AU  - Anna Permyakova
AU  - Hanna Rosenmann
AU  - Alexander Lossos
AU  - Joseph Tam
AU  - Berge A. Minassian
AU  - Or Kakhlon
AU  - Miguel Weil
TI  - A new drug candidates for glycogen storage disorders enhances glycogen catabolism: Lessons from Adult Polyglucosan Body Disease models
AID  - 10.1101/2021.03.18.436069
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.03.18.436069
4099  - http://biorxiv.org/content/early/2021/04/01/2021.03.18.436069.short
4100  - http://biorxiv.org/content/early/2021/04/01/2021.03.18.436069.full
AB  - This work employs Adult Polyglucosan Body Disease (APBD) models to explore the efficacy and mechanism of action of 144DG11, a new polyglucosan-reducing lead compound discovered by a high-throughput screen (HTS). APBD is an adult onset glycogen storage disorder (GSD) manifesting as a debilitating progressive axonopathic leukodystrophy. APBD is caused by glycogen branching enzyme (GBE) deficiency leading to poorly branched and insoluble glycogen inclusions, which precipitate as neuropathogenic polyglucosans (PG). 144DG11 led to prolonged survival and improved motor parameters in a GBE knockin (Gbeys/ys) APBD mouse model. Histopathologically, 144DG11 reduced PG and glycogen levels in brain, liver, heart, and peripheral nerve. Indirect calorimetry experiments revealed that 144DG11 increases carbohydrate burn at the expense of fat burn, suggesting metabolic mobilization of pathogenic PG. These results were also reflected at the cellular level by increased glycolytic, mitochondrial and total ATP production. Mechanistically, we show that the molecular target of 144DG11 is the lysosomal membrane protein LAMP1, whose interaction with the compound, similar to LAMP1 knockdown, enhanced autolysosomal degradation of glycogen and lysosomal acidification. Enhanced mitochondrial activity and lysosomal modifications were also the most pronounced effects of 144DG11 in APBD patient fibroblasts as discovered by image-based multiparametric phenotyping analysis and corroborated by proteomics. In summary, this work presents a broad mechanistic and target-based characterization of 144DG11 in in vivo and cell models of the prototypical GSD APBD. This investigation warrants development of 144DG11 into a safe and efficacious GSD therapy.One Sentence Summary A new compound, demonstrated to ameliorate APBD in vivo and ex vivo by autophagic catabolism of glycogen, may potentially become a universal drug for glycogen storage disorders.Competing Interest StatementThe authors have declared no competing interest.