This work employs adult polyglucosan body disease (APBD) models to explore the efficacy and mechanism of action of the polyglucosan-reducing compound 144DG11. APBD is a glycogen storage disorder (GSD) caused by glycogen branching enzyme (GBE) deficiency causing accumulation of poorly branched glycogen inclusions called polyglucosans. 144DG11 improved survival and motor parameters in a GBE knockin (Gbeys/ys) APBD mouse model. 144DG11 reduced polyglucosan and glycogen 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 polyglucosan. At the cellular level, 144DG11 increased glycolytic, mitochondrial, and total ATP production. 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. 144DG11 also enhanced mitochondrial activity and modulated lysosomal features as revealed by bioenergetic, image-based phenotyping and proteomics analyses. As an effective lysosomal targeting therapy in a GSD model, 144DG11 could be developed into a safe and efficacious glycogen and lysosomal storage disease therapy.
Bibliographical noteFunding Information:
We would like to thank Inoviem Scientific and Zakharia Manevich, Edward Berenshtein, Hava Glickstein, William Breuer, and Hadas Segev‐Yekutiel from the Hebrew University for their valuable help in experimental procedures. This work was funded by the Israel Ministry of Science and Technology Personalized Medicine Program Award (grant # 60300 to OK and MW), the Israel Innovation Authority Kamin grant (grant # 61224 to OK and MW), Orphan Disease Center (grants # MDBR‐19‐134‐APBD and MDBR‐20‐100‐APBD to OK), and the Krigsner Foundation to MW. KM is a holder of the Lady Davis award. This work is dedicated to the memory of David Krigsner Zindeluk (z"l).
© 2021 The Authors. Published under the terms of the CC BY 4.0 license
- adult polyglucosan body disease