Conquer from Within – Treating APBD by viral delivery of cross-correction-enabled amylase
Awardee: Felix Nitschke
Institution: University of Texas Southwestern Medical Center
Award Amount: $121,268
Funding Period: February 1, 2021 - January 31, 2022
Summary:
Adult polyglucosan body disease (APBD), an adult-onset variant of GSD IV, presents as a progressive neurological disorder involving the central and peripheral nervous system. APBD is caused by recessive mutations in the glycogen branching enzyme gene (GBE1), and the consequent accumulation of poorly branched cytosolic glycogen aggregates called polyglucosan bodies (PBs) in the nervous system. There are presently no treatments for APBD, but attenuation of PB accumulation in the APBD mouse model by genetically interfering with glycogen synthesis leads to alleviation of disease symptoms. A treatment aiming at PB removal can, therefore, prevent worsening of and potentially reverse disease symptoms. Secreted AMY2A (amylase) fused to an antibody fragment clearly digests PBs in vitro, and, by continuous delivery to the CNS it drastically reduced PBs in brains of Lafora disease mice. This protein therapy requires continuous or repeat administration. We propose to vectorize the above construct and thereby design a single-dose AAV9 viral vector that delivers cross-correction-enabled amylase. Cross-correction greatly increases efficacy of gene therapy for soluble lysosomal CNS diseases. Fab-AMY2A is inherently set up for cytosolic cross-correction by containing a specific secretion signal and the Fab fragment conferring cell-penetration. We expect to clear the CNS of PBs and to identify the most efficacious delivery route in APBD model mice. Also, we will study the progression of PB accumulation and neuroinflammation. This will allow a better definition of the therapeutic window in future studies, aiming PB removal for alleviation of neuroinflammation and prevention APBD-related changes is behavior, gait and life expectancy.