Advanced Brain-Penetrant Enzyme Therapy to Treat Lafora Disease

Lafora disease (LD) is a fatal autosomal recessive neurodegenerative disorder characterized by myoclonus, seizures, and a rapid progression to dementia during the teenage years, culminating in death within a decade of onset. LD arises from mutations in genes encoding laforin, a glycogen phosphatase, or malin, an E3 ubiquitin ligase, leading to the accumulation of pathogenic polyglucosan bodies (PGBs) in the brain. Studies in LD mouse models have identified brain PGBs as the primary driver of disease sequalae, identifying the brain PGBs as the critical therapeutic target. Previously, Gentry and Vander Kooi developed an antibody-enzyme fusion (AEF) therapy that degrades brain PGBs and normalizes brain metabolism in LD mice following intracerebroventricular (ICV) administration of the AEF. This work demonstrated impressive proof-of-concept target engagement and brain metabolic recovery. However, clinical translation of this AEF was limited because it does not efficiently cross the blood- brain barrier (BBB). Wang and Gorman recently developed effective antibody-based brain shuttle platforms to allow biologic delivery across the BBB and into the brain parenchyma. This platform utilizes antibodies targeting human transferrin receptor (TfR), which enhance uptake into brain parenchyma by 10-30-fold. This R61/R33 project brings together these two novel technologies. We have engineered a brain-penetrant BBB-AEF therapeutic by fusing the TfR-targeting brain shuttle to the AEF, allowing systemic administration and robust brain PGB clearance. We demonstrate that this BBB-AEF fusion that crosses the BBB, penetrates brain parenchyma, accesses the cytoplasm, and degrades PGBs. A key feature for clinical translation is that the BBB-AEF fusions are humanized. Additionally, we have established a humanized TfR knock-in LD mouse model, designated hTfR-LKO, and developed the needed assays to assess target engagement. Thus, we have already generated preliminary data and necessary tools to develop a translational therapy. The R61 phase (1 year) will establish BBB-AEF target engagement by defining pharmacokinetics, determining an initial effective dose, and assessing PGB clearance in hTfR-LKO mice. Success will be defined by achieving >50% brain PGB degradation. The R33 phase (2 years) will refine dosing regimens to identify the minimum effective dose (MED), optimal treatment duration, and potential sex differences while evaluating physiological outcomes and preliminary safety. Success will be defined by establishing a MED and redosing parameters in both sexes along with defining the therapeutic window and physiological outcomes. This project unites complementary expertise to advance a first-in-class targeted therapeutic for LD and provides the needed data for continued development of this therapeutic. Beyond LD, this platform has the potential to facilitate brain delivery of other biologics, establishing a broadly applicable strategy for treating neurological diseases. Project Number: 1R61NS146312-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Matthew Gentry (+1 co-PI) | Institution: UNIVERSITY OF FLORIDA, GAINESVILLE, FL | Award Amount: $420,990 | Activity Code: R61 | Study Section: Special Emphasis Panel[ZRG1 NV-G (54)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11285782