Deep Tissue and Cellular Phenotyping of APBD: A Bench to Bedside Approach

Awardee: Priya Kishnani

Institution: Duke University Medical Center

Grant Amount: $50,000.00

Funding Period: February 1, 2024 - January 31, 2025

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Summary:

Adult Polyglucosan Body Disease (APBD) is an inherited metabolic disease that causes progressive neurodegeneration and reduced physical function and quality of life. There is currently no available treatment for APBD, but over the past decade, the APBD mouse model has been used to investigate potential therapeutics. However, without a full understanding of (1) the specific cells and tissues involved in APBD, and (2) how the disease pathology changes over the course of the disease, our ability to design effective treatments for APBD is limited. Utilizing a multidisciplinary approach with specialists in medical genetics and pathology, we will evaluate the extent of cellular involvement and degree of disease in human and mouse tissues. Ultimately, this work will provide precise therapeutic targets and measurable endpoints for both animal model experiments and progression to clinical trials.

Combinations of small molecule as potential therapeutic agents for APBD

Awardee: Or Kakhlon

Institution: Research Fund of the Hadassah Medical Organization

Grant Amount: $50,000.00

Funding Period: February 1, 2024 - January 31, 2025

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Summary:

This proposal intends to significantly improve already very promising compounds for obtaining a cure for the adult neurodegenerative disorder Adult Polyglucosan Body Disease which inflicts paralysis, loss of sensation, and lack of urination control on its victims. These compounds will be applied in special formulations which can stabilize them and increase their tissue penetration. Using this methodology and also compound combinations we anticipate that a cure for this devastating disorder will be within reach as a syrup or a pill. APBD, or Adult Polyglucosan Body Disease, is a neurological disorder inflicting paralysis, loss of sensation, and lack of urination control on its victims. The purposes of this proposal are (1) to further improve already promising compounds for the treatment of APBD and (2) to establish new markers for the disease. The compounds will be improved by applying them in combinations and in special formulations which can stabilize them and increase their tissue penetration. The new blood markers will be: (a) neurofilaments, which are proteins derived from fragmented dead neurons and thus should decrease if treatment is successful; (b) a set of molecules in the blood, called metabolites, which can recognize the severity of the disease and how effectively it can be improved by interventions, such as the mentioned compounds.

Glucan fingerprint as biomarker in Adult polyglucosan body disease (APBD)

Awardee: Berge Minassian

Institution: UT southwestern medical center

Grant Amount: $49,677.00

Funding Period: February 1, 2023 - January 31, 2024

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Summary:

The central paradigm in APBD is excessive and abnormal glycogen in the central nervous system. While it is impossible to non invasively measure this glycogen, we can measure the breakdown products of it in the urine. We devised a technique to profile many of these glycogen breakdown products and showed evidence of being able to use such molecules in the urine of APBD model mice. The current grant will establish testing for other breakdown products in mouse models and patient samples.

Defining APBD pre-clinical biomarkers and assessing a therapy in an APBD mouse model.

Awardee: Matthew Gentry

Institution: University of Florida

Grant Amount: $49,677.00

Funding Period: February 1, 2023 - January 31, 2024

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Summary:

Glycogen is a key energy storage macromolecule in cells. However, the accumulation of aberrant glycogen in the brain drives devastating diseases like Lafora disease (LD) and Adult Polyglucosan Body Disease (APBD). The Gentry laboratory has >15 years of experience defining disease mechanisms for LD and developing pre-clinical therapies and biomarkers that are being translated into the clinic. The Akman laboratory has >15 years of experience defining disease mechanisms for APBD and developing pre-clinical therapies. In this proposal, they will combine efforts to: 1) define the brain metabolic perturbations in an APBD mouse model to identify APBD biomarkers and 2) assess an enzyme therapy as a pre-clinical APBD treatment in the same mouse model. This project brings together two laboratories with non-overlapping expertise in studying glycogen storage diseases to tackle critical questions for the APBD community.

Discovery of glycogen synthase inhibitors for validation as a novel therapeutic target for adult polyglucosan body disease (APBD)

Awardee: Wyatt Yue

Institution: Newcastle University, UK

Grant Amount: $99,025

Funding Period: February 1, 2022 - January 31, 2023

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Summary:

Adult polyglucosan body disease is caused by a defective gene encoding glycogen branching enzyme GBE1, resulting in its low activity. The GBE1 enzyme is essential for making glycogen very compact inside the cell, otherwise the glycogen that is being synthesised by another enzyme glycogen synthase GYS1 will form clogging clumps. Drug development programmes for APBD and related diseases have largely sought to deliver an artificial version of the GBE1 gene, or turn down the native GYS1 gene, both emerging gene therapy approaches that remain experimental and costly for the long run. Our vision is to develop a daily pill for APBD patients as a transformative oral therapy. In the first step towards this goal, we aim to develop small molecules that act on the GYS1 enzyme as a drug starting point. To achieve this, we will take advantage of our unique knowledge about the shape of GYS1 enzyme, as well as cutting-edge computational and screening methods to find small molecules.

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

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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. 

Testing the efficacy of new pharmaceutical candidates for APBD

Awardee: Or Kakhlon

Institution: Research Fund of the Hadassah Medical Organization

Award Amount: $52,509

Gene Therapy for Adult Polyglucosan Body Disease (APBD)

Awardee: Baodong Sun

Institution: Duke University

Award Amount: $51,209

Gene Replacement Therapy for APBD

Awardee: Berge Minassian

Institution: UT Southwestern Medical Center

Award Amount: $53,455

Funding Period: February 1, 2019 - January 31, 2020

Pharmacological, histological and metabolic analyses of a new drug candidate for APBD

Awardee: Or Kakhlon

Institution: Hadassah-Hebrew University Medical Center

Award Amount: $53,455

Funding Period: February 1, 2019 - January 31, 2020

Testing APBD drug candidates for restoration of multiple cell features and geneexpression profile

Awardee: Or Kakhlon

Institution: Hadassah Medical Organization

Award Amount: $52,978

Funding Period: January 1, 2018 - December 31, 2018

Could restoring GBE in affected tissues be a treatment for APBD?

Awardee: Hasan Orhan AKMAN

Institution: Columbia University Medical Center

Award Amount: $52,978

Funding Period: January 1, 2018 - December 31, 2018

The efficacy of guaifenesin in the treatment of adult polyglucosan body disease

Awardee: Akman Hasan

Institution: Columbia University Medical Center

Award Amount: $50,500

Funding Period: January 1, 2017 - December 31, 2017

Treatment of adult polyglucosan body disease caused by an intronic mutation in glycogen branching enzyme gene.

Awardee: Akman Hasan

Institution: Columbia University Medical Center

Award Amount: $50,500

Funding Period: January 1, 2017 - December 31, 2017