Antibody based neuronal and axonal delivery vector for enzyme delivery in GM2 gangliosidosis

University Of Texas Hlth Sci Ctr Houston, Houston TX

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Abstract

Abstract: Selective delivery of bioactive molecules (cargo) to neuronal/axonal compartments can be used for modulation of their functions. Progress with therapeutic modalities, especially in neurodegenerative disorders, which can prevent neural degeneration and enhance neural repair has been strikingly slow. This is particularly relevant to various disorders affecting spinal motor neurons. Recent advances in biotechnology have allowed generation of specific bioactive molecules including enzymes, growth factors, proteins, peptides, and small molecules. However, targeted transportation/homing of these agents due to need to cross blood-tissue barriers is extremely inefficient. The overall goals of this exploratory project are to examine whether a monoclonal antibody or its fragments directed against neuronal/axonal surface glycans (complex ganglioside GT1b) can be used as neuronal and axonal delivery vectors (NADVs) for targeted ligand (enzyme) delivery (TLD) to peripheral nervous system neurons, particularly spinal motor neurons. In these ?proof of principle? studies we will examine the feasibility of enzyme replacement therapy (ERT) by antibody based NADV to neuronal (anterior horn) lysosomal compartments in transgenic mice lacking Hexoamindase b (a model of Sandhoff?s disease), which has clinical and pathologic phenotype including spinal cord anterior horn cell injury. Our preliminary studies show that an anti-ganglioside mAb can be used for delivery of different cargos to PNS axons and neurons and it localizes to endolysosomal subcellular compartments. Based on these findings we hypothesize that an anti- GT1b mAb (AGmAb) and its fragments are viable as vectors, which can be used for TLD to PNS neurons for ERT. This new application will test this hypotheses under following aims: Under Aim 1 AGmAb and its Fab and F(ab')2 fragments will be conjugated with Hexoamindase b enzyme and these conjugates will be characterized in terms of their functionality in ex vivo assays and for neuronal and subcellular lysosomal uptake in primary dorsal root ganglion neuron cultures. The conjugates identified under Aim 1 will be used under Aim 2 to determine whether they can be used as tools for ERT in a transgenic animal model of neuronal lysosomal storage disease, i.e., Sandhoff?s disease. If this approach is successful then it has translational implications for lysosomal storage disorders. Development of antibody-based NADVs for selective delivery of bioactive molecules to specific PNS neuronal populations to modulate their functions has therapeutic applications relevant to a number of neurologic disorders.