Nanoparticle Distributed Intravenous Enzyme Replacement Therapy (NanoDIVERT)

Enzyme replacement therapy (ERT) has been successful in ameliorating symptoms of patients with non-neuropathic lysosomal storage disorders (LSDs), making it a viable therapeutic approach for these rare, orphan genetic diseases. Despite its promise in the clinic, ERT cannot be used to treat 50-70% of LSDs with central nervous system manifestation due to the blood-brain barrier (BBB) which prevents the passage of recombinant enzymes from the blood into the brain. One of these diseases and the focus of this proposal, GM1 gangliosidosis, arises from variants in GLB1 that leads to decreased production of lysosomal β-galactosidase (βgal). Preliminary data in a feline model of GM1 gangliosidosis shows that with the addition of an apolipoprotein on the surface, polymersomes transport active βgal across the BBB within 48 hours after an intravenous forelimb injection. This approach to treatment, titled nanoparticle distributed IV ERT (NanoDIVERT), can potentially extend ERT into the central nervous system, which could impact not only GM1 gangliosidosis but also other orphan neuropathic LSDs.

Funded by the National Institutes of Health program in Neurologic Disorder and Stroke

Delivery of Cas9 for Gene Editing in Neural Disease

According to the World Health Organization, neurologic diseases remain one of the world’s largest growing global burdens due in part to the difficulty of overcoming transport across the blood-brain barrier (BBB). However, the PI has obtained evidence that polyethylene glycol-b-polylactic acid based polymersomes are capable of delivering an active enzyme, β-galactosidase, across the BBB to the entirety of a feline brain using an apolipoprotein E (apoE) targeted approach. This discovery now enables the delivery of alternative enzymes across the BBB to treat the central nervous system, for the first time allowing gene regulation and editing techniques to be applied to the brain in vivo. The implications of this discovery are widespread; however, our team is currently exploring gene editing for the treatment of GM1 gangliosidosis, a lysosomal storage disorder.

Funded by the National Institutes of Health program in General Medical Sciences
Center for Human Genetics COBRE

Delivery of Nerve Regenerative Peptides for Peripheral Nerve Injury Repair

Nerve cell damage is repaired within the Peripheral Nervous System (PNS) by translation of mRNA using neurotrophic factors. However, this translation isn’t successful within the Central Nervous System (CNS). Specifically, RasGAP SH3 domain binding protein 1 (G3BP1) forms stress granules, preventing nerve regeneration. To break down stress granules, peptides from different domains of G3BP1 have been developed by collaborator Jeffrey Twiss, with one peptide able to limit stress granule formation. However,  the blood-brain and nerve-blood barriers prevent small molecules and drugs from entering the brain and nervous system, which limits the effectiveness of free peptide injections. Nanoparticles made from amphiphilic di-block copolymers can protect and deliver the peptides past these barriers to help nerve regeneration. Additionally, by understanding the cellular uptake methods and intracellular degradation employed by polymersomes, nanoparticle properties can be fine-tuned to improve targeted delivery. 

Funded by the National Science Foundation EPSCoR Program
MADE in SC
This work is done in collaboration with Dr. Jeff Twiss and Dr. Modi Wetzler

Development of Nerve Growth Promoting Hydrogels

Citrate-based biomaterials demonstrate promise in regenerative medicine due to their radical scavenging and iron-chelating properties. Specifically, we are exploring citrate-containing hydrogels for regenerative medicine applications, mainly focused on wound healing, stem cell delivery, and the spinal cord.

Funded by NIH IDeA through NIGMS
SC INBRE

Thermally-Responsive Hydrogels for Glioblastoma Treatment

The incidence of brain tumors in the United States is about 16.5 per 100,000 each year, with “best” survival rate of two years after diagnosis with the current gold standard treatment. Due to the difficulty in crossing the blood-brain barrier (BBB), many drugs have difficulty reaching the brain resulting in a very large systemic dosage to achieve adequate treatment. Thermally responsive hydrogels can be directly injected and encapsulate drug products to better treat brain tumors, bypassing the BBB altogether. By utilizing the natural characteristics of polymeric hydrogels and optimizing mechanical characteristics, we can best create a fully injectable material to match the brain moduli for a direct delivery method.