A nanoparticle-based drug could help fight neurodegenerative disease by improving the health of neurons and blood vessels, according to a Northwestern Medicine study published in the journal Brain.
The drug, called nano-VEGF, is a synthetic peptide designed to mimic a much larger growth factor protein that has successfully slowed spinocerebellar ataxia type 1 (SCA1) in mouse models of the disease. This study serves as a proof-of-concept for a treatment that could expand to other conditions, said Puneet Opal, MD, PhD, professor in the Ken & Ruth Davee Department of Neurology in the Division of Movement Disorders and senior author of the study.
“This is one of the first applications of nanoparticles in neurological disease,” Opal said.
SCA1 is a hereditary, progressive disease characterized by neurodegeneration in the cerebellum, leading to a loss of coordination and abnormal gait in patients. The disease is caused by mutations in a protein called ataxin-1, which, among other functions, plays a direct role in restricting expression of vascular endothelial growth factor (VEGF), a common protein that stimulates formation of blood vessels.
A previous study led by Opal showed that replenishing VEGF in the brains of mice modeling SCA1 slowed cerebellar atrophy and led to increased connections between neurons and better coordination in the mice. However, synthesizing full-length proteins is costly and time-consuming, Opal said.
Instead, the scientists turned to a synthetic peptide drug developed in the laboratory of Samuel Stupp, PhD, director of the Simpson Querrey Institute for BioNanotechnology and co-author of the paper. First tested by Stupp as a therapy for peripheral artery disease, nano-VEGF contains just the essential part of VEGF: peptide molecules that activate VEGF receptors in target cells.
“VEGF and other growth factors have been shown to be experimentally beneficial in several neurodegeneration disease models including Alzheimer’s and ALS, but it has been difficult to translate these findings into drugs that work in the clinic,” Opal said. “They are extremely costly to manufacture as full-length proteins and they tend to be biologically unstable. This nanoparticle-based delivery solves many of these issues.”
Jennifer Yuan-Shih Hu, PhD, a postdoctoral fellow in Opal’s laboratory and first author of the study, administered this synthetic peptide to mice modeling SCA1, finding they exhibited both behavioral and anatomical improvements after the treatment.
“Their neuron connectivity and capillaries had improved, and the animals could balance and walk better,” Opal said. “In fact, it was as good as conventional VEGF.”
The synthetic peptide has another benefit: There is theoretically a smaller chance of stimulating antibodies that are often produced when full-length proteins are delivered, and can interfere with their efficacy, according to the study.
However, stimulating growth has the potential to cause harmful side effects, Opal warned.
“Making too many capillaries could cause edema or inflammation,” Opal said. “We’ve not seen it yet, because we’ve been using a relatively low dose, but we would want to know before going on to human patients.”
In addition, Opal wants to explore if treatment with the synthetic peptide earlier in disease can actually reverse SCA1, instead of just slowing progression, and whether this platform could be extended to other diseases.
Patients with other neurodegenerative disorders like ALS and Alzheimer’s are deficient in a wide range of growth factors, according to previous research. The nanoparticle delivery system is versatile and could be attached to a wide variety of potentially therapeutic peptides that could mimic the functions of these other growth factors, Opal said.
“What would change would be the business end of that molecule, but that backbone could be kept the same,” Opal said. “Basically any bioactive peptide that acts on a surface could be engineered and delivered by this approach.”
Other Feinberg co-authors include Marco Martina, MD, PhD, associate professor of Physiology; Chandrakanth Reddy Edamakanti, PhD, a postdoctoral fellow in Opal’s laboratory; and Jeehaeh Do, a fifth-year student in the Northwestern University Interdepartmental Neuroscience (NUIN) graduate program.
Ameet Kini, MD, PhD, professor of Pathology at Loyola University Chicago Stritch School of Medicine, was also a co-author of the study.
Stupp is the Board of Trustees Professor of Materials Science and Engineering, Chemistry, Medicine and Biomedical Engineering, professor of Medicine in the Division of Endocrinology, and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
This study was supported by National Institutes of Health grants R01 NS062051, R01 NS082351, R01 HL116577-02, R21 NS099962 and R21 NS090346, and the Northwestern University Regenerative Nanomedicine CRN Catalyst Award.