Written by Dr. Chandrakanth Edamakanti Edited by Dr. David Bushart

VEGF nanoparticles offer a new avenue for developing treatments for SCA1 and other neurodegenerative disorders

Spinocerebellar ataxia type 1 (SCA1) is a neurogenerative disorder with symptoms that typically begin in the third or fourth decade of life. The disease is characterized mainly by motor incoordination that becomes progressively worse with age. Eventually, patients succumb to the disease about fifteen years after onset due to breathing problems. SCA1 is known as a “polyglutamine expansion” disorder, which means it is caused by a glutamine-rich region of a protein becomes abnormally large due to a genetic mutation. In SCA1, the polyglutamine expansion occurs due to a mutation in the ataxin-1 gene (ATXN1), causing the subsequent ataxin-1 protein to have abnormal functions.

Previously, a research team led by Dr. Puneet Opal found that the levels of a protein called VEGF (vascular endothelial growth factor) is reduced in cerebellum of a mouse model of SCA1. The team was able to improve disease symptoms in these mice by restoring VEGF protein levels using two different methods: i) by crossing the SCA1 mice with another strain of mouse that expressed high levels of VEGF, and ii) delivering recombinant protein (rVEGF) into the brains of SCA1 mice (Cvetanovic M et al 2011). However, the researchers noted that it would be challenging to implement the rVEGF delivery strategy for clinical therapy, since one would need to overcome the extreme financial cost and difficulty that comes with using recombinant proteins.

VEGF is crucial for maintaining the microvasculature (small arteries and veins) in the brain and also supports neuronal health and regeneration. Current evidence suggests that VEGF therapy could be beneficial for several neurodegenerative conditions such as stroke, Alzheimer’s disease, Parkinson’s disease, and ALS. Unfortunately, significant impediments have prevented the translation of recombinant VEGF therapy to the clinic. In a recently published ‘Brain’ research article, Dr. Opal and his team sought to address this obstacle by exploring a potential low-cost VEGF treatment strategy known as VEGF peptide mimetics. These peptide mimetics are smaller and simpler molecules that mimic biological compounds; in this case, VEGF. Peptide mimetics are typically smaller than the original molecule (small enough to be considered “nanoparticles”), which helps limit side effects and makes delivery to the target much easier than using recombinant proteins like rVEGF.

In order to design ways to better deliver these VEGF-mimicking nanoparticles, Dr. Opal’s team collaborated with Dr. Samuel Stupp to improve upon previous designs by increasing the molecule’s stability in the brain. These newly-designed nanoparticles were then delivered to SCA1 mice at advanced stages of disease to determine whether they were able to improve disease symptoms. VEGF nanoparticle-treated mice showed significant improvements in motor coordination, cerebellar Purkinje cell structure, and cerebellar blood flow. VEGF nanoparticle treatment also improved Purkinje cell activity, which is typically abnormal in SCA1 patients. Treated SCA1 Purkinje cells show improved electrical activity when compared to non-treated SCA1 cells.

These results suggest that the use of VEGF nanoparticles could lead to novel and effective therapeutic strategies for SCA1. Peptide mimetic nanoparticle-based therapies are likely to be applicable for many other neurodegenerative diseases, where one could mimic many different bioactive proteins. Many of these proteins, including BDNF, GDNF, NGF and IGF1, have been implicated as possible methods of treatment for a variety of neurodegenerative diseases.

Key Terms

Recombinant protein: A protein that has been manipulated in some way (usually to produce large quantities of protein for delivery into various tissues)

Peptide mimetics/peptide mimics: Smaller, simpler versions of proteins that biologically mimic the original protein’s function

Conflict of Interest Statement

Dr. Chandrakanth Edamakanti, who wrote this piece, is also an author on one of the original scientific articles reviewed. Dr. David Bushart, who edited this piece, has no conflicts of interest to declare.

Citations of Articles Reviewed

Cvetanovic, M. et al Vascular endothelial growth factor ameliorates the ataxic phenotype in a mouse model of spinocerebellar ataxia type 1. Nat Med. 2011 Oct 16;17(11):1445-7.

Hu, Y.S. et al Self-assembling vascular endothelial growth factor nanoparticles improve function in spinocerebellar ataxia type 1. Brain. 2019 Feb 1;142(2):312-321.