TY - JOUR
T1 - Self-assembling vascular endothelial growth factor nanoparticles improve function in spinocerebellar ataxia type 1
AU - Hu, Yuan Shih
AU - Do, Jeehaeh
AU - Edamakanti, Chandrakanth Reddy
AU - Kini, Ameet R.
AU - Martina, Marco
AU - Stupp, Samuel I.
AU - Opal, Puneet
N1 - Funding Information:
The Northwestern University Behavioral Phenotyping Core facility provided mouse behavioural analysis instruments; we thank Jessica Yishan Huang and Vicky Hwang for assisting in behavioural testing. Northwestern University Pathology core facility assisted the VEGF staining of patient cerebellum. The Simpson Querrey Institute Peptide core at Northwestern University synthesized the VEGF peptide. The U.S. Army Research Office, the U.S. Army Medical Research and Materiel Command, and Northwestern University provided funding to develop this facility, and ongoing support comes from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF ECCS-1542205). We thank Dr. Arnulf H. Koeppen of Albany, NY for providing SCA1 patient brain material; autopsies were performed through a national tissue donation program supported by the National Ataxia Foundation. We thank V.L. Brandt for critical comments on the manuscript.
Funding Information:
P.O. was supported by NIH grants R01 NS062051, R01 NS082351, R21 NS099962; M.M. was supported by NIH grant R21 NS090346; and S.I.S. was supported by Northwestern university regenerative nanomedicine CRN catalyst award and NIH grant R01 HL116577-02.
Publisher Copyright:
© The Author(s) (2019).
PY - 2019/2/1
Y1 - 2019/2/1
N2 - There is increasing appreciation for the role of the neurovascular unit in neurodegenerative diseases. We showed previously that the angiogenic and neurotrophic cytokine, vascular endothelial growth factor (VEGF), is suppressed to abnormally low levels in spinocerebellar ataxia type 1 (SCA1), and that replenishing VEGF reverses the cerebellar pathology in SCA1 mice. In that study, however, we used a recombinant VEGF, which is extremely costly to manufacture and biologically unstable as well as immunogenic. To develop a more viable therapy, here we test a synthetic VEGF peptide amphiphile that self-assembles into nanoparticles. We show that this nano-VEGF has potent neurotrophic and angiogenic properties, is well-tolerated, and leads to functional improvement in SCA1 mice even when administered at advanced stages of the disease. This approach can be generalized to other neurotrophic factors or molecules that act in a paracrine manner, offering a novel therapeutic strategy for neurodegenerative conditions.
AB - There is increasing appreciation for the role of the neurovascular unit in neurodegenerative diseases. We showed previously that the angiogenic and neurotrophic cytokine, vascular endothelial growth factor (VEGF), is suppressed to abnormally low levels in spinocerebellar ataxia type 1 (SCA1), and that replenishing VEGF reverses the cerebellar pathology in SCA1 mice. In that study, however, we used a recombinant VEGF, which is extremely costly to manufacture and biologically unstable as well as immunogenic. To develop a more viable therapy, here we test a synthetic VEGF peptide amphiphile that self-assembles into nanoparticles. We show that this nano-VEGF has potent neurotrophic and angiogenic properties, is well-tolerated, and leads to functional improvement in SCA1 mice even when administered at advanced stages of the disease. This approach can be generalized to other neurotrophic factors or molecules that act in a paracrine manner, offering a novel therapeutic strategy for neurodegenerative conditions.
KW - VEGF
KW - nanoparticle
KW - neurodegeneration
KW - neurotrophic therapy
KW - spinocerebellar ataxia type 1
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U2 - 10.1093/brain/awy328
DO - 10.1093/brain/awy328
M3 - Article
C2 - 30649233
AN - SCOPUS:85060803730
SN - 0006-8950
VL - 142
SP - 312
EP - 321
JO - Brain
JF - Brain
IS - 2
ER -