Noninvasive, Targeted, and Non-Viral Ultrasound-Mediated GDNF-Plasmid Delivery for Treatment of Parkinson’s Disease


A growth factor called Glial cell line-derived neurotrophic factor (GDNF) has the remarkable ability to supports the growth and survival of dopamine-using neurons. Dopamine-using neurons are the cells that die off in Parkinson’s disease (PD). Providing GDNF to dopamine-using neurons can help them survive , but getting GDNF genes into the central nervous system relies on invasive intracerebral injections in order to pass through the blood-brain barrier.

Typically, genes are placed into the central nervous system by means of genetically engineered viruses. Viruses, however, are often recognized by the immune system and are destroyed before they can deliver their genetic payload. Therefore, non-viral gene delivery that can pass through the blood-brain barrier is an attractive alternative, since it is non-invasive. Unfortunately, such a high-yield technique is not yet available.

A new study by workers in the laboratories of Hao-Li Liu from Chang Gung University and Chih-Kuang Yeh from National Tsing Hua University, Taiwan has utilized a novel, non-viral gene delivery system to deliver genes into the central nervous system.

In this study, Lui and Yeh and their research teams used tiny bubbles made from positively-charged molecules to carry genes across the blood brain barrier. These bubbles formed stable complexes with GDNF genes, and when the skulls of laboratory animals were exposed to focused ultrasound, the bubble-gene complexes permeated the blood brain barrier and induced local GDNF expression.

(A) Schematic of GDNFp-cMBs and mechanism for controlled gene transfection of GDNFp-cMBs into brain triggered by FUS. (B) Left: Microscope bright-field images; middle: TEM images; right: PI staining image of cMBs and GDNFp-cMBs. (C) Size distributions of cMBs, GDNFp-cMBs and nMBs. (D) Zeta potential of nMB and cMB before and after adding GDNFp. (E) DNA loading efficiency of GDNFp onto nMB and cMB. The left axis was the amount of GDNFp bound onto MBs (solid line). The right axis was the GDNFp loaded efficiency onto MBs (dotted line). Single asterisk, p < 0.05, versus nMBs. Data were analyzes by Student’s paired t-test presented as mean ± SEM (n = 6 per group).
(A) Schematic of GDNFp-cMBs and mechanism for controlled gene transfection of GDNFp-cMBs into brain triggered by FUS. (B) Left: Microscope bright-field images; middle: TEM images; right: PI staining image of cMBs and GDNFp-cMBs. (C) Size distributions of cMBs, GDNFp-cMBs and nMBs. (D) Zeta potential of nMB and cMB before and after adding GDNFp. (E) DNA loading efficiency of GDNFp onto nMB and cMB. The left axis was the amount of GDNFp bound onto MBs (solid line). The right axis was the GDNFp loaded efficiency onto MBs (dotted line). Single asterisk, p < 0.05, versus nMBs. Data were analyzes by Student’s paired t-test presented as mean ± SEM (n = 6 per group).

In fact, this technique outperformed intracerebral injection in terms of targeted GDNF delivery. The amount of GDNF expressed in these laboratory animals that received the GDNF gene/microbubbles + ultrasound protocol was significantly higher than those animals that had genes directly injected into their brains. Furthermore, these higher levels of GDNF genes increased the levels of neuroprotection from PD. Animals that had a form of PD and had received nonviral GDNF gene therapy showed reduced disease progression and restored behavioral function.

This interesting study explores the potential of using ultrasound-induced passage through the blood brain barrier to bring genes into the central nervous system. This noninvasive technique successfully delivered genes into the brain to delay the effects of, and possibly treat, a neurodegenerative disease.

This study was published in Scientific Reports 6, Article number: 19579 (2016), doi:10.1038/srep19579.

 

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Published by

mburatov

Professor of Biochemistry at Spring Arbor University (SAU) in Spring Arbor, MI. Have been at SAU since 1999. Author of The Stem Cell Epistles. Before that I was a postdoctoral research fellow at the University of Pennsylvania in Philadelphia, PA (1997-1999), and Sussex University, Falmer, UK (1994-1997). I studied Cell and Developmental Biology at UC Irvine (PhD 1994), and Microbiology at UC Davis (MA 1986, BS 1984).