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Glial cell line-derived neurotrophic factor (GDNF), a disease-modifying drug for Parkinson’s disease (PD) is in Phase 2 clinical trials (EudraCT number: 2011-003866-34), however it is administered by direct intrastriatal delivery via stereotaxy, which is accompanied with intracranial infection, brain tissue damage, and other complications. In addition, because of complex administration routes, clinical trials of GDNF have yielded contrary results, largely due to differences in dose and concentration brought by intracranial device. Herein, a small molecular agonist SC79 was screened to open blood-brain barrier (BBB) and promote GDNF liposomes to get into brain. SC79 reversibly reduces the expression of claudin-5, one of dominant tight junctions of BBB. Animal study showed SC79 promoted liposomes to enter into brain parenchyma 2.43 times more than that of the control. Motor deficits of PD mice receiving SC79 and brain-targeted GDNF liposomes were recovered by 36.70% and tyrosine hydroxylase positive neurons in striatum were restored by 39.90%. Our combination therapy effectively avoids the side effects such as secondary infection and uneven delivery caused by intracranial injection, improving patients’ compliance and providing valuable research ideas for the clinic.

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Publication history
Copyright
Acknowledgements

Publication history

Received: 05 July 2022
Revised: 30 July 2022
Accepted: 01 August 2022
Published: 14 September 2022
Issue date: February 2023

Copyright

© Tsinghua University Press 2022

Acknowledgements

Acknowledgements

We thank Jingyao Chen and Qiong Huang from the public technology platform of Zhejiang University School of Medicine for their help in immunohistochemical experiments on brain slices. We thank Hangjun Wu in the Center of Cryo-Electron Microscopy (CCEM), Zhejiang University for their technical assistance on two photon imaging. This work was supported by the National Natural Science Foundation of China (No. 81973267) and Natural Science Foundation of Zhejiang Province (No. LD19H300001).

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