TY - JOUR
T1 - Nanoparticle delivery of CRISPR into the brain rescues a mouse model of fragile X syndrome from exaggerated repetitive behaviours
AU - Lee, Bumwhee
AU - Lee, Kunwoo
AU - Panda, Shree
AU - Gonzales-Rojas, Rodrigo
AU - Chong, Anthony
AU - Bugay, Vladislav
AU - Park, Hyo Min
AU - Brenner, Robert
AU - Murthy, Niren
AU - Lee, Hye Young
N1 - Funding Information:
We thank J. Doudna for advice, B. Staahl for discussions and technical support, and H. Kim, A. Rao and K. Kataoka for technical support. We thank M. A. Bhat and members of the Bhat Lab for technical support. We thank M. West in the CIRM/QB3 Shared Stem Cell facility for technical support. This work was supported by the National Institutes of Health grant R01EB023776 to N.M, and by the National Science Foundation grant 1456862 to R.B.
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/7/1
Y1 - 2018/7/1
N2 - Technologies that can safely edit genes in the brains of adult animals may revolutionize the treatment of neurological diseases and the understanding of brain function. Here, we demonstrate that intracranial injection of CRISPR-Gold, a nonviral delivery vehicle for the CRISPR-Cas9 ribonucleoprotein, can edit genes in the brains of adult mice in multiple mouse models. CRISPR-Gold can deliver both Cas9 and Cpf1 ribonucleoproteins, and can edit all of the major cell types in the brain, including neurons, astrocytes and microglia, with undetectable levels of toxicity at the doses used. We also show that CRISPR-Gold designed to target the metabotropic glutamate receptor 5 (mGluR5) gene can efficiently reduce local mGluR5 levels in the striatum after an intracranial injection. The effect can also rescue mice from the exaggerated repetitive behaviours caused by fragile X syndrome, a common single-gene form of autism spectrum disorders. CRISPR-Gold may significantly accelerate the development of brain-targeted therapeutics and enable the rapid development of focal brain-knockout animal models.
AB - Technologies that can safely edit genes in the brains of adult animals may revolutionize the treatment of neurological diseases and the understanding of brain function. Here, we demonstrate that intracranial injection of CRISPR-Gold, a nonviral delivery vehicle for the CRISPR-Cas9 ribonucleoprotein, can edit genes in the brains of adult mice in multiple mouse models. CRISPR-Gold can deliver both Cas9 and Cpf1 ribonucleoproteins, and can edit all of the major cell types in the brain, including neurons, astrocytes and microglia, with undetectable levels of toxicity at the doses used. We also show that CRISPR-Gold designed to target the metabotropic glutamate receptor 5 (mGluR5) gene can efficiently reduce local mGluR5 levels in the striatum after an intracranial injection. The effect can also rescue mice from the exaggerated repetitive behaviours caused by fragile X syndrome, a common single-gene form of autism spectrum disorders. CRISPR-Gold may significantly accelerate the development of brain-targeted therapeutics and enable the rapid development of focal brain-knockout animal models.
UR - http://www.scopus.com/inward/record.url?scp=85048993748&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85048993748&partnerID=8YFLogxK
U2 - 10.1038/s41551-018-0252-8
DO - 10.1038/s41551-018-0252-8
M3 - Article
C2 - 30948824
AN - SCOPUS:85048993748
SN - 2157-846X
VL - 2
SP - 497
EP - 507
JO - Nature Biomedical Engineering
JF - Nature Biomedical Engineering
IS - 7
ER -