, Volume 11, Issue 4, pp 817–839 | Cite as

Gene Therapy for the Nervous System: Challenges and New Strategies

  • Casey A. MaguireEmail author
  • Servio H. Ramirez
  • Steven F. Merkel
  • Miguel Sena-Esteves
  • Xandra O. Breakefield


Current clinical treatments for central nervous system (CNS) diseases, such as Parkinson’s disease and glioblastoma do not halt disease progression and have significant treatment morbidities. Gene therapy has the potential to “permanently” correct disease by bringing in a normal gene to correct a mutant gene deficiency, knocking down mRNA of mutant alleles, and inducing cell-death in cancer cells using transgenes encoding apoptosis-inducing proteins. Promising results in clinical trials of eye disease (Leber’s congenital aumorosis) and Parkinson’s disease have shown that gene-based neurotherapeutics have great potential. The recent development of genome editing technology, such as zinc finger nucleases, TALENS, and CRISPR, has made the ultimate goal of gene correction a step closer. This review summarizes the challenges faced by gene-based neurotherapeutics and the current and recent strategies designed to overcome these barriers. We have chosen the following challenges to focus on in this review: (1) delivery vehicles (both virus and nonviral), (2) use of promoters for vector-mediated gene expression in CNS, and (3) delivery across the blood-brain barrier. The final section (4) focuses on promising pre-clinical/clinical studies of neurotherapeutics.


Gene delivery Central nervous system Virus vector Nonviral gene delivery Gene therapy 



We thank Ms. Suzanne McDavitt for skilled editorial assistance, Ms. Emily Mills at Millstone Design for preparation of figures and Dr. Thurman Wheeler for scientific insights. This work was supported by National Institutes of Health/National Cancer Institute (NIH/NCI) U19 CA179563, which is supported by the NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director and CA069246 and Voices Against Brain Cancer (XOB). The work performed in the authors’ laboratory is supported by grants from a National Institute on Drug Abuse (NIDA) training grant: T32 DA007237 (S.M.), NIH/National Institute of Neurological Disorders and Stroke (NINDS) R01 NS086570-01 (S.H.R.) and The Shriners Hospitals for Children 85110-PHI-14 (S.H.R.). C.M. is supported by an NIH/NINDS R21 NS081374-01. C.M. has a financial interest in Exosome Diagnostics, Inc. C.M.’s interests were reviewed and are managed by the Massachusetts General Hospital and Partners HealthCare in accordance with their conflict of interest policies. C.M. has filed patent applications related to the vexosome technology.

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Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2014

Authors and Affiliations

  • Casey A. Maguire
    • 1
    Email author
  • Servio H. Ramirez
    • 4
  • Steven F. Merkel
    • 4
  • Miguel Sena-Esteves
    • 3
  • Xandra O. Breakefield
    • 1
    • 2
  1. 1.Department of Neurology, Massachusetts General Hospital, and Neuroscience ProgramHarvard Medical SchoolCharlestownUSA
  2. 2.Department of Radiology, Massachusetts General Hospital, Neuroscience ProgramHarvard Medical SchoolBostonUSA
  3. 3.Department of NeurologyUniversity of Massachusetts Medical SchoolWorcesterUSA
  4. 4.Pathology and Laboratory MedicineTemple University School of MedicinePhiladelphiaUSA

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