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Zinc Finger Nucleases for Site-Specific Correction of Adenosine Deaminase Deficiency

  • Author(s): Joglekar, Alok Vishnu
  • Advisor(s): Kohn, Donald B
  • et al.
Abstract

Adenosine Deaminase (ADA) Deficiency is an inherited disorder resulting in immunodeficiency.

Currently, gene therapy for ADA Deficiency is performed using retroviral or lentiviral vectors

that pose a risk of insertional oncogenesis. In this project, an alternative, potentially safer

approach for correcting ADA deficiency was investigated. This approach uses site-specific zinc

finger nucleases (ZFNs) to achieve genome editing. In this study, various aspects of using ZFNs

at the ADA locus in human hematopoietic cells were investigated. To ensure efficient delivery of

ZFNs and donor templates, Integrase-Defective Lentiviral Vectors (IDLVs) were used. The

vector design of IDLVs was optimized. The use of Histone Deacetylase Inhibitors was tested in

conjunction with IDLVs to enhance their efficiency further. In addition, small molecule

inhibitors of DNA-dependent protein kinase (DNA-PK) were tested for their ability to increase

the efficiency of gene modification. These studies provide novel findings that are potentially

applicable to the entire genome modification field and will benefit current and future work on

similar approaches.

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