Fanconi anemia (FA) is an autosomal recessive, multisystem DNA repair disorder with
prominent defects in the hematopoietic stem cell maintenance that result in the progressive attrition and
failure in the early school age. Allogeneic stem cell transplantation has proved curative for patients with
suitable donors. This, along with the characteristic survival advantage of phenotypically normal over
non-corrected FA stem cells underscores the compelling rationale for stem cell gene therapy in the FA.
While integrating lentiviral vectors (LV) have become the preferred platform for genetic correction in
several hematologic and immunodeficiency disorders, the residual oncogenic potential by these vectors
raises concerns in the FA stem cells about insertional mutagenic genetic lesions. On this backdrop, investigators
are developing a new generation of non-integrating viral vectors capable of nuclear persistence
through serial mitotic cycles and stable under selection to offset the comparatively lower transduction
rates. Here, we review the competing approaches to develop such non-integrating lentiviral (NILV)
episome vectors that faithfully replicate in the stem cells.
Keywords: Fanconi anemia, Hematopoietic stem/progenitor cells, Gene therapy, Viral vectors, S/MAR.
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