Sperm-Mediated Gene Transfer: Concepts and Controversies

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Sperm-mediated gene transfer (SMGT) represents a novel set of technologies for animal (or in the future, human) genetic modification using the sperm as a vector, as opposed to more traditional ...
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SMGT Research Findings: An Overview

Pp. 12-25 (14)

Ilaria Sciamanna and Corrado Spadafora

Abstract

The finding that spermatozoa of virtually all animal species can spontaneously bind exogenous DNA molecules and deliver it to oocytes at fertilisation first suggested that these cells can be used as vectors for introducing new genetic and phenotypic traits in animals. That has led to the development of a novel approach to animal transgenesis, namely Sperm Mediated Gene Transfer (SMGT). Here we review findings obtained using this experimental approach. A critical examination of published evidence indicates that the alternative between direct binding to the plasma membrane of sperm cells, or its bypass, represents a crucial parameter for the fate of exogenous nucleic acid molecules: in the former case, episomal structures are mainly generated; in the latter, integration in the host genome is more frequent. The original protocol was based on the direct interaction between sperm cells and foreign DNA. Several alternative variants have been developed thereafter to improve the efficacy of the method. Improved protocols include the combination of SMGT with: i) ICSI (intracytoplasmic sperm injection) technology, ii) restriction enzymes favoring DNA integration (REMI), or iii) linker-based (LB), in which the DNA binding is mediated by an antibody recognizing a membrane antigen. In another approach, the aim is to produce “transgenic spermatozoa”: for example, in testis-mediated gene transfer (TMGT) the foreign DNA is microinjected directly into testis; in virus-mediated transgenesis, new genes are delivered to spermatogonal stem cells by viral vectors. The recent finding that mature spermatozoa are the source of non-integrated, transcriptionally competent retrogenes also suggests a potential use of SMGT for embryonic gene therapy.

Keywords:

SMGT, Transgenesis, Episomal structures, DNA integration, RNA-mediated transgenesis, ICSI, REMI, TMGT, Non-Mendelian characters, Sperm-mediated gene therapy.

Affiliation:

Italian National Health Institute, Viale Regina Elena 299, 00161 Rome, Italy