Gene Editing for Treatment of Neurological Infections

Abstract

The study of neurological infections by viruses defines the field of neurovirology, which has emerged in the last 30 years and was founded upon the discovery of a number of viruses capable of infecting the human nervous system. Studies have focused on the molecular and biological basis of viral neurological diseases with the aim of revealing new therapeutic options. The first studies of neurovirological infections can be traced back to the discovery that some viruses have an affinity for the nervous system with research into rabies by Louis Pasteur and others in the 1880s. Today, the immense public health impact of neurovirological infections is illustrated by diseases such as neuroAIDS, progressive multifocal leukoencephalopathy, and viral encephalitis. Recent research has seen the development of powerful new techniques for gene editing that promise revolutionary opportunities for the development of novel therapeutic options. In particular, clustered regulatory interspaced short palindromic repeat-associated 9 system provides an effective, highly specific and versatile tool for targeting DNA viruses that are beginning to allow the development of such new approaches. In this short review, we discuss these recent developments, how they pertain to neurological infections, and future prospects.

Keywords: CRISPR/Cas9; Gene editing; NeuroAids; Neurological infections; Progressive multifocal encephalopathy.

Fig. 1

Schematic of clustered regulatory interspaced short palindromic repeat (CRISPR)/CRISPR-associated 9 (Cas9) action on viral DNA. A guide RNA (gRNA) is designed that is specific for a target sequence immediately adjacent to a 3’ protospacer adjacent motif (PAM) sequence (blue) within the genome of the virus. The gRNA is expressed in host cells together with the Cas9 endonuclease, which are shown schematically as scissors. CRISPR cleaves the viral DNA at the target site resulting in a double-strand break (DSB), which is repaired by nonhomologous end-joining (NHEJ). As NHEJ is error prone, small insertions and deletions (InDel) are found in the repaired DNA that inactivate the target gene

Fig. 2

Schematic of excision of integrated HIV-1 proviral DNA by (CRISPR)/CRISPR-associated 9 (Cas9). A guide RNA (gRNA) specific for the HIV-1 long terminal repeat (LTR) present at each end of the HIV-1 proviral genome is used together with Cas9. This results in cleavage at 2 sites that flank the HIV-1 genome and consequently the excision and subsequent degradation of the proviral DNA