Effect of intranasal administration of Semliki Forest virus recombinant particles expressing interferon-β on the progression of experimental autoimmune encephalomyelitis

Abstract

Abstract. The effect of intranasal (IN) administration of Semliki Forest virus (SFV) recombinant particles expressing interferon-ß [IFN-ß, a partially effective treatment for multiple sclerosis (MS)] on the progression of experimental autoimmune encephalomyelitis (EAE, a murine model for MS)was investigated. The murine IFN-ß gene was cloned from SFV-infected mouse brain by RT-PCR into an SFV-enhanced expression vector, pSFV10-E, from which IFN-ß-expressing recombinant particles (rSFV10-E-IFN-ß) were prepared. Expression studies using immunohistochemistry and viral inhibition assay in BHK and murine L929 cells confirmed increased expression of IFN-ß. High level expression in the central nervous system (CNS) following IN inoculation was confirmed by the excision of olfactory bulbs, brain and spinal cord, and the detection of IFN-ß levels in homogenised tissue by ELISA. rSFV10-E-IFN-ß particles were administered IN to C57/Bl6 mice that had been induced for EAE using the encephalogenic peptide myelin oligodendrocyte glycoprotein (MOG) 35-55. The progression of EAE was measured by clinical score, weight loss and pathology. As previously shown, treatment with empty rSFV10-E particles moderately exacerbated EAE, as did continuous treatment with rSFV10-E-IFN-ß particles. Inhibition of disease with rSFV10-E-IFN-ß particles was dependent on the number and timing of treatments. Fewer treatments, administered before the effector stage, led to an improvement in clinical and pathology score.In conclusion, the timing and frequency of IN administration of rSFV10-E-IFN-ß particles are critical to disease outcome, with treatment prior to the effector stage being most effective. IntroductionSemliki Forest virus (SFV) is a positive-strand enveloped RNA virus that has been developed into a prototype vector for vaccine construction and cancer therapy (1,2). Due to its ability to penetrate the central nervous system (CNS) following both intranasal (IN) and peripheral inoculation, SFV has also been developed as a gene therapy agent for the CNS (3-6). After IN inoculation, the virus reaches the CNS via the olfactory bulb. Once there, it infects neurons and oligodendrocytes and travels through the limbic pathways to further infect other areas of the brain (7,8).The SFV split helper system, based on the SFV4 strain of SFV, has also been employed as a means of therapeutic delivery to the CNS. In this system, the viral structural gene open reading frame is replaced with a multiple cloning site (MCS) to allow insertion and expression of a foreign gene. Structural genes are supplied in trans from two separate helper vectors, the helper spike and the helper capsid. On cotransfection of all three vectors into BHK cells, defective recombinant particles, capable of one round of virus multiplication only upon infection of susceptible cells, are produced and released from the cells. In the process, the cloned foreign gene is expressed transiently but at a high level (9).Administration of recombinant SFV particles expressing the reporter gene EGFP s...

The therapeutic effects of MSc1 nanocomplex, synthesized by nanochelating technology, on experimental autoimmune encephalomyelitic C57/BL6 mice

“…[46][47][48] The significant point in the present study was the higher percentage of weight gain with the medium dose of MSc1 during the acute phase of disease compared to the control groups.…”

Alphavirus vectors as tools in neuroscience and gene therapy

“…Administration of SFV-IL10 significantly reduced EAE while the disease worsened after delivery of SFV-EGFP and empty SFV vectors. Similarly, intranasal delivery of SFV-IFN β inhibited EAE (Quinn 2008). However, success was strongly dependent on the timing and number of injections of the SFV administration.…”

Therapeutic and prophylactic applications of alphavirus vectors

“…It was concluded that the timing and frequency of intranasal administration of IFN-β-expressing particles are critical to disease outcome, with treatment prior to the effector stage being most effective (Ref. 43). However, these experiments on EAE do indicate that, in a mouse model at least, intranasal administration of SFV VLPs may be used for noninvasive treatment with biologically active proteins in the CNS, bypassing the blood–brain barrier.…”