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gene therapy question

Dr. J.P. Clewley jclewley at crc.ac.uk
Mon May 23 17:28:03 EST 1994

In article <2rps0q$3j0 at news.u.washington.edu>, frv at u.washington.edu (Franklin Vincenzi) writes:
> I am working on an antisense RNA project involving IHNV (a salmonid
> rhabdovirus) at Eastern Washington University.  I keep looking at the
> rhabdovirus and it looks like a very appealing delivery system for
> theraputic antisense RNA.  Can someone tell me if this possibility has
> been explored?  I am quite new to biotech (being pre-vet, I am mostly
> used to restraining and vaccinating animals), so I do NOT claim to be
> particularly knowledgable in this area.  Anyway, I would appreciate some
> mail explaining whether this has been investigated, and what problems
> might be expected in this method.  Medline/SciSearch did not show me
> anything.
> Thanking you in advance,
> Franklin
> who is also at <fvincenzi at ewu.edu>.
I don't know if this is being explored or not, but off the top of my head,
trying to remember rhabdovirus replication. When the virus infects, mRNA
is transcribed from the -ve sense genome by the virion transcriptase.
The -ve genome (probably) doesn't exist except as a RNP complex.

So as a therapeutic -ve strand virus you'd need to deliver virions
without a transcriptase, and to ensure that the antisense genome got
uncoated & released so it could hybridize with the mRNA you're
trying to block. I would think it'd be easier just to make synthetic
stable antisense RNA, maybe with a protective protein/lipid delivery
system - VLPs maybe?

Otherwise you'd want to engineer a positive sense copy of the mRNA you
wanted to block into the rhabdovirus. Then when it infected lots of
-ve strand would be transcribed. The insert would have to be a discrete
transcription unit. A problem here is that if you were envisaging new
infectious virions being produced that could go on to infect other cells,
the cells would have to tolerate a limited amount of foreign, virus
protein & RNA synthesis.

So I can't, at the moment, see an advantage to trying the suggested
approach, compared to making stable (sulphyl?) RNA and developing
an effective delivery system. 

What does anyone else think?

Jon Clewley
Virus Reference Division, CPHL, UK

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