CMV Anti-Sense Drug Goes into Human Trials

Isis Pharmaceuticals of Carlsbad, California is set to begin
initial human trials of a radically new drug to treat CMV
retinitis. CMV (cytomegalovirus) retinitis causes blindness
if left untreated; it eventually infects the retinas of 20
percent or more of people with advanced AIDS. There are
currently two CMV drugs available, ganciclovir and foscarnet,
but both only retard the course of the disease for a few
months in most cases. They also frequently cause severe side
effects. Ganciclovir reduces white blood cell counts, while
foscarnet can cause kidney toxicity.

Isis 2922, for which the company filed an Investigational New
Drug application with the FDA on October 27, is one of the
furthest developed of a new class of medications -- antisense
RNA. These compounds are synthetic creations that are exactly
complementary to the RNA sequences produced by viral (or
cancer) genes within a cell. The function of RNA is to convey
instructions to the rest of the cell from any of the
multitude of DNA-based genes in the cell nucleus. RNA encodes
the structure of individual enzymes and other proteins
necessary for cell function.

Antisense RNA locks onto the RNA produced by the disease-
provoking genes, thus preventing the "bad" RNA from directing
undesired protein production within the cell. It is hoped
that antisense RNA will be so specific that it will nullify
the disease process while leaving cells' natural chemical
machinery alone.

The Isis drug blocks the functioning of CMV's IE2 gene. This
gene encodes instructions for a protein that regulates the
production of new CMV virus particles. Since Isis 2922 does
not kill cells already infected with CMV, it is a long-term
maintenance therapy and not a cure. Isis plans to try the
drug by injecting it directly into volunteers' eyes on a
weekly or biweekly basis. The initial 12-week safety trial
will involve 25 people with CMV retinitis who are failing on
standard therapies. This trial is not available to the
general public. The volunteers will come from the practices
of four physicians, whose identities have not been disclosed.

If the first trial is promising, Isis will conduct larger
trials in the future. It is also considering some kind of
expanded access program for people outside the official
trials. Future development plans include trying Isis 2922 as
first line therapy for CMV retinitis and as a treatment for
CMV infections elsewhere in the body.

Antisense is a new and speculative field. In the past the use
of antisense drugs has run into problems with unthinkably
high cost, finding a critical target gene, delivering the
drug to the proper tissues and cells, stability within the
body, and low effectiveness. Whether antisense drugs really
leave normal body processes alone also remains open to
question. The local injection method Isis is using for CMV
retinitis minimizes most of these concerns. Similarly. the
company's other antisense drug in human trials is an anti-
genital wart medicine that is administered directly to the
warts.

Isis is considered among the leading companies in antisense
technology. However, another company, Hybridon, of Worcester,
Massachusetts, is embarking on human trials of an antisense
compound aimed at HIV. (See AIDS TREATMENT NEWS #185.)

Isis has set up a voice mail line for inquiries about its CMV
therapy. Questions can be left by calling (619) 929-3898.