Marking Milestones

Fifteen years ago this month (August 1998) saw the first United States Food and Drug Administration (FDA) approval of an antisense-based drug. Fomivirsen, developed by Isis Pharmaceuticals and marketed by Novartis as Vitravene^®, is a phosphorothioate oligonucleotide aimed at the RNA of the major immediate-early transcriptional unit of cytomegalovirus (CMV). Fomivirsen is injected into the eye to combat CMV retinitis, a common complication of human immunodeficiency virus infection/acquired immunodeficiency syndrome (HIV/AIDS) in the earlier years of the epidemic. Although no longer marketed (in large part because of other therapeutic advances in managing HIV that have dramatically reduced the incidence of opportunistic infections like CMV retinitis), fomivirsen remains an important proof-of-concept for antisense-based approaches to treating disease.

Earlier this year saw the second FDA approval of an antisense-based drug, also developed by Isis Pharmaceuticals and subsequently licensed to Genzyme Corporation. Mipomersen (brand name Kynamro^®), which targets the mRNA of apolipoprotein B, was approved as an adjunct treatment for the rather narrow indication of homozygous familial hypercholesterolemia. However, like fomivirsen before it, it is an important milestone in nucleic acid therapeutics as the first FDA approval of a systemic antisense treatment.

It is possible to look at a gap of 15 years between FDA approvals of nucleic acid-based therapeutics as more of a disappointment than a cause for celebration. To that end, though, it is instructive to revisit a remarkable review article that appeared in the journal Blood, also 15 years ago this month (Gewirtz et al., 1998). The article, authored by the late (and greatly missed) Alan Gewirtz and his colleagues Deborah Sokol and Mariusz Ratajczak, provided a “complete, but not exhaustive” overview of the field of nucleic acid therapeutics at that time, and attempted to divine its future. The article—a milestone in its own right—is perhaps most remarkable for its sober blend of optimism and realism, and it is just as relevant today as it was the year it was written.

The many difficult challenges facing the field in 1998, well articulated by Gewirtz and colleagues, still face us today, particularly in the areas of delivery, regulation, and off-target effects. But as the authors note, there are real grounds for optimism on all these fronts, as continuously and regularly demonstrated in the pages of Nucleic Acid Therapeutics and elsewhere. In addition, since the appearance of Gewirtz et al., the human genome project has led to an explosion of new findings about the genome, including new nucleic acid entities like micro RNA, large intergenic non-coding RNAs (lincRNAs), etc. that are being exploited for therapeutic benefit, greatly extending the field of nucleic acid therapeutics beyond antisense approaches.

Although progress may seem slow, particularly in light of the unacceptable suffering and death of countless patients from diseases we seek to address (which continues to motivate the entire field), it is important to step back and realistically assess where we are and where we are headed, à la Gewirtz et al. Though a difficult thing to do, we will likely come to the same conclusion with which the authors ended their prescient review: “We have no doubt then that the goal of making useful ‘antisense’ drugs will be achieved. The pace at which this will occur is dependent, as always, on the ability of the field to continue to attract talented investigators, and agencies disposed to funding their research.”