Gene therapy in cardiac surgery: is there a role?

ene therapy has been billed as a method of curing most humandiseases. Despite a large amount of initial enthusiasm and a vastamount of resources spent in this area, however, except in isolatedcases gene-directed treatment has yielded only modest or littlesuccess. Indeed, there have been several instances in which genetherapy has resulted in adverse events and even death. Why thelimited success despite initial optimism? As with most clinical issues or problems,the answer is multifactorial. With gene therapy, it is hypothesized that by theintroduction of a piece of genetic material (DNA) into the host genome, the host willbe able to produce enough of a protein through translation from the resultantmessenger RNA to provide beneﬁcial results. These results can be increased bloodvessel growth through angiogenesis, providing a deﬁcient vital protein involved inimmune defense, or increasing the body’s ability to tolerate oxidative stress in theheart after ischemia.First, the genetic material (DNA) needs to be incorporated into the host genome.Some investigators have attempted to inject naked DNA encoding a certain proteininto the tissue at various isolated areas and have reported fairly dramatic effects. Iam personally somewhat skeptical that this approach will ever have much of a rolein the treatment of patients. The efﬁciency of transfection, or the incorporation ofthe DNA into the genome, is extremely low with this method, and the local deliveryof the DNA to such a small locus is not likely to have a widespread effect. However,other methods of gene delivery have been more successful. Second, a promoter,either native or exogenous, needs to be present to produce, or transcribe, a signif-icant amount of messenger RNA. Messenger RNA, as opposed to DNA, is not stableand rapidly breaks down chemically through the activation of one of severaldegradation enzymes. This makes teleologic sense, because a genetic message in theform of messenger RNA should not hang around forever. The body needs toconstantly reassess the local environment and make modiﬁcations in the cellularmilieu. Third, from the messenger RNA a protein is translated. This process is alsounder the tight control of other structural proteins and enzymes. The protein is alsosubject to degradation through the activation of proteosomes and other enzymes.Fourth, the protein product then acts on the cells, usually through transmembranereceptors, and produces some signal or change the structure of the tissue. Finally, itis assumed that the protein encoded by the DNA will indeed cure the patient or atleast have a positive effect. Enough of the protein needs to be around for longenough to provide a signiﬁcant beneﬁt. If any of these processes is interrupted, orif the protein actually has no effect in vivo, gene therapy will fail.The optimal method for introduction of the DNA into the host genome has beendebated and depends on the clinical situation. Injection of naked DNA strands witha syringe, as mentioned previously, is certainly the simplest method, but the efﬁcacyof transfection is low and the DNA tends to be present for only a few days. Littleprotein tends to be produced. Viral vectors make the process much more efﬁcient.The adenoviral vector is often used to move the DNA into the cell and cause itsincorporation into the host genome. Expression may be extended to several weekswith adenoviral vectors. However, native circulating antibodies to the virus that areoften present in the blood may neutralize the vector and markedly reduce theexpression of the gene. Other viral vectors have other advantages and disadvantagesrelative to adenovirus. Some viral vectors, such as adenoassociated virus andlentivirus, may produce more prolonged expression. In many cases that may not be