Blocking of TNF, a major pro-inflammatory protein, is one of the most widely used and generally accepted therapeutic methods in IBD. Such inhibition is performed using antibodies (anti-TNF; Remicade, Humira) which attach to the TNF and inhibit its physiological functions. The main problems with such treatments lie in the organism's immune response which reacts against anti-TNF agents and in turn produces antibodies which neutralize them, thus compromising treatment efficacy.

Proteins are encoded by our genes. Invariably, gene “reading” which leads to protein production implies an intermediate stage requiring the intervention of a particular molecule referred to as “messenger RNA”. In order to propose an alternative to the use of anti-TNF antibodies, a wise strategy would consist of neutralizing the TNF before it reaches the protein form, when it is still at this messenger RNA stage. This is what is referred to as ‘antisense RNA” strategy. The concept of such a therapeutic approach to IBD has been confirmed in a recent article published in the April issue of Gut. Using short nucleic acid sequences (the basic constituents of RNA and DNA) directed against messenger RNA of TNF, then secondarily modified so as to target a certain type of cell, the authors succeeded in specifically inhibiting production of TNF in the intestinal mucosa of mice. This inhibition significantly reduced the development of intestinal inflammation during induction of experimental colitis in these same mice. This antisense RNA approach to TNF would appear to have at least two advantages over the use of antibodies: (1) it specifically targets the TNF produced in the intestine, thus reducing secondary effects; (2) it maintains optimal treatment efficacy; indeed, since the nucleic acids are theoretically less easily recognized by the organism, this would decrease the risk of reactions which would neutralize the treatment. In this study, delivery of treatment was via the rectal pathway. These encouraging results now remain to be confirmed using a formula enabling delivery by the oral route.

Reference:

Targeting delivery of anti-TNFa oligonucleotide into activated colonic macrophages protects against experimental colitis. Longsheng Zuo et al., Gut 210; 59: 470-479