History and Properties of Morpholino Antisense Oligos

Special Article - Antisense Drug Research and Development

J Drug Discov Develop and Deliv. 2016; 3(1): 1019.

History and Properties of Morpholino Antisense Oligos

Summerton J*

Gene Tools, LLC, USA

*Corresponding author: Summerton J, Gene Tools, LLC, 1001 Summerton Way, Philomath, Oregon 97370, USA

Received: January 28, 2016; Accepted: April 04, 2016; Published: April 06, 2016


This paper provides a very brief overview of the beginning of the antisense field, including the first antisense structural types, first patent, and first company in the field. The evolution of the Morpholino antisense structural type is then described in some detail, starting with Carbamate-DNA, then Carbamate- Morpholino, and finally the motivation for and development of the current Phosphorodiamidate-Morpholino structural type.

The current Morpholino structural type is then compared with the main competing antisense structural types: S-DNA, PNA, and siRNA. Finally, the challenges of in vivo delivery are briefly discussed, and the promise of new developments in this regard, as well as an exciting new application of Morpholinos which it is hoped will soon lead to safe, effective, and affordable cures for virtually all cancers - possibly by 2020.

Keywords: History of morpholinos; Morpholino versus siRNA


Birth of the antisense therapeutics strategy

The antisense therapeutics strategy entails using a strand of genetic material, or a specially designed analog of genetic material, (the antisense drug) to very specifically bind and thereby block or destroy a complementary sequence of RNA or DNA (the sense target). In principle this antisense strategy offers the possibility of safe and effective drugs for a host of currently un-treatable or poorly-treatable diseases, such as viral diseases, cancers, some genetic defects, and many other diseases and conditions. However, in practice there were a number of daunting technical challenges that had to be surmounted in order to go from that simple antisense principle to safe, effective, and affordable antisense drugs based on that principle.

From 1967 through the end of the 1970s at least four groups independently worked on this antisense strategy, apparently with each group being unaware of the other groups’ activities. These groups included: Belikova, Zarytova & Grineva [1], three women scientists at the Academy of Science of the USSR in Novosibirsk, Siberia; Miller and Ts’o [2,3] at Johns Hopkins Univ.; Summerton (myself) & Bartlett [4-6] at Berkeley, Zamecnik & Stephenson [7,8] at Harvard. In 1978 the first patent on such antisense agents issued to me & Bartlett, and was assigned to Nat Inst of Health (US Patent 4,123,610). In 1980 I founded the first antisense company focused on developing and commercializing antisense drugs. That company was “ANTIVIRALS, Inc. (AVI)”, subsequently renamed “AVI Biopharma”, and more recently renamed “Sarepta Therapeutics”. (In 1997 I left AVI to found GENE TOOLS, LLC, focused on providing custom-sequence Morpholinos to the research community).

In the early 1980s my company, AVI, and various academic research groups investigated a substantial number of possible antisense structural types, and by 1984 two antisense structural types stood out as showing the most promise for future therapeutic applications. One was Methylphosphonate-DNA (Figure 1) developed at Johns Hopkins by Miller and Ts’o [3]. The other was Carbamate- DNA (Figure 1) developed at AVI by me, with much chemical advice from Dwight Weller in the Chemistry Department at Oregon State Univ [9]. A comparison of the advantages and limitations of these two leading structural types is below (Table 1).