MEET US AT TIDES VIRTUAL
ASOs act on the DNA/RNA level and confer gene silencing in different ways: 1) formation of DNA-RNA hetero-duplexes and subsequent degradation of the target mRNA (most common mechanism, mediated by RNase H), 2) inhibition of translation by a steric blockade of the ribosome and 3) prevention of assembly of the translation machinery by interaction with the 5′-terminus of the target mRNA.
In addition to gene silencing, certain ASOs function as regulators of RNA splicing and are of therapeutic interest to restore the function or expression of a protein involved in diseases. A prominent example is the application of splice-switching ASOs for the treatment of Duchenne muscular dystrophy (DMD), overcoming a frameshift mutation and thus restoring the expression of a functional, yet truncated, dystrophin protein.
siRNAs inhibit mRNA translation, employing the RNA interference (RNAi) pathway, and have potential for the cure of virus-transmitted and genetic diseases including cancer. siRNAs initially occur as RNA duplexes, but only one strand (guide strand) induces gene silencing, while the other (passenger strand) is enzymatically degraded.
Gene silencing takes place after binding of the guide strand to a complementary mRNA sequence and subsequent cleavage of the latter, employing the RNA-induced silencing complex (RISC). Synthetic siRNA duplexes are typically 19 to 22 bp in length, which is sufficient for function, but short enough to avoid most of the interferon response triggered by duplexes larger than 30 bp in length.
While ASOs continue to be used for gene silencing, the robustness of siRNAs and the relative ease of identifying active siRNAs have increased their clinical relevance. One of the challenges remains for example delivery, since ASOs as well as siRNAs must cross biological membranes to exert their activity.
S. Karaki et al., Antisense oligonucleotides, a novel developing targeting therapy. IntechOpen, (2019)
J.K. Watts and D.R. Corey, Silencing disease genes in the laboratory and the clinic. J. Pathol., 226(2), 365-79 (2012)
A. Deiters, Small molecule modifiers of the microRNA and RNA interference pathway. AAPS J, 12(1), 51-60 (2010)
A. Khvorova and J. K. Watts, The chemical evolution of oligonucleotide therapies of clinical utility, Nat. Biotechnol., 238-248 (2017)
Oligonucleotide therapeutics are a novel class of drug products comprised of strings of synthetic nucleotides. The potential of oligonucleotides as therapeutic drugs has generated hundreds of clinical trials. Currently, there are over 260 companies and organizations sponsoring clinical trials for oligonucleotide drug candidates.
The top five study sponsors of ongoing clinical trials of oligonucleotides include Ionis Pharmaceuticals, Alnylam Pharmaceuticals, Astra Zeneca, Biogen and Arrowhead Pharmaceuticals. Ionis is developing antisense oligonucleotides such as IONIS-AGT-LRX for the treatment of hypertension and IONIS-PKK-LRX for hereditary angioedema. Alnylam Pharmaceuticals is developing RNAi therapeutics such as lumasiran for primary hyperoxaluria type 1 and vutrisiran for the treatment of transthyretin-mediated (ATTR) amyloidosis. Meanwhile, Astra Zeneca has several oligonucleotide drug candidates in Phase I and Phase II studies such as AZD-8601 for Congestive Heart Failure and AZD-2693 for the treatment of Non-Alcoholic Steatohepatitis (NASH). In addition, Biogen has four antisense oligonucleotides currently in clinical studies for the central nervous system therapeutic area including nusinersen, tofersen sodium, BIIB078 and BIIB-094. Furthermore, Arrowhead Pharmaceuticals is leveraging RNAi technologies in several therapeutic areas including developing ARO-AAT for the treatment of liver disease associated with alpha-1 antitrypsin deficiency and JNJ-3989 for chronic hepatitis B infection.
In total, there are currently over 280 ongoing clinical trials of oligonucleotide drug candidates. The breakdown by clinical phase is shown in Figure 1.
Figure 1 – Number of Ongoing Clinical Trials by Phase. For more information on clinical phase definitions, please compare for example reference 3.
The top therapeutic areas among the ongoing clinical trials is overwhelmingly oncology with 116 studies. Other top therapeutic areas include central nervous system, metabolic disorders, genetic disorders and infectious disease. The top 10 therapeutic areas for the current ongoing clinical trials are shown in Figure 2. The top indications for clinical trials of oligonucleotides include neurology, solid tumors, gastrointestinal tract cancer, skin cancer and blood cancer.
Figure 2 – Ongoing Clinical Trials by Top 10 Therapeutic Areas.
With the recent approvals in 2020 and 2019 for NS Pharma’s Viltepso®, Sarepta Therapeutics’s Vyondys 53®, Alnylam Pharmaceuticals’s Givlaari®, Akcea Therapeutics’s Waylivra® and a loaded pipeline of clinical phase drug candidates, oligonucleotide therapeutics are on the edge of delivering on the promises of two decades of research and development efforts.
1) Clinicaltrials.gov (2019)
2) GlobalData (2020)
What is your official job title at Bachem?
I am a Project Chemist.
How long have you been with Bachem? Where did you work before Bachem?
I have started in the R&D IV group at Bachem nearly four months ago. Before, I was employed as a post-doctoral fellow in a top-ranking research institute in Switzerland.
Briefly, what do you do at Bachem?
The focus of our work is set on the development and the synthesis of oligonucleotides.
What is your academic background/degrees or training?
I did my PhD in molecular life science with an emphasis on the chemistry of nucleic acids. During my post-doctoral years, I collected experience in the enzymatic synthesis of base modified oligonucleotides and the Darwinian selection of nucleic acid ligands. Additionally, I had the chance to synthesize therapeutic small interfering RNAs and evaluate their pharmaceutic potential.
What do you like to do outside of work?
I like to go on cycling tours, to play football with friends or simply go running. This helps me to get a clear mind and recharge my batteries. I also enjoy reading books and learning all sorts of new things.
What makes a perfect day for you?
On a perfect day, I will find enough time to do sports and meet with friends besides my work. Ideally, there is just little bureaucracy in order to focus on solving chemical problems. Some challenges are always nice and motivating to me.
What do you like most about your job?
I appreciate the fact, that my job here at Bachem is very versatile. I have to deal with all the facets of oligonucleotide production and I am in contact with our customers. Being a part of the oligonucleotide field, that expands so fast at the moment is fantastic. Furthermore, the great work atmosphere is contributing a lot to the quality of this job.
Have you had any particular expectation when you came to Bachem and have these been fulfilled?
After my first visit at the site in Bubendorf, I was very impressed by the oligonucleotide synthesis infrastructure that was set up within a short time. Therefore, I expected a purposeful and efficient work environment. This is exactly what I have experienced during the last months.
What do you do for fun?
Besides doing sports, I like watching football games and having a good time with my friends.
Thank you very much Pascal.
Interesting news about oligonucleotides in basic research and pharmaceutical development:
New muscular dystrophy treatment shows promise in pre-clinical trials-Drug Target Review
One-time treatment generates new neurons, eliminates Parkinson’s disease in Mice-UC San Diego Health