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German-headquartered Isarna Therapeutics is developing a portfolio of antisense therapies targeting an emerging therapeutic field in human biology – transforming growth factor beta (TGF-B) signaling.
Precise modulation of TGF-B pathways using antisense therapy may result in safer and more effective treatment options for a broad range of indications.
Isarna Therapeutics’s lead compound, ISTH0036, is in clinical development in ophthalmology.
On the podcast this week we chat with René Rückert, chief operating officer at Isarna Therapeutics, who explains TGF-B and antisense oligonucleotides’ role in tackling disease.
Table of contents
Transforming growth factor (TGF)
There are three isoforms of transforming growth factor-beta (TGF-beta 1, beta 2 and beta 3) in mammals.
They play critical roles in growth regulation and development. All three are secreted by most cell types, usually in a latent form. They require activation before they can do any biological activity.
Rückert said TGF-Beta is involved in many different activities in the immune system and also in the morphologic activity in the body.
“TGF-Beta is a key driver of fibrosis. Fibrosis is a process that is involved in many different pathologies. Fibrosis is the key driver of pathology in the lungs, pulmonary fibrosis, a very severe disease. Pulmonary fibrosis is very hard to treat. And TGF-BETA is one of the drivers for this.”
Rückert explained that inhibiting TGF-Beta can suppress fibrosis.
What are antisense oligonucleotides and how do they work?
Antisense oligonucleotides (ASOs) were first explained in 1978, Rückert said. They are short, single-stranded synthetic RNA or DNA molecule. ASOs bind to complementary nucleic acid sequences impacting the associated functions of the targeted nucleic acids. They modulate protein expression through several different mechanisms.
ASOs are an emerging area of drug development that target the disease source at the RNA level.
Rückert added that there have been many modifications of antisenses, one reason being to increase stability.
“Now there are plenty of different methods to stabilize it and to add other molecules,” he said.
He explained that there are currently more than 10 drugs on the market that are based on antisense.
“I’m surprised that’s not more, since the treatment is very specific. It really targets one molecule that could be responsible for one indication for one disease,” he said.
One major advantage, Rückert said, of ASOs, is they target, intracellularly, production of a cytokine, for example interleukin 2 or TGF-beta 2.
“So, it’s not released at all. You hit the target before it can do any damage or can even be produced. So that’s a major advantage,” Rückert said.
How are ASOs delivered?
Rückert said the delivery of ASOs has changed greatly since 1978, when they were a pure nucleotide that was unstable.
“Now, we can do a targeted delivery, and deliver antisense in different ways. You can inject antisense and most of the therapies, I think all of the therapies that are approved at the moment, are injected in some way; subcutaneous or intravenous injection.
“There are new studies that show bioavailability orally, as a tablet.”
Making therapies easier to take makes it easier to target larger populations, he observed.
ASO research
Research into ASOs is ongoing. Rückert said ASOs have great potential: there are more than 25,000 papers on ASOs, which leads him to believe more companies should be working in the field.
“There are recent data on new stabilization methods that show that antisense could be stable for many, many months. So, that is something that is obviously promising for other indications.”
“You hit the target before it can do any damage.” René Rückert, chief operating officer, Isarna Therapeutics
ASO applications
While Isarna Therapeutics is using antisense in ophthalmology, oncology is another area where ASOs show promise.
“We have very early preclinical data generated many years ago. But you can also generate antisense against not only messenger RNA, but also against microRNA, for example,” Rückert said.
“miRNA, which is a non-coding RNA, everyone believed until five years ago that that’s just junk RNA, but it is not. There are very important molecules that regulate transcription and many, many biologic processes. So, the micro and non-transcribing RNA are particularly important in cancer pathology. I think it’s where many, many options are.”
Isarna Therapeutics’ ISTH0036 drug in phase 2a clinical study
Isarna Therapeutics has one drug in clinical development, ISTH0036.
The company recently presented the first data from its BETTER study, a parallel, two-segment phase 2a clinical study to evaluate ISTH0036 in patients with wet age-related macular degeneration (wet AMD) and diabetic macular edema (DME).
“It’s a blockbuster indication,” Rückert explained.
“Both are diseases of the retina. We have seen good efficacy in both and we’re just looking for a partner, or looking for investors, to continue the development of the drug. We’ve seen a good safety profile. There are very few side effects.”
Rückert said ISTH0036 works differently to the current gold standard.
“Currently, the gold standard in AMD and DME are injections into the eye, intravitreal injections, with drugs on the market for 15 years. They all target the same molecule and they work in the beginning.
“But all the patients develop a fibrosis. And therefore, the vision goes down.
“You may need to have a combination therapy in a few selected patients. But in most of the patients, it works on its own with injection every other month. We could extend it to every three or four months, hopefully. And it really showed some benefit in suppressing the fibrosis and suppressing the development of the fibrosis, which is the key concern, the highest medical need in both AMD and DME, and our first data that we presented look very good.”
Isarna Therapeutics is currently finalizing its phase 2a, in anticipation of a phase 2b or phase 3 study, with a partner.
To learn more about this topic:
Here are some links to more articles on the subject of drugs for antisense oligonucleotides.
- Five ophthalmology biotech companies to look out for (Labiotech.eu)
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