Once under­es­tim­ated, now a beacon of hope


Once under­es­tim­ated, now a beacon of hope

Inter­view on RNA Medi­cine with Jörg Vogel, Würzburg

In the Corona pan­demic, mRNA vac­cines proved their effect­ive­ness and safety. They mark the begin­ning of a new era in medi­cine, says Würzburg infec­tion bio­lo­gist Jörg Vogel. In this inter­view he describes the begin­ning tri­umph of ribo­nuc­leic acid medicine.

Pro­fessor Vogel, one of the main top­ics of the anniversary meet­ing in Leipzig is RNA medi­cine. What makes this new thera­peutic dir­ec­tion so interesting?
The well-foun­ded hope that pre­vi­ously incur­able dis­eases can finally be treated. This was triggered by the great suc­cess of mRNA vac­cines in the Corona pan­demic. Not only could the vac­cines be developed very quickly, but they also proved to be highly effect­ive and safe. There is cur­rently an incred­ible sense of optim­ism world­wide; some are even talk­ing about a med­ical revolu­tion. The task now is to trans­fer the act­ive prin­ciple to as many dis­eases as possible.

Which dis­eases could be considered?
There are hardly any lim­its. Research is cur­rently focus­ing on can­cer and car­di­ovas­cu­lar dis­eases. But other com­mon dis­eases such as demen­tia are also pos­sible can­did­ates. And for numer­ous rare dis­eases, espe­cially when they are caused by defects in a single gene, RNA medi­cine could finally bring a break­through. Some RNA drugs are already on the mar­ket in the EU, and I expect to see many new ther­apies soon.

RNA seems to be an all-rounder. How does it man­age that?
It has to do with its many cap­ab­il­it­ies, which have long been over­looked. In the past, almost everything focused on mes­sen­ger RNA, or mRNA for short, a mes­sen­ger molecule that car­ries genetic blue­prints from the cell nuc­leus to the pro­tein factor­ies in the cytosol. In addi­tion to tRNA, which has also been known for some time and which trans­ports amino acids to the pro­tein factor­ies, the ribosomes, and rRNA, which is a com­pon­ent of these pro­tein factor­ies, many other classes of RNA have been dis­covered in recent years. They have been given names such as miRNA for micro-RNA or siRNA for small inter­fer­ing RNA. More than a dozen dif­fer­ent RNA classes are now known, and new ones are being added all the time. What is clear today is that RNA con­trols vital pro­cesses in cells, and errors in this con­trol can cause dis­ease. Or, to exag­ger­ate a bit: RNA is the real player in our cells and organs.

How can the mir­acle molecule be used medically?
In two ways: in mod­i­fied form as a drug and, when it comes to the body’s own RNA, as a tar­get for tailored drugs. mRNA vac­cines are a good example of the first mode of action. For example, Biontech/Pfizer’s Corona vac­cine con­tains a labor­at­ory-gen­er­ated mRNA vari­ant of the spike pro­tein of SARS-CoV-2. After vac­cin­a­tion, the body gen­er­ates this spike pro­tein vari­ant, which eli­cits a strong immune response. The vac­cine func­tions as an anti­gen that trig­gers the pro­duc­tion of anti­bod­ies by the immune sys­tem. Sim­il­arly, it is hoped to stim­u­late the immune sys­tem to pro­duce anti­bod­ies against can­cer cells with the help of spe­cific­ally mod­i­fied RNA. Sev­eral stud­ies are already under­way. The lung cells of cystic fibrosis patients could also be mod­i­fied using the CRISPR-Cas method so that they pro­duce a vital pro­tein in the cor­rect form. It is not yet pos­sible to pre­dict which of these ther­apies will pre­vail from a med­ical and cost perspective.

Please also explain the second act­ive prin­ciple with an example.
In car­diac medi­cine, for example, research is being car­ried out to pre­vent the pro­duc­tion of patho­genic pro­teins by arti­fi­cially pro­duced siRNA. To do this, RNA snip­pets are cre­ated in the labor­at­ory that have a struc­ture exactly com­ple­ment­ary to the sequence of the body’s own RNA – so-called anti­s­ense molecules. The idea is to couple them to small lipo­somes and inject them under the skin. These lipo­somes are to enter the heart to deliver their siRNA cargo into the cells. The cargo, the plan goes, docks with the body’s own RNA and para­lyzes it. In a sim­ilar way, non-cod­ing RNA, which does not make pro­teins in the body but regulates many pro­cesses, could be dir­ec­ted in the desired dir­ec­tion when it malfunctions.

In short, what can RNA medi­cine do that con­ven­tional drugs cannot?
One major advant­age is pro­gram­mab­il­ity: act­ive ingredi­ents can be designed exactly as needed. Another advant­age is speed. You can design a thera­peutic on screen in minutes and then man­u­fac­ture it quickly if the pro­duc­tion capa­city is there. Just think about mRNA vac­cines, which were avail­able very quickly.

But do RNA ther­apies do exactly what they are sup­posed to?
They are very spe­cific. Per­haps even more spe­cific than con­ven­tional drugs that tar­get pro­teins. This has to do with the exact base pair­ing in nuc­leic acids.

And if ser­i­ous side effects occur: Can the RNA be recovered?
We don’t know exactly yet. So far, it has­n’t been neces­sary because the mRNA quickly dis­ap­pears from the body again. But we will have to think about some­thing for the future. So far, it is only a research idea to cre­ate depots with replace­ment pro­teins in the body. But if this suc­ceeds, we must of course have pro­tect­ive mech­an­isms ready in case of incom­pat­ib­il­it­ies. How­ever, I do not see a prob­lem in prin­ciple, because an anti­dote could also be designed here. For example, an anti-CRISPR-Cas molecule that is admin­istered on demand.

Unlike today’s drugs, RNA is very unstable. How do you pre­vent it from rap­idly decay­ing in the body and becom­ing ineffective?
To do that, you have to change its chem­ical struc­ture. The mRNA vac­cine again provides a fit­ting example. The fact that it works so well is thanks to bio­chem­ist Katalin Karikó. Together with immun­o­lo­gist Drew Weiss­mann, she incor­por­ated a vari­ant of the base urid­ine, pseudour­id­ine, into the mRNA well in advance. This not only makes the molecule more stable and effi­cient, it also reduces the risk of immune sys­tem overreactions.

A pion­eer­ing achieve­ment that made the sav­ing vac­cines pos­sible in the first place?
Yes, and cer­tainly worthy of a Nobel Prize. If you con­trast exper­i­ments with non-mod­i­fied mRNA, it shows that it can’t be done without this modi­fic­a­tion. That’s the reason why some other vac­cine can­did­ates have failed so far.

Let’s cla­rify a few tech­nical issues. RNA molecules are large and very neg­at­ively charged. How do you get them where you want them in the body?
In the case of mRNA vac­cin­a­tion, this works very well: the vac­cine injec­ted into the upper arm muscle is taken up by cer­tain immune cells in the muscle and from there leads dir­ectly to an immune response. How­ever, as already men­tioned, depots near tar­get organs such as the lungs, liver or kid­neys are also being con­sidered. Sprays are also under dis­cus­sion. Over­all, this is a big research topic right now. Com­pli­ance is also always import­ant: How well is the ther­apy accep­ted by patients and how do they stick to it – all this plays a role.

Today, RNA molecules are mainly pack­aged in lip­ids in order to smuggle them into the cells. Is this the best method?
At present, yes. Nanoc­ages, which can be thought of as cages made of DNA for trans­port­ing RNA, are also being tested. The most import­ant thing is to pro­tect the com­par­at­ively large RNA molecules from attacks by the immune sys­tem and degrad­a­tion by enzymes – all meth­ods must be meas­ured against these criteria.

How long does the effect of RNA ther­apy last?
That depends on the tech­no­logy. In mRNA ther­apy, sim­ilar to Corona vac­cin­a­tion, the pro­tein is pro­duced for a few days after admin­is­tra­tion – after which the mRNA is degraded. The pro­tein, in turn, can exist in the body for days to weeks and exert its effect until it is then also degraded. For example, in the treat­ment of spinal mus­cu­lar atrophy SMA, the drugs that pro­mote mRNA mat­ur­a­tion must be given every two to four months.

How far along is test­ing in humans?
Among the most advanced is a CRISPR-Cas trial of an RNA agent to treat the inher­ited dis­ease beta-thalassemia. Until now, patients have required reg­u­lar blood trans­fu­sions. If the new ther­apy proves suc­cess­ful, that will no longer be neces­sary. Then their bod­ies will pro­duce the miss­ing hemo­globin. New mRNA-based vac­cines are also under­go­ing clin­ical tri­als, for example against influ­enza or malaria.

Why has RNA medi­cine only now become a big topic?
It took the pan­demic to build up pres­sure. It provided the neces­sary push and showed that mRNA vac­cines and RNA medi­cine as a whole are effect­ive and safe.

You are con­sidered a pion­eer in RNA medi­cine. What brought you in this direction?
I stud­ied bio­chem­istry and worked in molecu­lar bio­logy labor­at­or­ies as a stu­dent, includ­ing in plant genet­ics. I then also did my doctorate there, on molecu­lar mech­an­isms of cata­lytic RNA molecules in bar­ley chloroplasts.

You have headed the Helm­holtz Insti­tute for RNA-based Infec­tion Research for more than five years. Where do you stand today?
The insti­tute has developed mag­ni­fi­cently, in par­al­lel with the grow­ing import­ance of RNA research. When we star­ted out, the topic of vac­cines was still primar­ily thought of as pro­teins as act­ive agents, not RNA. That has changed dra­mat­ic­ally in recent years. Today, innov­a­tions are expec­ted primar­ily from RNA research. At our insti­tute, we bene­fit greatly from high-through­put sequen­cing: This allows us to look inside the cells as if with a micro­scope and see which RNA is cur­rently being pro­duced. Mean­while, we’re also pretty good at modi­fy­ing RNA to make it med­ic­ally useful.

Is med­ical util­ity a big issue with you?
When it comes to new approaches, yes. But we are basic research­ers. Fur­ther devel­op­ment is a mat­ter for industry.

Does your insti­tute work with phar­ma­ceut­ical companies?
So far, hardly at all, but that is set to change. We are cur­rently pre­par­ing the first spin-off. It involves RNA-based dia­gnostics and tests that can detect many dif­fer­ent patho­gens simultaneously.

There is still no cure for the com­mon cold. Will RNA medi­cine be able to cope with it?
Why not? We already have ideas!

Ribo­nuc­leic acid (RNA)
As mRNA, ribo­nuc­leic acid (RNA) ensures that the inform­a­tion stored in DNA is con­ver­ted into the pro­teins neces­sary for life. Other RNA classes reg­u­late the activ­ity of genes or have cata­lytic func­tions. RNA is sim­ilar in struc­ture to DNA. Unlike DNA, it is usu­ally single-stran­ded, which makes it less stable but also more chem­ic­ally ver­sat­ile than DNA. Chem­ical evol­u­tion on earth began with RNA – all organ­isms prob­ably evolved from it.

RNA bio­logy is his main research focus: Pro­fessor Jörg Vogel 

About the person
Jörg Vogel is Pro­fessor of Molecu­lar Infec­tion Bio­logy and found­ing dir­ector of the Helm­holtz Insti­tute for RNA-based Infec­tion Research (HIRI) in Würzburg. The insti­tute is oper­ated as a site of the Braun­sch­weig Helm­holtz Centre for Infec­tion Research together with the Uni­ver­sity of Würzburg. It is the world’s first insti­tute to bring together RNA bio­logy and infec­tion research. In par­al­lel, Jörg Vogel heads the Insti­tute for Molecu­lar Infec­tion Bio­logy at the Uni­ver­sity of Würzburg. In 2017, he received the Leib­niz Prize of the Ger­man Research Found­a­tion for his work on RNA biology.

Inter­view by Lilo Berg.
The ori­ginal ver­sion of this inter­view can be found on the webpage of the GDNÄ