According to the SiRM report ‘Academy-driven drug development’, the academy can contribute to effective therapies for patients who currently cannot be adequately treated. These include patients with rare diseases. A particular example is treatment with antisense oligonucleotides (AONs), for which the Dutch Centre for RNA therapeutics (DCRT) has been established in the Netherlands.

‘We focus on patients with unique genetic disorders. So we develop a unique RNA drug for each patient, in close cooperation with the treating doctors in the MUMCs. Commercially that is not interesting for companies and it does fit well with our academic expertise,’ says Prof Annemieke Aartsma-Rus, professor of translational genetics in Leiden and together with her colleagues from Nijmegen and Rotterdam and director of the DCRT. Prof Willeke van Roon-Mom, DCRT director and professor of translational studies of hereditary brain disorders at the Department of Human Genetics in Leiden: ‘We do collaborate with companies, for example for the production and quality testing of the drugs we develop. At least that is still necessary now, but it does determine the price tag of the treatment.’

The Ministry of Health, Welfare and Sport welcomes the DCRT’s efforts. ‘It is very nice what these researchers are doing and we hope that this approach can help patients,’ says Dr Jasper Claessen of the Medicines and Medical Technology Directorate of the Ministry of Health, Welfare and Sport. ‘At the same time, of course, there is always a tension when it comes to how you test effectiveness and safety, and the cost of a treatment that can only help one patient. We are therefore very happy that attention is also being paid to this and we like to think along with all parties involved to create opportunities for this group of patients within that field of tension’. In addition to VWS and the DCRT, the Medicines Evaluation Board (CBG), the Healthcare Institute of the Netherlands (ZIN) and the Central Committee on Human Research (CCMO), for instance, are involved in the developments surrounding AONs.

Molecular correction tape
There are currently no patients in the Netherlands being treated with a custom-made RNA drug, but more than 20 such unique AONs have already been developed in the United States. The treatment builds on two AONs that have been registered as drugs for neurodegenerative disorders and for which safety and efficacy have thus been demonstrated in groups of patients. Nusinersen is an AON active in spinal muscular atrophy. It affects the process of splicing: the cutting and pasting of non-coding portions from the messenger RNA precursor. Alternative splicing creates a modified messenger RNA, which forms the basis for a functional protein. This allows the patient’s body to still have this protein, reducing the symptoms of the inherited disorder. Tofersen works in a rare hereditary variant of the muscle disease ALS. This AON turns off the messenger RNA for the disease gene, preventing the production of the harmful gene product and slowing down the disease process.

So the AONs that the DCRT plans to deploy will have to be a solution for the (rare) inherited diseases where this approach works. In one of the US patients, for example, the disease was based on an error in one of the non-coding parts of the gene. An AON was developed that affects splicing in such a way that a functional protein was created. Aartsma-Rus: ‘Finding out that the problem is in the non-coding parts of the gene is a challenge in itself. Those are often not investigated. And even if you do a whole genome sequence where you do look at them, it can still be very difficult to detect this problem. After all, there are always a lot of variations in the non-coding parts, which usually have no functional consequences.’ An important limitation that the researchers impose on themselves is that it has to be disorders where the AON can be administered into the nervous system (via an epidural) or into the eye. Van Roon: ‘This reduces the likelihood of side effects in other organs. Moreover, the drug stays in the nervous system or in the eye longer, so you don’t have to administer it as often.’

Complex questions
Although specific AONs for individual patients have not yet been developed in Europe, researchers and practitioners have been working together for some time to make this possible. This involves research not so much into the technology, but into the optimal approach and answers to a multitude of questions, such as: At what point do you start developing an AON for an individual patient? When do you discuss your options with the patient or their parents? How advanced may the disease already be? What should you already know about the course of the disease? How do you measure progress, deterioration, or inhibition of disease progression? What safety tests are possible and necessary before administering the drug to the patient?

‘Ultimately, a local medical ethics review committee has to give permission. For them, it is often very unfamiliar material, so they fall back on the usual conceptual framework that works for regular drugs. But with unique patients, you don’t have a control group and you often don’t know what the natural course would be,’ says Van Roon. ‘This is really pioneering work. I quite understand that review committees are reluctant, but if you wait too long, treatment no longer makes sense. Then the patient is dead, or blind,’ says Archma-Rus. To provide a clear framework for the review, the DCRT is working on a national protocol for the development of individual AONs. Within Europe, Dutch researchers are working with colleagues on such protocols. Although each case involves a unique genetic disorder and an often equally unique clinical picture, there are plenty of similarities throughout the development process.

Another common factor is the production of the RNA fragments and the necessary quality tests before they can be administered to a patient. Van Roon: ‘If we were to use this therapy more often in the Netherlands, it becomes interesting to set up a central facility for it, which we as academic institutions would use jointly. That way it can be much cheaper than if we have to buy it commercially.’ Aartsma-Rus: ‘Unfortunately, I often notice that when it comes to money, everyone starts thinking from their own local interests anyway. I very much hope that with RARE-NL we will start thinking more nationally from the patients‘ interests and the affordability of care.’

Claessen welcomes the work on protocols and standardisation: ‘This is an exciting development, of which I certainly see value for the Netherlands. At the same time, I realise that developments can move fast and that can affect how you test and produce such a unique product, and ultimately also what the treatment costs. So we have to keep an eye on that. Academic cooperation can help ensure that such innovations become available to patients and remain affordable for society.’