RNA technology already helped thousands of patients

“RNA-based technology can help babies with spinal muscular atrophy reach milestones such as sitting, standing and walking”, says rare disease expert Prof. Annemieke Aartsma-Rus (Leiden University Medical Center, the Netherlands).

This Wednesday 25 January the European Parliament’s Panel for the Future of Science and Technology will hold its Annual Lecture on the future of RNA-based technology. We spoke with one of the speakers, Annemieke Aartsma-Rus, PhD. As Professor of translational genetics at the Department of Human Genetics of the Dutch Leiden University Medical Center, she is an expert in the field of RNA-technology and rare diseases.

Most people are already familiar with the fact that some of the vaccines against COVID-19 involve the use of RNA. Could you please explain, in simple terms, what RNA technology is?

Annemieke Aartsma-Rus profileAnnemieke Aartsma-Rus: Our genes (DNA) contain the code to make the proteins we need to function as humans. When proteins are needed to be produced, the gene is copied into an RNA transcript, which is translated into protein. As a comparison, if DNA is the cookbook, then RNA is the temporary note containing a recipe that you take with you into the kitchen and throw away once the meal has been prepared.

RNA technology uses synthetic ribonucleic acid (RNA) – a molecule essential in various biological roles in coding, decoding, regulation and expression of genes. It can either adapt transcripts, when proteins have to be repaired, or break transcripts down, when proteins are toxic; there are multiple ways in which proteins can become toxic. Most commonly due to mutations, proteins start to aggregate, which interferes with normal processes in the cell.

How can RNA technology help with the treatment of rare diseases?

Annemieke Aartsma-Rus: The majority of rare diseases is of genetic origin, in other words diseases caused by variants in a single gene that causes the production of non-functional or toxic proteins.

RNA technology can help allow the production of proteins that are missing and it can also prevent the production of toxic proteins. This technology is called ‘antisense oligonucleotides’ (ASO); small pieces of DNA or RNA that can bind to specific molecules of RNA to do just that.

How far advanced is this, have patients already been treated?

Annemieke Aartsma-Rus: Next to the mRNA vaccines, currently nine RNA therapies have been approved in the EU (13 in the USA). Thousands of patients have already been treated.

Probably the most notable example of RNA therapy for rare diseases is spinraza (nusinersen) for the treatment of spinal muscular atrophy. The most severely affected patients, babies, do not live beyond two years of age and never learn to sit or stand or walk due to this genetic disorder. Timely treatment with spinraza prevents death and also results in patients achieving milestones such as sitting, standing and walking.

Are there any challenges that we still need to overcome? Of course rare diseases are rare, and this has in the past meant that developing treatments were difficult, and ultimately the medication prices and costs were very high – would RNA-technology be able to change this – or not?

Annemieke Aartsma-Rus: The challenges for RNA technology are multiple. Most importantly:

  1. Delivery: delivery to liver, brain and eye (the last two with local injection) is possible. However, for other tissues, delivery is currently suboptimal or impossible;
  2. For rare diseases specifically: small numbers of patients makes therapeutic development of little profit and risky.

Developing therapies is expensive overall – the cost of drugs is usually largely determined by the cost of development, not how expensive it is to produce (manufacture) the therapy.

The problem is that the development costs of medicines for rare diseases and common diseases are about the same. Because there are fewer patients with rare diseases, the price per patient is higher.

Unfortunately, RNA therapy is as expensive as other therapies, unless we – instead of testing in clinical trials – move to a different way of developing therapies for rare diseases. Then RNA therapy has a huge advantage because it is programmable – so RNA therapy could be developed more cheaply than other therapies that require much more upfront work.

What is the focus of the research you are conducting?

Annemieke Aartsma-Rus: My work focus is twofold:

  1. Duchenne muscular dystrophy: I was one of the pioneers of ASO therapy for Duchenne patients. This is a mutation specific therapy so different ASOs need to be developed to treat subgroups of patients. Currently four ASOs are approved for Duchenne treatment in the USA (based on IP generated by my institute). Approval was based on restoration of the missing protein, albeit at very low levels (~1%). Functional effects on disease pathology have yet to be confirmed. Lacking the functional evidence, these ASOs were not approved in Europe.The fact that the missing protein is restored shows that the technology works, but the very low levels show that there is room for improvement. My work currently focuses on trying to improve ASO therapy for Duchenne by generating new model systems, studying the pathology in more detail, studying the gene transcript processing in more detail, studying different ASO chemical modifications, studying different conjugates to improve delivery to ASOs to the target tissue (muscle and heart for Duchenne).
  1. ASOs for very eligible patients with very rare mutations: here we try to develop individualised patient-specific ASOs for patients with unique mutations that are very eligible to ASO treatment. As these are unique cases, treatment can be done in a named patient setting (in Europe). We are trying to develop this within an academic setting, aiming to keep costs as low as possible and to develop these ASOs as quickly as possible. The target patients have severe progressive diseases of the central nervous system and ‘time is neurons’: every day these patients lose cells in the central nervous system and with that they progressively lose function.

Here we are not focusing on a single disease, but rather on patients with eligible mutations with neurological diseases.

What is happening in Europe to support this technology? Is more needed?

Annemieke Aartsma-Rus: Networks on ASO and RNA therapies have been funded in the past through the Actions of the Cooperation of science and technology: COST Action BM1208 (2013-2017) and CA17103 (Darter, running until April 2023).

The challenge with RNA therapies regarding funding is that they often apply to rare diseases. For rare diseases there are specific calls, but mostly on advanced therapeutic medicinal products, cell therapy and gene therapy (ATMPs). ASOs are a different category and often are just outside of the scope of rare disease specific calls. This means the research in my group and that of colleagues in other EU countries is often done with small funds at a local level, while more substantial funding is needed to allow the collaborative research approach that is need to really move this field forward within the European Union.

Concerning the second focus (developing individualised ASOs): this is something that has not been done yet in Europe – only in the USA at a small scale. We know that geographic differences apply with regard to regulations of individualised ASOs and what applies in the USA does not in the EU.

To streamline the individualised ASO development, we are collaborating within the EU in the “1 mutation 1 medicine” (1M1M) network and we also have a dialogue with the European Medicine Agencies.

As we are literally discovering the wheel, support is needed to do the research to create the different aspects of the wheel. But we also need funding to allow networking in order to make sure we are not inventing different wheels in different EU countries.

We have of course applied to EU grants for this work, but as we are pioneering and doing something unique, it often is difficult to ‘fit’ in most of the scopes of the existing calls. Hence, work is currently going slowly and is mostly funded internally, from within institutes involved.

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