IMPlementation of Affordable gene Correction Therapies

Informazioni relative al progetto

IMPACT

ID dell’accordo di sovvenzione: 101189464

DOI

10.3030/101189464

Progetto chiuso

Data della firma CE 25 Settembre 2024

Data di avvio 1 Gennaio 2025

Data di completamento 30 Giugno 2026

Finanziato da

• European Research Council (ERC)

Costo totale

Nessun dato

Contributo UE

€ 150 000,00

Coordinato da

UNIVERSITAIR MEDISCH CENTRUM UTRECHT
Netherlands

Periodic Reporting for period 1 - IMPACT (IMPlementation of Affordable gene Correction Therapies)

Periodo di rendicontazione: 2025-01-01 al 2026-06-30

Sintesi del contesto e degli obiettivi generali del progetto

Rare genetic diseases affect around 30 million people in Europe. Each one is rare on its own, but together they are common. While they are very diverse in presentation, they all have the same cause: a specific spelling error in the patient's DNA. Ror most of these diseases, no treatment exists that addresses that underlying cause.

Recent advances in gene editing make it possible, for the first time, to correct such errors directly. IMPACT builds on a technique called prime editing, which can rewrite a faulty piece of DNA into its healthy version. The editing tools are delivered into the body inside tiny fat droplets called lipid nanoparticles, the same class of delivery technology used in COVID-19 vaccines. These droplets naturally accumulate in the liver. Because the liver is the body's main metabolic organ, correcting DNA in the liver could relieve the symptoms of many inherited diseases with a single infusion, instead of a lifetime of mainly supportive treatment.

The science is promising, but a therapy that never reaches patients helps no one. For rare diseases the obstacle is not only scientific. Bringing any medicine to patients requires proving that it works, satisfying medicines regulators, manufacturing it to pharmaceutical standards, and paying for the whole development and clinical trajectory. Those costs are largely fixed, whatever the number of patients eventually treated. When only a handful of people worldwide share the same mutation, no company can recover costs, so therapies that are scientifically feasible are simply never developed because of a lack of return on investments.

IMPACT therefore asked a deliberately practical question: what would it take to bring a gene correction therapy developed inside a university hospital to patients, and can it be made affordable? Using a severe inherited liver disease, methylmalonic acidemia, as the test case, the project pursued several aspects: showing that the therapy reaches and works in human liver tissue, mapping the regulatory, the manufacturing and the financial requirements and exploring intellectual property rights that follow from that.
The intended impact is a template. The same platform needs only a small change to address a different mutation, so that the established route can be reused. Describing that route clearly lowers the barrier not for one disease, but for many.

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

Establishing which rules apply.
Medicines in Europe are regulated according to the category they fall into, and that category determines what a developer must prove before treating a patient. We found that this is unclear for our therapy, which consists of two components. Only one of the components meets the formal definition of a gene therapy. Similar gene-editing products have been placed in different categories from one another, and no prime-editing therapy has been categorised so far. We identified the official European procedure that settles such questions and prepared a request, so that the answer is established before the next steps are taken.
We also held discussions with the national medicines authority about the safety testing required before a first patient is treated. In particular, we discussed how to check for unintended edits elsewhere in the genome. The agreed strategy was recorded in writing and now serves as our working framework. This had been an important unresolved question on our route to the clinic.
Separately, we identified a second possible route to treating a first patient through a very small clinical study, which does not depend on the categorisation question.

Showing that the therapy reaches human liver cells.
Before a new therapy can be given to a patient, it must first be shown to be effective in vivo. This is generally done in animals, but animals differ from humans and often predict human responses poorly. We were able to work directly with human tissue instead. Occasionally a donated liver turns out to be unsuitable for transplantation; such an organ can be kept alive outside the body on a perfusion machine, which pumps a blood-like fluid through it and keeps the tissue functioning for days.
We added our particles to that circulating fluid, mimicking an injection into a patient's bloodstream, and followed what happened over two days. The test was successful. The particles left the fluid and entered the liver tissue, the liver cells took them up, and the cells read the genetic instructions the particles carried and produced the corresponding protein. This is the essential proof that the delivery system works in a human organ.

Understanding what manufacturing would cost.
Medicines given to patients must be produced under pharmaceutical-grade conditions in certified facilities to meet standards far stricter than those used for research. We had expected that our own academic facilities could do this. We established that they cannot meet these standards in the coming year(s), because this type of product needs different equipment and expertise than currently available in our hospital. We therefore identified specialist external manufacturers capable of producing our therapies and obtained cost estimates. Producing a single treatment currently costs several million euros. Rather than the science, this is at present the largest obstacle to reaching patients.

Exploring whether these therapies can be paid.
Working with investors and other stakeholders, we sought for a sustainable financial model. However, for an ultra-rare disease, not enough patients share the same correctable mutation to recover the fixed costs. We therefore rebuilt the analysis around a more common disease (cystic fibrosis), in which a single mutation is shared by the majority of patients. Here, a one-off correction compares favourably against the cost of the decades of daily therapy it would replace.

Securing the rights.
Both the editing tool and the delivery particle are covered by patents held by others, so permission is required to use them in a treatment. We established that both can indeed be licensed for treating patients, not only for research. We also filed a patent application of our own and analysed the wider patent landscape to confirm that we are free to operate within it.

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

IMPACT produced three results that go beyond current practice.

First, a new way to test effects in a relevant human model. Trying out a gene editing therapy in an intact, living human liver outside the body has not been done before. Animal testing remains the standard, yet it predicts human responses imperfectly and requires substantial animal use. Our results show that a perfused human organ can answer questions about delivery and safety directly in human tissue, and this approach is now being prepared for use by others developing similar therapies.

Second, a clear explanation of why affordable gene therapies for rare diseases fail to appear. The limiting factor is not the cost of the raw materials, nor the design of the editing tools, both of which are inexpensive and easily adapted. It is the combination of very high fixed manufacturing costs per treatment and the absence of any public or not-for-profit route to pharmaceutical-grade production in Europe. Whether a therapy is viable therefore depends largely on how many patients happen to share the same mutation, rather than on how strong the medical case for treating them is.

Third, a documented route through the rules, comprising an informal position on the safety testing required before treating a first patient, an identified procedure for settling the legal status of this class of therapy, and a second independent route to a first treatment. Other academic developers can reuse each of these routes.

The work has already led to a funded continuation. With additional funding to a national research consortium, including several liver transplantation centres, we are preparing the next experimental stage: developing personalized gene correction therapies for patients with a specific inherited liver disease awaiting a liver transplant, and testing these therapies in their own livers after explantation.

Three things are needed to take this project further. Most urgent is an affordable, publicly supported route to pharmaceutical-grade manufacturing in the Netherlands/Europe; without this, therapies developed in academic hospitals will remain undeliverable however good the science. Clarity from regulators on how gene-editing therapies of this type are categorised would remove significant uncertainty guide the developmental route. Finally, payment models suited to one-time (curative) treatments are required, since current reimbursement systems are built around recurring payments for (lifelong) chronic treatment.