Gene therapies have become revolutionary new treatments for diseases that previously had no cure. Instead of only treating the symptoms of a disease, these therapies involve replacing the faulty gene that is causing the disease.
For people with rare diseases, gene therapy can be a game-changer. Many genetic conditions are caused by a single gene mutation that causes a depletion in a certain specific protein expression. Nearly 80% of rare diseases are genetic conditions, and about 95% lack approved treatment protocols – most treatment strategies tend to reduce the symptoms without curing the disease.
One of those diseases is hereditary spastic paraplegia type 47 (SPG47). This is a neurodevelopmental disorder that slowly progresses, leaving patients with developmental delays, moderate to severe intellectual disabilities, speech problems, seizures and movement issues.
A group of parents with children with this condition set up CureAP4 a charity and joined efforts with LifeArc to fund pre-clinical efforts for a gene therapy to tackle this disease. But before trials could take place, a certain amount of evidence was needed.
“We did quite a lot of safety studies as part of the ARDAT project investigating the mouse model on hereditary spastic paraplegia type 47,” says Mimoun Azzouz, professor of neuroscience at the University of Sheffield, who is the scientific project coordinator of ARDAT.
“We generated a package of data that enabled us to approach the FDA and secure support to initiate a clinical trial.”
The initial trial will consist of five patients, which is typical when dealing with an ultra- rare disease. If that trial is successful, follow-up trials will be organised.
A series of safety studies supported by ARDAT were pivotal in convincing the FDA to approve the clinical trial, which is due to start in 2026.
One of the key safety studies that ARDAT supported for the hereditary spastic paraplegia type 47 gene therapy investigated a new route of delivery for the treatment. The gene therapy will be administered in the cisterna magna, a fluid-filled space in the back of the brain. This would allow administering lower doses of gene therapy vector compared to delivery in the blood.
This route of administration was tested in mice and the study found no significant adverse events associated with it. The project also carried out immunogenicity tests and other studies to prove the safety of this method.
Gene therapies are often delivered to the site of treatment by viral carriers, derived from viruses that have been genetically modified to make them safe for human gene therapies. The problem is that the body can react quite strongly to these vectors, as it is trained to do. The immune system’s job is to attack viruses, but the response of the immune system can cause unwanted side effects in patients receiving gene therapies.
ARDAT showed that less virus was required to deliver the gene therapy effectively. This is important because the less virus present, the weaker the immune response will be, and fewer side effects will have to be endured by the patient. When so many patients of rare diseases are children, this is even more important, notes Azzouz.
A spin-off company, BlackfinBio, was set up as a result of the project’s work to develop the gene therapy treatment for hereditary spastic paraplegia type 4. Blackfin Bio is currently leading the preparations for initiating the clinical trial SPG47 patients.
Advancing regulatory science for gene therapies
A critical advantage of gene therapies is that they are one-shot, making this a complete revolution for patients – instead of facing years of treatments, they can receive one dose of medicine and be completely cured.
Yet, gene therapies are still relatively new and for this reason they face regulatory hurdles.
“The regulatory system is designed for small molecules, not advanced therapies so there is a lot of adaptation required from a regulatory point of view,” says Christopher Mann, scientific and regulatory director at Asphalion and Co-lead of the Regulatory work package in ARDAT.
The ARDAT project took one area that affects most gene therapies, immunogenicity, and examined the issues that may arise as regulators try to assess these therapies. The results were then written up in a peer-reviewed journal, Cell Reports Medicine.
The immune system, when it encounters a foreign substance in the body, launches an attack, and immunogenicity refers to how likely a substance is to provoke an attack. Because of the viral vectors that carry gene therapies, this becomes complicated. Most regulatory processes require the medication to fly under the radar of the immune system, ideally not provoking a response. Gene therapies, by their very nature, can’t align with that requirement.
“Gene therapy is fighting against the evolutionary requirements of the immune system, which is to detect large, complicated molecules that are probably foreign and get rid of them,” says Mann. “It’s a long-term battle, but slowly some victories are coming.”
Of course, gene therapies should be developed to provoke a minimal response, and regulators do need to assess how immunogenic these therapies are. The paper published in Cell Reports Medicine investigated how regulators are assessing gene therapies for immunogenicity globally, so as to identify areas of agreement and discrepancy, propose areas where guidelines could be harmonised and predict areas that future guidance may address.
“Guidelines and scientific recommendations should be used in a harmonised way to make it simpler to develop these products,” says Mann. “The point of that paper is to try and push the regulation closer to where the technology front is.”
What needs to be done to allow regulators to move faster and bring these therapies to patients? Some regulators are working on fast-tracks, involving more testing with in vitro models and reducing the use of animals.
“This is a major milestone because it will reduce not only timelines, but also the cost of the development of these therapies,” said Azzouz.
For the researchers, the public-private structure of the ARDAT project enabled them to talk to regulators in a structured and useful way. The EMA and the FDA were on the scientific advisory board of the project, but ARDAT also spoke to national regulators like the Spanish Agency of Medicines and Medical Devices (AEMPS) and the Medicines and Healthcare Products Regulatory Agency in the UK.
“A really important part of the project was to tell [the regulators] what we were going to do, get some feedback about which direction to go in, and then tell them what we’ve achieved,” says Mann. “And actually, the response we’ve had from most of them was very positive, they were interested.”
For Azzouz, the public-private partnership structure of ARDAT helped in the preparations for submitting a proposal to the FDA for the clinical trial.
“It’s very, very helpful to have experts involved in our data from different disciplines, from industry, academia, neuroscience, across immunology and the regulatory sector as well,” says Azzouz. “It was extremely important and helped prepare us for approaching the FDA.”
The future of gene therapies
Looking towards the future, the researchers think that viral capsids can be further developed to help with targeting and dosage. Viral capsids, the protective protein shell that covers a virus, are being investigated as part of ARDAT in a couple of ways: AI is being used to generate new capsids for specific targeting and new vector systems are being investigated that could be safer in terms of immunogenicity.
ARDAT is supported by the Innovative Medicines Initiative, a partnership between the European Union and the European pharmaceutical industry.