This month, Dr. Helene Puccio’s lab at INSERM in France published a new paper with some very exciting results showing the effects of an AAV (adeno-associated virus) gene therapy in a new mouse model of FA. This work gives a lot of hope for gene therapy for FA. Is this a treatment for FA? Unfortunately, not yet.

Promising Results:
The mouse model is designed such that the mouse frataxin can be switched off completed in specific cells in the nervous system, cells that are vulnerable in FA. Puccio’s lab demonstrated that once the frataxin is removed from these cells, the mice develop neurological symptoms similar to severe Friedreich’s Ataxia, although more severe since no frataxin is present. These effects could be prevented by inserting a human frataxin gene by AAV gene therapy. If the gene therapy was used after the mice had developed symptoms, the mice still showed great improvement, which suggests that at least some symptoms of FA may be reversible, in the mouse, if frataxin can be produced in the cells where it is needed. This is very exciting work, with a lot of learnings that will be critical to moving forward with gene therapies for FA.

Mice are not Patients:
These experiments were done on mice, which are not perfect models for human patients. The mice show symptoms similar to human patients, which can be reversed with the gene therapy. This is very encouraging for patient treatment! However, the mouse model differs from human patients in many ways, so while this is a very positive indication, the result will not necessarily directly translate to people, and there are many steps to go. We must first test animals whose size and physiology is closer to humans.

Finding an Effective and Safe Dose:
We need to work out what dose we need – how much therapy will be effective and safe in humans? You cannot scale this directly from mice by size, so you have to look in mice, rats, NHP, and possibly other animals. to figure out what dose might be effective. As (for now) gene therapies can only be administered once to a given patient, it is important to understand how much to give to have an effect before treating anyone.

At the same time, we have to do a large number of studies to look at safety, to make sure that we understand any safety concerns around the treatment – both the gene and the virus that delivers it, and how that changes with dose (almost any medication is toxic at some level, so we need to understand the “window” of doses where the treatment may be both effective and safe).

Then, we need to be able to deliver the treatment to the important organs in humans – mice are much smaller and gene therapies get in much more easily than in people and distribute to different tissues than in humans. So, we need to work out how to deliver the therapy to the places we need it in the cerebellum, spinal cord, heart etc. in humans.

Moving into Clinical Trials:
The worldwide regulatory agencies ensure that therapies that go into humans are manufactured to certain standards, to make sure that you get a pure version of the therapy in question that does not contain any harmful compounds, and does contain a known quantity of the agent which makes it effective (in this case, the AAV vector containing frataxin), so that you really know what dose you are giving people. This is essential both to make sure that the experimental treatment is likely to be safe and to make sure that the patient is getting the treatment they think at the dose they want.

These agencies (FDA, or Food and Drug Administration in the US, EMA or European Medicines Authority in Europe) review safety, dosing, manufacturing and efficacy data. If they think the proposed therapy is likely to be safe and may be effective, they will authorize the testing of the therapy in human patients in clinical trials. After significant testing in patients, if the therapy appears to have a benefit that is greater than the risks or side effects of treatment, the new therapy may be approved and prescribed by doctors.

Right to Try:
What about the new “Right to Try” mechanism in the US? Doesn’t that mean we can access such treatments now if we think the course of the disease is worth the risk of a not fully studied therapy? This law allows patients who are dying to request access to experimental treatments when they have been through Phase 1 safety trials in humans but have not completed later stages of clinical testing. This gene therapy needs a lot of work before it gets to a Phase I trial, so would not be covered by this law. Furthermore, the law does not guarantee that a company will give the patient access to the drug when asked, and there is no precedent yet as to what groups of patients are covered by the law. FARA joins the National Organization for Rare Disorders (NORD) and numerous rare disease advocacy groups in opposing the Right to Try Legislation. To read this statement from NORD, click here

In Conclusion:
Gene therapy in FA is a very exciting area right now, with several groups working on similar, but subtly different therapies. These all use different methods of delivery and vary in the precise gene therapy that is used. They all aim to introduce frataxin, but each has its own construct that may result in different levels of expression of frataxin in different tissues and therefore could affect different symptoms of FA to different degrees. None of these have yet reached human trials, but the first is expected to reach the clinic soon. At least three companies, as well as several academic groups, are working to move these therapies forward for FA. Many of these groups are working together – for example, Dr. Puccio acknowledges her role as an advisor to Voyager Therapeutics in this paper. Thus, lessons learned from papers like this one are shared with the wider community and help all of the projects move forward.

Work, like this work from the Puccio lab, is incredibly encouraging and teaches us a lot about what we need to be looking for in developing these therapies, how they may work, and how to optimize them to make them as effective and safe as possible. The new mouse model by itself is a very useful tool for exploring critical questions around the development of these genes therapies, as well as other therapies. This paper is a big step forward for the field and will help gene therapy research for FA move forward, but we still have work to do before a therapy is available.