This article has been extracted from the special “Grand Angle dossier” on rare diseases, produced by CommEdition, published in Le Monde on 27 February 2021. It has been translated to English (below). You can also download the original French publication from this webpage.

The emergence of a new generation of treatments in biotechnology has aroused much hope in rare diseases. A visit with Eric Pauwels, Chief Business Officer of PTC Therapeutics, the source of major scientific breakthroughs in the field of gene therapy, and Pierre-Olivier Boyer, Chief Executive of the subsidiary of the pharmaceutical company in France.

Tell us about the origin of PTC.

Eric Pauwels Chief Business Officer

Eric Pauwels: It was founded in 1998 by Stuart Peltz, an active scientist. PTC Therapeutics’ mission is to provide patients with access to novel therapeutics that fulfill unmet medical needs. A pioneer in the treatment of rare diseases, the pharmaceutical company works in the discovery, development, and marketing of drugs for patients with Duchenne muscular dystrophy, aromatic l-amino acid decarboxylase (AADC) deficiency, Huntington’s disease, and spinal muscular atrophy.

What gene therapy projects are currently underway?

E. P.: PTC Therapeutics is currently conducting two gene therapy development programs – one in AADC deficiency, the other in Friedreich ataxia, a genetic neurodegenerative disorder – with the goal of creating lasting solutions for diseases for which there was no therapeutic response before. In addition to their impact on the disease, these gene therapies bear the advantage of only requiring a single administration. We produce them in our own factory, which will be extremely helpful for their distribution.

Pierre-Olivier Boyer: Thanks to the French early-access system (for example, ATU (Autorisation Temporaire d’utilisation [Temporary Authorization for Use), two French patients with AADC deficiency who were surgically treated at the Montpellier CHU (Centre Hospitalier Universitaire [University Hospital]), received our treatment on 04DEC2020 and 10FEB of this year.

E. P.: They were among the first patients treated in Europe. This breakthrough will make it possible for French experts to share their experience with their European and American counterparts. Beyond its work in drug development, PTC also focuses on improving patient diagnosis and provides support for healthcare professionals. We work together on the development of genetic tests in order to reduce diagnostic delay and work with European expert centers, offering them technical support, so that treatment can start as soon as possible after the product is approved by the European Medicines Agency. In France, a real-life patient registry currently in place is an important element for the long-term follow-up of gene therapy in AADC.

Would you say France is the champion in gene therapy?

P.-O. B.: Gene therapy is a revolution for the management of certain rare diseases. PTC is proud to contribute to this issue in France. We are working on it together with the health authorities, and this constructive collaboration must be  acknowledged, since it helps us, in France, have early access to treatments. The commitment of healthcare professionals is also outstanding: they have all adjusted to the inherent obligations associated with this type of drug, such as storage at – 65 degrees. Without them, nothing would have been possible. Three clinical trials in France on PTC products are planned for 2021, one of which will be on gene therapy in Friedreich ataxia. There are still many challenges to overcome to give patients access to gene therapy. Sustainably reinforcing the country’s attractiveness by improving and simplifying the healthcare access system is vital. PTC will know how to handle this.

How does PTC Therapeutics fit into the French ecosystem of rare diseases management?

P.-O. B.: One of France’s strengths lies in its very well-known rare diseases networks. We work closely with the health authorities and hospitals. We also work with associations like AFM-Téléthon and the French Association for Friedreich Ataxia to understand patient needs. Our goal is to provide patients with solutions to improve their management and quality of life. By familiarizing clinicians with these diseases, we also hope to reduce diagnostic delay. A rare disease, as its name implies, is unlike any other disease, therefore it must be quickly identified.

Why are private/public partnerships so important?

E. P.: a partnership between the hospitals, authorities, and pharmaceutical companies is the best way to find solutions for patients. PTC has invested enormously to produce complex drugs and has made a long-term commitment to gene therapy. We hope that our work finds other applications in rare diseases, for example in Angelman syndrome, or even in more common neurological diseases. But, for patients to be able to quickly access these potential therapeutic innovations, cooperation between the authorities and pharmaceutical companies is vital.

Answers received by Christine Colmont




As a doctor, what have you learned about this rare disease?

Agathe Roubertie: The AADC enzyme plays a major role in the production of chemical neurotransmitters in the brain, such as dopamine, which help regulate control and movement of the body, cognitive function in particular. An AADC deficiency is caused by a gene mutation. The symptoms in children will make it possible to suspect this disease: movement disorders, hypotonia, developmental delay, and temperature and sleep regulation disorders. Genetic testing confirms the diagnosis.

Our pediatric neurology department at the Montpellier CHU manages patients with this rare disease. Other practitioners also reach out to the CHU because of its expertise in movement-related diseases. It comes as a result of 20 years of work in the management of AADC deficiency and other neurotransmitter disorders.

Thomas Roujeau: The Montpelier CHU has extensive experience in the management of abnormal movements in children, but also in deep brain stimulation to treat the diseases behind these disorders. As a neurosurgeon, I am involved in the treatment of these AADC-related diseases, as well as in other gene therapy protocols by intracranial injection to supplement a gene-related deficiency.

What has gene therapy contributed to the Montpellier CHU?

A. R.: Patients who have this rare disease are documented in France. A community of physicians is specialized in movement disorders in children. In 2020, we spoke frequently with our colleagues to evaluate potential candidates for gene therapy administered at Montpellier. A special thanks to our colleagues for trusting us.

T. R.: For the procedure to take place in the best possible conditions, we have worked on synchronizing the entire team to prepare and administer the gene therapy at the right time in the operating suite. We practiced the procedure itself, which consists of an injection, followed by medical imaging that confirms there are no complications and that accurately shows us the delivery (intracellular) of the drug.

Besides common neurosurgical procedures, we had to master the particular technique, which consists of injecting the product, keeping in mind its low volume and low-flow. We performed synchronization test phases with the pharmacists for issuing the product and calibration of the injectors. The day of the surgery, we performed an MRI of the sleeping child’s brain to accurately locate the targets and trajectories for this injection combining a viral vector and coding gene.

A. R.: After the surgery, it takes some time for the genetic code to take hold and produce dopamine that will act on its targets: the receptors.

Four weeks after the surgery we detected dopamine on functional imaging of the treated patient’s brain. We can expect this procedure to improve symptoms: a better quality of life, less sleep problems, and, especially, an increase in mobility and muscle tone. This technical prowess was made possible by the support of the CHU Board, the participation of multiple hospital teams, and collaboration with the pharmaceutical company that developed this virus/drug.

How was the partnership with the pharmaceutical company formed?

T. R.: We were chosen as the reference center because of our experience in AADC and gene therapy. From the start of the collaboration in late 2019 to early 2020, we worked together to implement every procedure: from receipt of the product to the injection, including preparation, administration, and injector selection.

A.R.: We worked together so that the process could be reproducible and safe. The PTC Therapeutics teams helped us address many demands, such as operation of the pumps, material, preparation of the operating suite, the technique, even the injection, the speed and amount used.

What are your key takeaways from these innovations?

T. R.: This new innovative surgery consists of performing the transplant at the cellular and genetic level. We are at a technological crossroads between neurosurgical expertise, enabling us to cross the brain accurately without causing injury to reach a target, and an innovative biotechnology combined with a repair gene.

A. R.: Gene therapy offers new perspectives for patients with serious rare diseases, while also creating new ethical issues. Patients, children, or adults with other rare and severe diseases could benefit from the future of these kinds of therapies.