Lifesaving Gene Therapies: Will They Reach Those Who Need Them Most?

Généthon maintains that the development of gene therapies for ultra-rare diseases should be a success story, not a cautionary tale

Frederic Revah
Frédéric Revah, PhD
CEO, Généthon

Here at Généthon, a nonprofit research organization, we have a history of accepting big challenges. At our founding in 1990, we devoted ourselves to genetics research. Seven years later, we transitioned to the development of gene therapies for rare and ultra-rare diseases. Doing so was hard work, but it was gratifying, too. It eventually contributed to the success of several gene therapies in clinical trials. Today, we face an even greater challenge—ensuring that gene therapies for rare and ultra-rare diseases become readily available and realize their lifesaving potential. We believe that patients in need, primarily children, must benefit.

Highlighting two examples amongst the 13 products currently in clinical trial stemming from our R&D, for several years, our scientists have been developing a successful gene therapy for Wiskott-Aldrich syndrome, an ultra-rare disease that affects between 1 and 10 males per million worldwide. This year, we are conducting a pivotal trial of a gene therapy for Crigler-Najjar syndrome, a similarly ultra-rare condition that affects about 1 person (male or female) per 750,000 to 1 million people worldwide.

Both treatments represent first-ever gene therapies for these patients, whose inherited genetic diseases are usually diagnosed soon after birth and can be deadly. However, at present, we have no way to provide these treatments to all patients, making celebrations frustrating for our dedicated scientists and the heroic families and their children who serve as research subjects.

Populations are small but add up

The dilemma epitomizes what Généthon and other proponents of gene and cell therapies have identified as the lack of interest in these pathologies by pharmaceutical or biotechnology companies, which would rather focus on more profitable indications with larger patient populations.

Then when you add to this exasperation a lack of adequate public and private funding, it translates into a maddening irony. Some 300 million people worldwide who suffer from one of more than 7,000 rare diseases may never gain access to new gene therapies. Two thirds of these diseases afflict children, and the vast majority have no relief. Ninety-five percent of rare diseases lack appropriate treatment, and 85% of these are considered too rare for private industry investment in clinical development and commercialization.

Genethon lab
Généthon researchers seek to overcome the roadblocks to gene therapy treatments for even the smallest patient populations. However, not all the roadblocks can be overcome in the laboratory. If daunting development and commercialization costs are to be met, a new economic model may be necessary, one that is better suited to smaller patient populations.

Better options may be neglected

Our Wiskott-Aldrich and Crigler-Najjar gene therapies provide an instructive case in point. Wiskott-Aldrich syndrome is caused by a mutation in the Wiskott-Aldrich syndrome protein gene, or WAS gene, in hematopoietic cells, resulting in hemorrhages, severe infections, severe eczema, and (in some patients) cancers. The only treatment currently available is bone marrow transplantation, which requires a compatible donor and can cause serious complications.

Crigler-Najjar syndrome is a liver disease characterized by abnormally high levels of bilirubin in the blood (hyperbilirubinemia). It is caused by a deficiency of the UGT1A1 enzyme, responsible for transforming bilirubin into a substance for elimination by the body. High levels of bilirubin can result in neurological damage and death if not treated quickly. At present, patients undergo phototherapy for up to 12 hours a day to keep bilirubin levels below the toxicity threshold.

Our Wiskott-Aldrich gene therapy involves extracting from patients the blood stem cells carrying the genetic abnormality, correcting them in the laboratory with a healthy WAS gene (which is delivered with a lentivirus vector), and transplanting them back into the patients. The Crigler-Najjar gene therapy combines normal copies of the UGT1A1 gene (which codes for the bilirubin-metabolizing enzyme) with an adeno-associated virus vector. It is administered intravenously.

Despite these remarkable achievements, we struggle with how to make these lifesaving therapies available to patients who live in many countries.

A new model is needed

If we had standardized clinical development regulations that were specifically adapted to the rarity of these pathologies, and if we had enough funding, we could partner with hospitals, open clinical trials in places with significant concentrations of patients, and treat them on a compassionate use basis.

Because most rare disease patient populations are too small, existing government incentives in the United States and Europe are not sufficient for biopharmaceutical companies to invest in development and commercialization. A new kind of economic model will be required if patients are to receive the care that we owe them.

Généthon lab
Généthon is a not-for-profit research center that was created by the French Muscular Dystrophy Association (AFM-Telethon). Since its creation in 1990, more than 70% of its resources came from donations from France’s annual Telethon, and it now runs the largest gene therapy R&D operations for rare diseases in the European Union.

To help address these challenges, Généthon joined the Bespoke Gene Therapy Consortium (BGTC), an initiative of the NIH- and FDA-led Accelerating Medicines Partnership. The BGTC is coordinating private and public efforts to develop platforms and standards that will speed the development and delivery of customized or bespoke gene therapies that could treat the millions of people affected by rare diseases.

We are hopeful that the U.S.-based BGTC will have an impact. But unless similar initiatives are coordinated at the international level, milestones such as our Wiskott-Aldrich and Crigler-Najjar gene therapies may end up being a cautionary tale about our failure to deliver the cures for patients who desperately need them.


Frédéric Revah, PhD, is the CEO of Généthon.

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