Published on 8 November 2018
Thérapies géniques

Gene therapy is the focus of much research and brings the right to hope. Research carried out at University Paris-Saclay is giving very encouraging results in the animal. Some clinical trials on humans are also underway.

Might the development of a treatment against Alzheimer's disease be feasible through gene therapy? This is the path that Nathalie Cartier at the CEA has been following for several years, with positive results. “The brain's cholesterol could be a therapeutic target for neurodegenerative illnesses, whether they have a genetic origin, such as Huntington disease (a hereditary and orphan disease which results in a neurological degeneration) or not, such as Alzheimer's” explains the researcher. The cholesterol is actually produced locally and does not cross the blood-brain barrier. It is thus present in great quantity in the brain that contains 25% cholesterol when it represents just 2% of the body weight! The reason is simple: cholesterol is vital to form myelin sheaths which protect the nerve fibres and for the membranes of the neurons. It is a question of dosage: if there is not enough or too much then the signal transmitted by the neurons does not operate correctly. “There is, therefore, in the brain, a chain hat regulates cholesterol and it depends in particular on an enzyme named CYP46A1. It transforms excessive cholesterol that can then be evacuated by the rest of the body”, explains Nathalie Cartier. “This enzyme is however absent in the brain of patients who are suffering from Alzheimer's or Huntington disease, and the result is an abnormal cholesterol metabolism”.

Mice… and men against Huntington

Researchers therefore asked an apparently simple question: will providing the brain with this enzyme affect symptoms? The answer is yes! In any case this works on mice. “Gene therapy consists in giving a coding gene for this enzyme through a small, non-toxic virus (AAV) injected in the brain of Alzheimer's and Huntington diseases' mice models. Their clinical signs have greatly improved”, reveals Nathalie Cartier. Nathalie Cartier's team has decided to offer a first therapeutic trial to patients suffering from Huntington's disease, where the area in the brain that requires treatment is smaller. If the result is positive it will open up the way for trials in different conditions. “Diffusion tests of the product and toxicity, essential before treating patients, have been carried out on primates and worked well. We are now producing a drug vector, at a clinical grade, thanks to the start-up BrainVectis which has been created specifically for this”, says the researcher. “In parallel, we are preparing for the clinical trial with the French Brain and Spinal Cord Institute (ICM) team, where the test will take place.” It will hopefully start in 2020.

Resistant antisenses in the body

Providing a new treatment to patients is also the aim of Luis Garcia and his team of the Inserm unit END-ICAP, at the University of Versailles Saint-Quentin-en-Yvelines. They are developing gene therapies for several progressive genetic diseases that affect the muscles (Duchenne muscular dystrophy, Spinal amyothrophy and Pompe disease). “Our approach is different to usual gene therapies as we do not aim to repair the protein by direct access to the gene but through a messenger RNA, a stage between the gene and the protein”, reveals Luis Garcia. To accomplish this the team is working on perfecting antisenses: small nucleic acid analogues (the core of DNA and RNA) are created chemically so they will resist several hours, days or weeks to natural breakdown in the body and so that they have the time to reach their target and repair the messenger RNA, while it is being produced. “This method is easier than targeting the gene directly but implies renewing the treatment at a frequency that will depend on which gene is aimed, the life-span of the protein or even the quantity of protein necessary to allow for improvement”, explains the researcher.

From tests on non-human primates to clinical tests on men

And it works! The team is now working on developing a new generation of molecules that will be effective in a preclinical phase. They hope to bring them to a clinical phase on the three illnesses in the next few years. In the mice modelling the Duchenne muscular dystrophy, on human blood and in non-human primates, the tests have been successful. Analysis of the final samples should give the go-ahead to start the clinical study. “This study will be carried out on the Duchenne muscular dystrophy, but the same strategy will apply to the other indications, even if the drug and the targeted gene are not the same”, announces Luis Garcia. Mass production of antisenses will become feasible as patient associations that support research have created start-ups to enable the clinical trials… positive results should attract partners in the industry and enable commercialisation.

A. Goyenvalle et al., Functional correction in mouse models of muscular dystrophy using exon-skipping tricyclo-DNA oligomers, Nature Medecine 21, 2015.

Nathalie Cartier"The same approach can be used to treat rare genetic illnesses but also more frequent diseases such as Alzheimer's."

Nathalie Cartier is a trained paediatrician and she is Head of research at the Inserm where she runs a gene therapy group. Her research on leukodystrophy, that is ongoing since 1990, came to fruition in 2009 with the first clinical trial to treat adrenoleukodystrophy with the HIV virus. This research opened the way to other tests on other illnesses and amongst others, Alzheimer's.


The original version of this article was published in L'Edition #8