Gene therapy aimed at slowing down — or even stopping — frontotemporal dementia, the pathology from which American actor Bruce Willis suffers, will soon be tested in Montreal. The Neuro (the Montreal Neurological Institute-Hospital), where this clinical study will be conducted, is currently recruiting patients suffering from this dementia who would agree to participate.
Frontotemporal dementia (FTD) is not only much less common than Alzheimer’s disease, but it also develops significantly earlier, between the ages of 40 and 50. This neurodegenerative disease can manifest itself in a so-called behavioral form, where the person presents a personality change, or in a linguistic form, affecting various components of language.
Between 20% and 30% of cases of FTD are hereditary and attributable to a genetic mutation. Several mutations have been discovered, but three of them are responsible for most cases. The gene therapy that we are about to test at the Neuro is aimed at people who carry one of these three mutations, namely that which affects the PGRN gene, which is responsible for the synthesis of progranulin, an anti-inflammatory protein. -inflammatory essential for maintaining the health of nerve cells. People with this mutation do not produce enough progranulin, leading to early degeneration of the frontal and temporal lobes of their brains.
In this genetic form of FTD, a single abnormal copy of the PGRN gene is sufficient to induce the disease. If one of the two parents carries a mutated gene, their children therefore have a one in two probability of inheriting it and developing the disease.
The goal of the treatment that will be tested is to increase the amount of progranulin in the brain. To do this, “you cannot simply take a progranulin supplement [par voie orale]we must ensure that the brain produces more, hence the idea of using gene therapy,” explains Dr.r Simon Ducharme, specialist in fronto-temporal dementia and head of the clinical trial at the Neuro.
The Montreal institute is one of three treatment experimentation sites, with that of the University of Pennsylvania – with which the Passage Bio company, project manager of the study, is associated – and another in Brazil.
Introduce a healthy gene
The treatment consists of viruses that have been stripped of their own genetic content and into which a copy of the normal progranulin gene has been introduced. A neurosurgeon injects these viruses into the base of patients’ skulls, specifically into the subarachnoid space, where cerebrospinal fluid circulates, which will allow them to enter the brain.
These doctored viruses will then enter nerve cells in the brain, where they release the progranulin gene. These will then transcribe the sequence of this gene into a messenger RNA which produces a progranulin protein.
“These viruses have no toxicity, they are not contagious and will not spread. We only use their envelope to deliver the normal gene into the brain. And the administration of a single dose should be enough, because the new genetic code that we are going to inject will remain in the neurons in perpetuity,” assures the Dr Some charm.
The study that we are about to carry out at the Neuro is the first phase of a clinical trial whose objectives aim to verify that “the treatment is well tolerated by patients, as well as to determine the optimal dose that it must be injected to obtain a therapeutic effect, because for the moment, we rely on [ce qu’on a observé chez] animal models of rodents and monkeys,” specifies the researcher.
Objective: curb the disease
For this first phase, the Neuro team is looking for patients who already present some symptoms of FTD, but whose disease is not too advanced, because “they must be able to travel to the hospital to undergo injection surgery and follow-up procedures.”
“If the patient already has symptoms, we would not realistically expect them to return to normal, even if theoretically this treatment could be curative. Because when we have symptoms, it means that there has been a little degeneration, that neurons have died. However, we will not be able to regrow these neurons,” warns Dr.r Some charm.
The optimal scenario, to which researchers aspire, would be to “block the progression of the disease or drastically slow it down”. “If we can do that, the next step would be to offer treatment to asymptomatic carriers – people who have the mutation, but who do not yet show symptoms,” he announces.
The mutation affecting the progranulin gene is quite rare in Quebec, indicates the Dr Some charm. However, we hope to recruit patients — as many as possible who have or have had a parent with FTD — who live in Ontario, the Maritimes or the eastern United States. One of the first steps before enrolling them in the study will be to carry out a genetic blood test to check if they are indeed carriers of the PGRN mutation.
Patients interested in participating in this study can contact the Neuro at 514 398-5500 or visit the Institute’s recruitment site.