Par Romain FOL Consultant – Financement de l’Innovation ACIES-ABGI Group
Recent studies estimate that the numbers of patients affected by AD will double every twenty years, reaching 130 million people in 2050 . However, social and economic consequences linked to the currently 50 million living dementia are already devastating. It is the case not only for patients themselves, but also their entourage. Indeed, 35% of caregivers report a worsening health due to their responsibilities. At a global scale, the economic burden represents 818 billion dollars, the GDP of Netherlands.
Even though recent studies evidenced genetic risk factors linked to the disease, the origin of the pathology continues to puzzle researchers. The only certain and strongest risk factor remains to be age.
Since its discovery in 1906, very few progresses have been made in the way to find a cure. Indeed, Dr Alois Alzheimer already evidenced the hallmarks of the disease more than a century ago. His patient, Auguste Deter, was displaying progressive memory loss, impaired thinking, disorientation, and changes in personality leading to a decreased independence. At a microscopic scale, Dr Alzheimer documented the two hallmarks of the disease: the amyloid plaques and the tau tangles . They are two different protein aggregates that are thought to disrupt neuronal communication, leading to their death and eventually to memory impairments.
Despite billions of dollars invested in R&D to find an effective treatment, AD clinical trials still have one of the highest failure rate of any disease: over 99% . This could be attributed in part to current animal models, which do not fully recapitulate the human AD course.
Indeed, current animal models are not consistent with human pathology. Most murine models (both mouse and rats) are transgenic based. They overexpress (often several times) mutated genes found in early affected patients. However, 98% AD patients suffer from a late onset disease occurring after 65 years old. As a consequence, transgenic models have a supra-physiological production of toxic metabolites (dozens of time more than human).
As a further matter, the large majority of them aimed to recapitulate the two protein aggregates found in patients. However, it is not rare to diagnose free protein aggregate patients with clinical symptoms of AD. In view of the limited transfer success of therapeutics from animal models to human a new way of thinking had to be made.
Recent research on animal models took advantage of gene transfer. This technology enables to transfer toxic metabolites producing genes directly into the brain. The biotechnology company AgenT recently published a human-like model based on the gene transfer of both APP and PS1 genes . As a result, toxic metabolites such as Aβ peptides and hyperphosphorylated tau proteins are produced in a physio-pathological manner. Hallmarks appear in chronological way similar to what happens in human. Moreover, the onset of cognitive deficits henceforth appears at advanced age of the rodent; like in human.
Such an innovative model could push forward the discovery of a brand new generation of therapeutics. Indeed, early diagnosis in AD is a real challenge and would enable a better care of patients. This is the aim of the presented model and the entire field. By pursuing in this direction, Azlheimer’s disease might soon be a bad memory.