Cell therapy and Alzheimer’s disease : therapeutic potential and mechanisms action of human olfactory nasal stem cells – AD HOC

Background
At present, Alzheimer’s disease (AD) affects 7 million European people. U.S. society spends at least $100 billion a year on AD and it is expected that AD will cost $500 billion a year by 2020. In addition to memory loss, AD is characterized by an extensive cell death. Worldwide, we are one of the three laboratories that have developed an efficient method for cultivating and purifying human nasal olfactory stem cells. We also demonstrated that these cells are multipotent and represent a potential source for autologous stem cell therapy in Parkinson’s disease.
The three academic partners of the current application showed for the first time that human nasal olfactory stem cells, transplanted in a mouse model of amnesia, restore learning and memory. Noticeably, adult human OE-MSCs i) migrated towards cerebral lesioned areas, ii) differentiated into neurons, iii) restored long term potentiation (LTP) and iv) promoted recovery of mnesic deficits. Interestingly, similar results were observed when OE-MSCs were injected into the cerebro-spinal fluid (CSF). In addition, we observed that intravenously transplanted OE-MSCs home in lesioned hippocampi. We now aim to confirm this therapeutic benefit in a transgenic mouse model for AD. In order to get closer to patients’ bed, we will assess behavioural and electrophysiological recovery when olfactory stem cells are intravenously grafted.

Project
AD HOC project involves three academic teams and a biotech company, VECT-HORUS, with a recognised expertise on the passage of the blood-brain barrier (BBB), that have already worked and published together. Using a transgenic AD mouse model (5xFAD) which displays cell loss and mnesic deficits, we will compare poorly invasive routes for cell delivery, namely intra-CSF and intra-blood transplantations. More specifically, our aims are to:
o assess the therapeutic benefit of an intravenous OE-MSC delivery
o unveil the cellular and molecular mechanisms involved in OE-MSC transmigration across the BBB and migration through the brain parenchyma.
o assess the role of amyloid beta peptides on the metabolism of OE-MSCs

Expected results
All techniques are in hand and no major technical drawback should be experienced. If our experiments are successful, we expect to:
o corroborate previous data on the beneficial repairing capacities of OE-MSCs and confirm that they can restore memory in an AD mouse model. We also wish to take a step forward in order to confirm that OE-MSCs can cross the BBB, home to lesioned areas and can be, in the future, transplanted in the blood;
o gain a better knowledge of the basic mechanisms underlying targeting of therapeutic cells to lesioned zones of the CNS;
o increase our knowledge on the molecular machinery used by OE-MSCs to cross the BBB and migrate through the brain parenchyma. We also anticipate to further disclose the signaling pathways involved in stem cell differentiation when in contact with amyloid beta peptides.
Since nasal OE-MSCs can be collected in every living individual, under local anaesthesia, and do not induce tumours, our work paves the way for clinical trials based on autologous transplantation, similarly to what we have done with another olfactory cell type in paraplegic patients.