Maximising prospects for successful clinical trials of stem cell therapy for neurodegenerative diseases such as Huntington's and Parkinson's is possible through solid cooperation between experimental and clinical researchers. The NEUROSTEMCELL ('European consortium for stem cell therapy for neurodegenerative disease') project is driving this effort, and positive results are already coming in. NEUROSTEMCELL is supported under the Health Theme of the EU's Seventh Framework Programme (FP7) to the tune of EUR 11.9 million.
Both Huntington's and Parkinson's diseases are triggered by the degeneration of specific types of brain neurons: striatal neurons in Huntington's and dopaminergic neurons in Parkinson's. Led by Professor Elena Cattaneo at the Università degli Studi di Milano in Italy, the NEUROSTEMCELL consortium comprises 13 research institutions and 3 small and medium-sized enterprises (SMEs) from 6 EU Member States as well as the United States. Developing safe and validated cells and clinical grade reagents (specifically for dopaminergic and striatal neurons that may be transplanted into patients) to be used in clinical trials and eventually also in drug discovery is the ultimate objective. Their work is proving fruitful for the team and for Europe as well.
In their latest development, the NEUROSTEMCELL team devised a novel strategy for the efficient transformation of human pluripotent stem cells (PSCs) into dopamine-producing neurons. These neurons can be implanted into animals where they show 'robust performance' by establishing new connections and achieving long-term survival. The outcome is advancement in the use of PSCs, helping develop new therapies for neurodegenerative diseases.
The project partners say the regulatory, ethical and societal issues linked to the use of stem cells for therapy are being considered as science advances from bench to bedside. The team notes how Huntington's and Parkinson's are ideal candidate diseases for restorative stem-cell–based therapies. The pathology of both diseases progresses slowly; it is characterised by the preferential loss of one type of neuron, the GABAergic medium-sized spiny neurons in Huntington's and the mesencephalic dopamine (mesDA) neurons in Parkinson's. The cell replacement strategy targets the substitution of the lost GABA and mesDA neurons by implanting new functional cells.
The NEUROSTEMCELL project is targeting the identification and systematic comparison of progenitor cell lines with the most favourable characteristics for mesDA and striatal GABAergic neuronal differentiation. These cell lines are derived either from human embryonic stem (ES) cells, from neural stem (NS) cells derived from ES cells or foetal brain, from induced pluripotent stem (iPS) cells or from in vitro short-term expanded neural progenitors from ventral midbrain grown as neurospheres (VMN, ventral midbrain neurospheres). The project team is performing rigorous and systematic testing of the most prominent candidate cells in appropriate animals models.
The partners are identifying procedures and safety systems that will enable full elimination of proliferative and/or tumour-forming cells from the graft cell preparations. They are also applying in vivo imaging tools for non-invasive monitoring of the survival and growth of the grafted cells, and they are developing criteria, procedures and protocols for reproducible, safe and large-scale manufacture of stem cells and their progeny to clinical-grade standard. The team is also establishing a banked stock of validated, safety-qualified and traceable cells for clinical use, as well as developing clinical protocols for use in phase-I trials in patients with Huntington's and Parkinson's.
Ethical and safety criteria are being established for guiding implementation of stem cell therapies in the clinic, and the team is also developing an interface with bio-industry and a product-specific regulatory strategy that is compatible with a future marketing authorisation. And finally, the NEUROSTEMCELL partners are providing information to both patient groups and laypersons about advances in the field, and about what steps will be taken to ensure success.
NEUROSTEMCELL partner Lorenz Studer of the Sloan-Kettering Institute for Cancer Research Corporation in the United States notes that while the results are encouraging, more work is needed.
'We are now gearing up to produce dopaminergic cells under conditions that would be suitable for clinical use,' Dr Studer says. 'The process involves careful adaptations in cell manufacturing, scale-up and safety testing. We expect completion of those studies within the next three to four years, the minimum time frame required for initiating studies potentially in human patients. We are very fortunate to be the only non-EU member of NEUROSTEMCELL ... My lab has greatly benefited from the collaborative and interactive environment, and the shared mission helped in driving the project forward.'
The NEUROSTEMCELL consortium comprises experts from Denmark, France, Germany, Italy, Sweden, the United Kingdom and the United States.