My research has been concerned with reparative and neuroprotective mechanisms in the CNS using cell replacement and gene transfer techniques. My group was early in the study of neural tissue transplants, and in the 1970ies we pioneered the development of methods for cell transplantation to the mammalian brain and spinal cord. Our most important contributions during this dynamic period included studies on the survival, integration and functional connectivity of fetal neuroblasts grafted to the CNS of adult rats (1976–79), functional cell replacement in rodent models of Parkinson’s disease (1979-1983) and Huntington’s disease (1984-1986), and in animal models of hippocampal damage (1981-1984) and cognitive decline (1982-1986).
In the mid-1980ies we performed a series of preclinical experimental studies that provided the experimental and methodological basis for the first open-label clinical trials that were initiated at Lund University Hospital in 1987. The results obtained in the Lund PD transplantation program have provided proof-of-principle that human fetal midbrain dopamine neurons can survive and function for many years (more than a decade) after transplantation to the striatum in patients with advanced Parkinson´s disease (1990-2005). The Lund PD transplantation program has over the ensuing decades been one of the leading programs in the development of restorative therapies in Parkinson´s disease.
During this time we developed an interest in neurotrophic factors and their neuroprotective/restorative effects in the brain. In collaboration with colleagues in California, we were the first to demonstrate the neuroprotective effect of Nerve Growth Factor (NGF) in the lesioned septo-hippocampal cholinergic system (1987) and the ability of intracerebrally administered NGF protein, or cell-based NGF-delivery, to ameliorate cholinergic neuron atrophy and cognitive impairments in animal models of cognitive decline (1987-1998). Similarly, we have been one of the leading groups in the exploration of GDNF and its neuroprotective and regenerative properties in the nigro-striatal dopamine system (1995-2004) and in the forefront of research aimed at developing recombinant AAV and lentiviral vectors for neuroprotective and restorative therapy in patients with Parkinson´s disease (2000 and onwards).
In parallel, we have over the last few years developed an interest in the mechanisms underlying L-DOPA-induced dyskinesia, and the role of dopamine released as a ”false transmitter” from serotonin terminals in the induction and triggering of this side effect of L-DOPA medication (2007 and onwards).
Current research in our group at the Wallenberg Neuroscience Center is developing along five lines:
(i) Generation of transplantable dopamine neuron precursors from embryonic and neural stem cells;
(ii) In vivo studies on cell replacement and functional recovery in animal models of Parkinson´s disease;
(iii) Use of recombinant AAV and lentiviral vectors for gene deletion and targeted delivery of putative therapeutic factors for neuroprotection and functional recovery in the brain;
(iv) Modeling of PD pathology in rodents based on vector-mediated overexpression of alpha-synuclein in the nigrostriatal system.
(v) Development of new treatments for L-DOPA induced dyskinesias based on pharmacological silencing of serotonin-mediated dopamine release.
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