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Full NameDr Eilis Dowd
Department:Pharmacology & Therapeutics
Organisation:National University of Ireland Galway
- cell and developmental biology/regenerative medicine
- neuroscience and mental health
Dr Eilís Dowd’s research is focused on developing and validating novel pharmacological, cell, gene and biomaterial therapies for Parkinson’s disease (PD). PD is a chronic and debilitating brain condition which affects millions of people worldwide. The main symptoms of the disease are related to loss of movement control caused by degeneration and death of the nigrostriatal population of dopaminergic neurons. One promising approach for the treatment of PD that is of particular interest to the Dowd group is cellular brain repair whereby the cells that have died in the condition are replaced by transplantation of healthy cells into the brain. However, this approach has faced several limitations including poor survival of the transplanted cells in the PD brain.
To address this limitation, the Dowd group has recently shown that biomaterials - that is, materials that have been specifically engineered to interact with living systems for therapeutic purposes – have the potential to dramatically improve cellular brain repair for PD. Specifically, when the brain cells were encapsulated in a biomaterial before transplantation into the (rat) PD brain, the survival of the cells was dramatically improved, and this enhanced healing and recovery of movement control. Indeed, this research was described by the BBC Science Focus Magazine as one of “five incredible advances in brain disease treatment”. Ongoing work in the Dowd group, funded by the EU and Michael J Fox Foundation, aims to continue and extend these previous findings.
Ultimately, if we can show that the biomaterials can improve the brain repair and movement control provided by transplanted cells. then future clinical trials of these cells should move towards including biomaterials in the transplantation approach as this could lead to a dramatic improvement in the outcome for patients.
This study will develop and assess a biomaterial-enhanced human induced pluripotent stem cell (iPSC)-derived dopaminergic cell replacement strategy for Parkinson’s disease (PD). We have recently demonstrated that dopaminergic cell replacement in the Parkinsonian rodent brain, using fetal-derived cells, is dramatically enhanced when the cells are transplanted in a neurotrophin-enriched, immune-shielding collagen hydrogel. The hydrogel provided the transplanted neurons with 1) a physical scaffold for cell-matrix adhesion, 2) a neurotrophin reservoir for sustained GDNF exposure after transplantation, and 3) shielding from the deleterious effects of the host microglial and astroglial innate immune response. Given that iPSC-derived dopaminergic cell replacement is accelerating towards the clinic, with the recent announcement of the first clinical trial in Japan, this study aims to determine if such benefits will also extend to human iPSC-derived dopaminergic neurons. To achieve this aim, human iPSCs will be differentiated into dopaminergic progenitors and transplanted into the (immunocompromised) Parkinsonian rat brain, plus/minus the biomaterial hydrogel, plus/minus neurotrophin and/or anti-inflammatory cytokine loading.
Outcomes to be assessed will be restoration of motor ability, dopaminergic neuron survival and engraftment, and host immune response. Shorter term studies will also be designed to investigate hydrogel polymerization, biodegradation, growth factor retention/release, and host immune response at earlier time points to investigate the mechanism of any beneficial effects seen. If this work demonstrates a substantial improvement in the outcome of iPSC-derived brain repair in rodent PD models, the clinical transplant field should move towards the incorporation of such biomaterials into future clinical trials using primary and/or iPSC derived neurons. Improving the safety and efficacy of such approaches, using this minimally invasive and injectable hydrogel that offers a neuroprotective and immune shielding microenvironment to the transplanted cells, could dramatically improve the reparative capacity of cell therapy for PD, and ultimately lead to an improved therapy for patients.