On the 19th and 20th November 2020, the annual NECTAR conference took place, bringing together people from all over the world to discuss the latest in the field of CNS disorders and novel treatment strategies, from pioneers in their respective fields, to students just starting their careers. The conference was held, for the first time, as an online webinar conference, due to the ongoing COVID-19 pandemic. The conference comprised of talks from expert speakers who have paved the way for both cell and gene therapies and a number of DataBlitz sessions, which gave the opportunity for students and post-docs to present their data and receive valuable feedback from a large, diverse audience. At the end of the first day, there was the opportunity to attend one of a number of breakout sessions, led by experts in the respective fields, which ranged from cell therapies in Parkinson’s disease to treatment strategies for Huntington’s disease. Notably, these sessions offered the opportunity for the audience to engage and learn from experts and encouraged invaluable discussion between Neurologists and basic scientists.
The conference kicked off with a talk from Professor Jun Takahashi, who delivered a fascinating overview of the recent CiRA trial, whose aim is to assess the safety and efficacy of iPSC-derived dopamine cells as a clinical option for HLA-matched Parkinson’s patients. This included extensive investigation into the safety and efficacy of this potential therapy using cellular and animal models. Professor Takahashi informed us that 4 patients have been grafted with iPSC-derived dopamine cells, to date, with a view of grafting a further 3 patients by 2021. Participants will be assessed for improvements in their motor function for 2 years after grafting. Professor Takahashi finished his talk, reminding the audience “Regenerative medicine is a comprehensive art”, prompting discussion into how cell therapies may be used in conjunction with other gene, rehabilitation or pharmacotherapies in the future.
As well as iPSC-based therapies, embryonic stem cell-derived (ESC) therapies are also of major interest in the field of cell therapies for Parkinson’s disease. Professor Lorenz Studer was the second speaker of the day and discussed the fascinating, ESC-based trial – NYSTEM-PD, which he assured, is due to start in the very near future. This exciting trial will explore the safety and efficacy of replacing lost dopamine cells in 10 moderate to severe Parkinson’s patients, with H9 embryonic stem cell-derived dopamine cells. Professor Studer also discussed the ATLas-PD trial, which is a longitudinal 3-year study, involving moderate to severe PD patients, with the aim of investigating the correlation between clinical biomarkers and disease progression. Alongside outlining the pipeline to clinical application, Professor Studer looked into the future and discussed the ultimate goal of an ‘off-the-shelf’ cell-therapy for Parkinson’s disease, and the bottlenecks that lie between clinical and commercial grade cell products.
While many planned and ongoing trials are focused on treating idiopathic Parkinson’s disease, some are aiming to treat specific, hereditary forms of the disorder. Dr Pablo Sardi delivered a very engaging talk about the most common genetic form of alpha synucleinopathy – GBA. The GBA gene encodes for the lysosomal hydrolase glucocerebrosidase (Gcase), mutations in which lead to dysfunction and the pathogenic accumulation of lipids such as glucosylceramide. This mutation has also been implicated in the onset and progression of Parkinson’s disease. Dr Sardi gave an elegant overview of ongoing AAV (adeno-associated virus) and small molecule therapies, such as Ambroxol, an activator of Gcase and Venglustat an inhibitor of glucosylceramide synthase for the treatment of GBA-PD. He finished by explaining the potential for such therapies to be broadened to treat both genetic and idiopathic forms of Parkinson’s disease. The final talk of the day came from Professor Krystof Bankiewicz. Professor Bankiewicz discussed the use of the AAV-AADC viral vector, as a method of restoring aromatic L-amino acid decarboxylase (AADC). AADC has a role in the production of both serotonin and dopamine. He started by discussing a Phase I/II clinical trial investigating AAV-AADC as a means of treatment for AADC deficiency – a rare paediatric neurodevelopmental disorder, which manifests as a number of motor and non-motor symptoms. One of the most moving moments of the day came when Bankiewicz showed pre and post-operative videos of AAV-AADC treated children and the vast improvements in both their motor and non-motor function, from 5 weeks to 2 years post-operative. Professor Bankiewicz ended by discussing the progress made using a similar approach in Parkinson’s patients and interestingly highlighted the difference in efficacy and the difficulties that come with treating a more elderly patient cohort. However, he was able to demonstrate that this approach could increase striatal dopamine levels, which correlated with improvements in motor function and a decrease in levodopa-equivalent dose in patients.
The second day started with a series of talks based on the recent advances in Parkinson’s disease and other neurodegenerative disease. The first of such talks was delivered by Professor Per Borghammer, who discussed his novel theory of ‘Brain and Body first Parkinson’s disease’. Professor Broghammer beautifully explained his theory that Parkinson’s disease can start primarily in the periphery of some patients and spread to the brain, while in others, pathology appears to originate in the amygdala and spread into the periphery at later stages. This fascinating talk was supported by a plethora of clinical data, correlating data from imaging studies with post-mortem data in order to support his theory. This talk was an excellent example of how imaging modalities are essential and wonderfully useful tools for understanding disease progression and pathology onset in man.
Following on from Professor Borghammers discussion was Professor Jorgen Kjems, who delivered an excellent discussion about the recent advances in the application of nanoscience for central nervous system diseases. Professor Kjems covered a range of topics, one of which included how multivalent tagging using nanoscaffolds can aid in allowing peptides to cross the bloodbrain-barrier, which has been a problem in the field for generations. Later in his talk, he also discussed how nanoscience technology and machine learning was being used to detect novel biomarkers for central nervous system disorders, from as little as a few microlitres of blood plasma. Another highlight of the talk was on circular RNAs and their identification and function in neuronal differentiation. In this way, Professor Kjems’ talk emphasised the synergy between both technological advancement and for the progression of science.
Kicking off the section on cell therapies for Huntington’s disease (HD) and other Central Nervous System (CNS) disorders was Professor Anne Rosser. Professor Rosser’s talk was about the next steps in cell therapies for HD where she provided solid foundations for understanding the challenges that the field of HD research currently faces, whilst highlighting new areas of ongoing research into cell therapies. Such studies and consortiums mentioned included Repair-HD which was a collaborative effort to take stem cell therapies into clinical application, TRIDENT, a trial focused on delivery of novel therapeutics and SC4HD (Stem Cells for HD) which is focused on developing a neural intra-cerebral stem cell-based therapy for HD reliant on the collaborative efforts of clinicians, scientists and patients alike. A clear message from Professor Rosser’s fantastic talk was the need for authenticity of stem cells and the scope there is for advancing cell therapies in HD.
As critical as neurons are in neurodegenerative disorders, the glial population must not be forgotten, the importance of which was emphasised in the talk by Professor Steven Goldman. His talk focused on the use of stem cell therapies for disorders of the white matter tract, whilst demonstrating how useful animal models still are in pre-clinical research. Professor Goldman showed some very exciting and promising results using stem cells in ameliorating some features of neurodegenerative disorders and ended by highlighting how HD could also be considered a glial therapeutic target.
In addition to the talks discussed above, we were treated to a number of DataBlitz 10 minute talks, which largely discussed novel methods of modelling PD and HD, with a specific emphasis on the use of 3D and organoid systems, as well as methods of improving differentiation capacity and graft efficacy for cell-replacement therapies. Also discussed were novel approaches to treating CNS disorders from neurotrophic approaches to rehabilitation with exercise.
Given the current climate we find ourselves in, the organisers did a brilliant job of putting together a selection of both topics and speakers that reached out to scientists and clinicians alike, making this a highly successful virtual event. The success of NECTAR 2020 only fuels anticipation for the next one!