Objective: To demonstrate the efficacy of a ready-to-graft 3D neural microtissue product – manufactured at large scale – as a therapeutically viable option to treat Parkinson’s disease.

Background: A breadth of preclinical studies is now supporting the rationale of pluripotent stem cell-derived cell replacement therapies to alleviate motor symptoms in Parkinsonian patients. Replacement of the primary dysfunctional cell population in the disease, i.e. the A9 dopaminergic neurons, is the major focus of these therapies. To achieve this, most therapeutical approaches involve grafting single-cell suspensions of dopaminergic progenitors. However, a considerable number of cells die during the transplantation process, as cells face anoïkis. One potential solution to address this challenge is to graft solid preparations, i.e. adopting a 3D format. Cryopreserving such format remains a major pharmaceutical hurdle and is not exempt from causing delays in the time to effect, as observed with the use of cryopreserved single-cell dopaminergic progenitors.

Method: We used a high-throughput cell-encapsulation technology coupled with standard bioreactors to provide a 3D culture environment that enables the directed differentiation of iPSCs into neural microtissues fit-for-cryopreservation. The product was characterized using orthogonal methods including flow cytometry, immunofluorescence labelling, RTqPCR and bulkRNAseq.  Controlled doses (low, high, maximum feasible dose [MFD]) of microtissues were administered into the striatum of 6-OHDA lesioned nude rats for functional assessment.

Results: We demonstrate a scalable process to generate off-the-shelf cryopreserved iPSC-derived 3D neural microtissues containing a mixture of ventral mesencephalic dopaminergic neurons and dopaminergic progenitors. Upon administration, the neural microtissues innervate the lesioned striatum of hemiparkinsonian rodents with TH+ dopaminergic projections and lead to motor recovery in a dose-dependent manner by 16 weeks (MFD and high dose) and 20 weeks (low dose) respectively.

Conclusion: These data demonstrate proof-of-concept efficacy of the dopaminergic neuron-containing neural microtissue product and support the intention to pursue preclinical studies to assess its safety and efficacy as a cell therapy for Parkinson’s disease.

References: This abstract or a similar version of it has been submitted to the American Academy of Neurology Annual Meeting, date of presentation: 15th April 2024; to the International Association of Parkinsonism and Related Disorders World Congress, date of presentation: 19-22 May 2024; to the International Society for Cell & Gene Therapy Annual Meeting, date of presentation: 28th May – 1st June 2024; and to the International Society for Stem Cell Research Annual Meeting, where abstract acceptance is pending.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/bioreactor-produced-ipscs-derived-dopaminergic-neuron-containing-neural-microtissues-innervate-and-restore-motor-function-in-a-dose-dependent-manner-in-a-parkinson-rat-model/