Custom-made neuron for cell therapy in Parkinson’s and Huntington’s disease
ERC Synergy Grant 2024 | European Research Council
Elena Cattaneo, professor of Pharmacology at the University of Milan,
Annalisa Buffo, Rita Levi-Montalcini Department of Neuroscience and NICO
Malin Parmar, Lund University, Sweden
Jenny Emnéus, Technical University of Denmark
The project aims to create and customise a portfolio of stem cell products for individual patients or groups of patients, particularly to treat Parkinson’s and Huntington’s disease.
The rising incidence of age-associated neurodegenerative diseases, due to increased life expectancy, poses a challenge to the brain’s limited regenerative capabilities. Stem cell-based therapies offer promise for addressing crucial neuron loss, particularly in Parkinson’s and Huntington’s diseases (PD and HD). Ongoing first-generation stem cell trials, replacing damaged neurons with healthy ones, represent a notable advancement. However, their impact is constrained by a ‘one-cell-fits-all’ generic therapy that does not take in account the diverse clinical needs due to variations in disease etiology, stage, patient heterogeneity, and daily fluctuations in graft requirements.
CUSTOM-MADE is a transformative initiative advancing knowledge and crafting a tailored portfolio of stem cell products for individual patients or patient subgroups, notably targeting PD and HD. Integrating stem cell technologies, genomics and bioengineering, CUSTOM-MADE develops rational graft composites of therapeutic neurons and complementary cells to meet the clinical needs of individual patients. Moving into preclinical animal models, the project refines graft connectivity and functional recovery post-transplantation. A groundbreaking leap involves modeling circuitry reconstruction in a fully humanized 3D in-vitro bioengineered system – the connectoids, allowing detailed studies at cellular and molecular levels for defining factors controlling correct and functional graft integration. For increased translatability, CUSTOM-MADE pioneers the generation of cell products whose activity can be self-regulated or tuned to the patients’ individual requirements. The project implements strategic measures to shield grafts from pathology and introduces the innovative concept of grafted cells exhibiting disease-modifying activity. In essence, CUSTOM-MADE drives the field toward customized stem-cell therapies for PD and HD, marking a paradigm shift in the treatment landscape of neurodegenerative diseases.
UNFOLD: A fully humanised integrated cellular system for scalable modeling of inflammatory demyelination
2024 – 2025 | Progetto Partenariato Esteso “MNESYS”, Spoke 3, Università Federico II, Napoli
Annalisa Buffo, PI and Research Unit coordinator
Here we aim to generate a fully human (i.e. derived from induced pluripotent stem cells – iPSCs), integrated (i.e. including oligodendroglia and neurons amenable for myelination along with astrocytes and microglia), scalable and standardized 2D cellular system to model inflammatory demyelination and provide a cellular platform for drug screening. The project includes a first phase of model set-up in rodent cultures, followed by the implementation of inflammatory demyelination in the human integrated system.
INITIATE: creation of a fetal tissue bank for the study of nervous tissue
2024 – 2026 | CRT Foundation
Annalisa Buffo, PI and Research Unit coordinator
The goal of this project is to expand the Davide Schiffer Biobank, recently inaugurated at the Department of Neuroscience at the University of Turin and previously dedicated to collecting samples from patients with neurodegenerative diseases, with the collection of fetal samples of healthy and diseased human nervous tissue.
Role of interleukin 6 in the pathogenesis of Rett syndrome: focus on astrocyte-neuron crosstalk and its therapeutic implication
2023 – 2025 | PRIN-PNRR 2022 MUR Ministry of University and Research
PI: Angelisa Frasca, University of Milan; co-PI: Enrica Boda
Rett syndrome (RTT) is a severe neurodevelopmental disorder, representing the first cause of intellectual disability in girls worldwide. The limited knowledge of RTT pathogenesis represents an obstacle for the development of rationale-based experimental therapies. Although initial studies supported the exclusive involvement of neurons, recent data indicated that astrocytes contribute to RTT pathogenesis through non-cell autonomous mechanisms. As synaptic defects represent a hallmark of RTT, in this project, we will investigate the mechanisms underlying the negative effect exerted by RTT astrocytes on the formation and maintenance of neuronal synapses. To this aim, we will exploit astrocytes and cortical neurons generated from human induced pluripotent stem cells (iPSCs) obtained from RTT patients
Targeting glial cell dysfunctions to treat cognitive defects and epilepsy in primary autosomal recessive microcephaly-17 (MCPH17) models
2023 – 2025 | PRIN – MUR Ministry of University and Research
Enrica Boda, PI
In this project, we propose a combination of experimental and pharmacological approaches aimed at correcting the dysfunctions of microglial cells, in order to support the maturation and function of nervous circuits in autosomal recessive primary microcephaly type 17 (MCPH17) models. The ultimate aim of the research is to propose a new therapeutic option – based on the targeting of glial cells and not of neurons – for patients with MCPH17. The project also involves the Research Unit of Dr. Eleonora Vannini at the Neuroscience Institute of the CNR in Pisa.
In vitro and in vivo molecular mapping of cell therapy for Huntington Disease at single-cell resolution
2023 – 2025 | PRIN – MUR Ministry of University and Research
Annalisa Buffo, PI
Huntington’s disease (HD) is a neurodegenerative disorder that compromises motor and cognitive functions as a consequence of the prominent loss of striatal Medium Spiny Neurons (MSNs). To restore the lost functions and ensure long-term therapeutic effect, newly transplanted neurons must fully qualify as MSNs and must establish appropriate functional connections after transplantation. In this project we aim to define the identity of the most therapeutic cells derived from human embryonic stem cells for effective cell replacement in HD. Towards this goal, in collaboration with prof. Elena Cattaneo (University of Milan), we will use advanced in vivo lineage tracing in combination with transcriptional profiling of the grafted neurons that integrate in the host brain and rewire lost circuits.
Targeting oligodendroglial cell dysfunctions to treat cognitive defects and epilepsy in primary autosomal recessive microcephaly-17 (MCPH17) models
2023 – 2025 | Telethon Foundation
Enrica Boda, PI
In this project we aim at targeting oligodendroglia and myelin dysfunctions in primary recessive autosomal microcephaly 17 (MCPH17) models, as an option to sustain neuronal/circuitries maturation and function, resulting in a beneficial effect on the functional outcome of MCPH17 models.
