Patient-derived human cellular models to study neurodevelopmental disorders and to design novel therapeutic approaches
Patient-derived human cellular models to study neurodevelopmental disorders and to design novel therapeutic approaches
Research group: Riccardo Brambilla, Ilaria Maria Morella
The primary objective of my laboratory is to translate our understanding of the molecular and cellular mechanisms that govern cognitive function into effective therapies for neurodevelopmental disorders (NDDs). Recently, we designed and validated several cell-penetrating peptides (CPPs), able to pass the blood brain barrier and disrupt protein-protein interactions. These CPPs are not only powerful tools for studying the molecular mechanisms underlying cognitive deficits, but also hold promise for the development of innovative therapies.
Our current research focusses on copy number variants (CNVs), including both deletions and duplications, at 16p11.2the chromosomal region. These rare and currently incurable genetic conditions are associated with syndromic forms of NDD, with symptoms in different domains, from intellectual disability, autism, attention deficit hyperactivity disorder (ADHD), mood and anxiety disorders, as well as epilepsy. Additionally, the 16p11.2 duplication is linked to prominent traits of psychosis/schizophrenia and bipolar disorder.
The 16p11.2 locus encompasses 27 genes, including MAPK3, which encodes ERK1, a protein with crucial roles in cognition and behavioural plasticity. We recently demonstrated that ERK pathway may be a valid therapeutic target for the 16p11.2 deletion syndrome. CPPs targeting this signalling pathway can indeed rescue the behavioural deficits and correct alterations in cortical development in a mouse model of 16p11.2 deletion syndrome.
Beyond mouse models, we recently established induced pluripotent stem cells (iPSC) which are derived from human carriers and differentiated into various neuronal types. This powerful approach enables us to study disease mechanisms and potential therapies within a human cellular context. Within the recently established Interdepartmental Neuro Stem Cell Facility (INSF), we will also develop novel cellular models of NDDs using genome editing technologies.
Recent Publications:
- Leone R, Zuglian C, Brambilla R, Morella I. Understanding copy number variations through their genes: a molecular view on 16p11.2 deletion and duplication syndromes. Front Pharmacol. 2024 Jun 14;15:1407865. doi: 10.3389/fphar.2024.1407865.
- Indrigo M, Morella I, Orellana D, d’Isa R, Papale A, Parra R, Gurgone A, Lecca D, Cavaccini A, Tigaret CM, Cagnotto A, Jones K, Brooks S, Ratto GM, Allen ND, Lelos MJ, Middei S, Giustetto M, Carta AR, Tonini R, Salmona M, Hall J, Thomas K, Brambilla R, Fasano S. Nuclear ERK1/2 signaling potentiation enhances neuroprotection and cognition via Importinα1/KPNA2. EMBO Mol Med. 2023 Nov 8;15(11):e15984. doi: 10.15252/emmm.202215984. Epub 2023 Oct 4.
- Pucilowska J, Vithayathil J, Pagani M, Kelly C, Karlo JC, Robol C, Morella I, Gozzi A, Brambilla R, Landreth GE. Pharmacological Inhibition of ERK Signaling Rescues Pathophysiology and Behavioral Phenotype Associated with 16p11.2 Chromosomal Deletion in Mice. J Neurosci. 2018 Jul 25;38(30):6640-6652. doi: 10.1523/JNEUROSCI.0515-17.2018. Epub 2018 Jun 22.