Neuropharmacology and Drug Targets Consortium (NDTC)
NDTCs vision: Diseases of the CNS share common pathological mechanisms and increased understanding of neuroscience and pharmacology of neural system will lead to therapeutic options in diseases with incomplete or unmet medical need.
NDTCs mission: We decipher and unravel common pathways that can be novel targets for both disease-modifying and symptomatic treatments for psychiatric, neurological and sensory diseases with unmet medical need. We characterize the effects in our models by translational approach.
Academy of Finland
The Neuropharmacology and drug targets consortium (NDTC) is based on three PIs expertise and interest in drug target discovery and drug development for psychiatric and neurodegenerative diseases, including retinal degeneration. In its research, the consortium utilizes basic molecular biology and pharmacology tools, behavioral assays, electrophysiology and omics analyses such as proteomics and transcriptomics. The consortium collaborates closely with e.g. drug design, medicinal chemistry and pharmaceutical analytics teams.
The consortium currently focuses on four paradigms:
- The eye as a window to the CNS
- Novel therapies targeting on common mechanisms in neurodegenerative and retinal degenerative diseases
- Novel models and treatment concepts for neuropsychiatric disorders
- Multimodal brain pharmacology – better understanding of drug effects on brain functions
- Precisely layered structure
- Hierarchical function and ease to precisely detect function by electroretinography (ERG) – Minimally invasive and same method in animals and humans (which is fast!)
- Transparency of the eye enables noninvasive anatomical imaging (structural images within minutes)
- Ease to dissect out without contamination quickly in disease models (~ 1 min)
- Direct connection to the mid-brain via ganglion cell axons
- Highly amenable tissue for local therapies, as exemplified by clinical anti-VEGF treatments
- Success of preclinical gene therapy easy and quick to image
- Available treatments of neuropsychiatric disorders such as Parkinson’s disease and schizophrenia, have only limited symptomatic efficacy. Novel treatments are needed to improve patient’s activities of daily living and quality of life. In addition, disease-modifying treatments are urgently needed to decrease disease burden.
- Limited understanding of the mechanisms of these disorders is a major challenge in early drug development. In addition, difficulty to model these disorders, both at pathological and symptomatic level, significantly hinder the development of novel treatments.
- We aim to set up and validate novel models for neuropsychiatric disorders to facilitate assessment of potential treatments. We develop novel treatment concepts, such as disease-modifying treatments for neurodegeneration and treatments for cognitive deficits in schizophrenia.
- Parkinson’s disease – partial striatal 6-OHDA, COMT-KO
- Schizophrenia – NMDA antagonist models, COMT-KO
- JNCL, common pathways of neurodegeneration – CLN3, 6-OHDA
- Brain PK/PD – drug access into the brain
- Understanding of drug effects on complex brain functions in health and disease is limited. In target validation and drug discovery as well as in early drug development, more comprehensive approach is needed to speed up the process and decrease the risk of incorrect go/no-go decisions
- Recent developments in biomarkers and data analytics enable building more comprenensive and time-dependent picture of brain effects
- Microdialysis – sampling for measurement of extracellular biomarkers
- Tissue biomarkers
- Functional tests – fMRI, functional connectivity
- Behavioral measures
- Brain PK/PD – pharmacologically active drug levels in the brain
- Analytics – neurotransmitter analytics, LC-MS, immunohistochemistry, metabolomics, proteomics
The eye as a window to the CNS
The retina, a sensory tissue with brain-like characteristics, is the best-characterized neuronal system in the body.
In the fetal development, the eyes develop from diencephalon and can be thus considered as a part of central nervous system (CNS). This leads the retina of the eye and the brain to share similar cell types and neurotransmitter system. Like the cerebral and cerebellar cortices, the retina develops into a layered array of different neuronal types. Retinal ganglion cells (RGCs) are neuronal cells that are the output station of the retina. They form the optic nerve which directly contacts the eye to the midbrain. Canonical lesson from textbooks is that there are two important information flows within the retina: 1. a vertically oriented photoreceptoràbipolar cellàRGC pathway where visual signals are hierarchically relayed inwards to the retina, and 2. a horizontally oriented pathway where horizontal cells and RGCs interplay to form visual contours.
We use the retina as a model tissue for pharmacology and drug target discovery research for several reasons:
Notably, the first ever clinically approved gene therapy is for the treatment of a retinal degenerative disease.
Novel therapies targeting on common mechanisms in neurodegenerative and retinal degenerative diseases
Neurodegenerative and retinal degenerative diseases still lack the disease-modifying treatments, and our research focuses to multitarget various toxic mechanisms that are common among these diseases.
Neurodegenerative diseases, Alzheimer’s and Parkinson’s diseases as the most common ones, are devastating diseases for the patients since the neuronal degeneration progresses causing more severe symptoms. Retinal degenerative diseases are blinding eye diseases that share many pathological characteristics with the brain diseases. Current drug therapies cannot delay the progression of degeneration, and therefore there is a huge need for novel therapies that could modify the disease progression. Interestingly, several neuro and retinal degenerative disease share similar toxic mechanisms, such as protein aggregation, cellular stress etc. (see figure).
Our aims in this branch of research are:
1)To identify drug targets that can be used to multitarget on the common toxic at the time.
2)Work in collaboration with modelling team and medicinal chemists to develop novel compounds.
3)Test the compounds comprehensively in cellular and animal disease models.
4)Characterize the target in disease models and in patient samples.
We have a long history with the prolyl oligopeptidase (PREP) and PREP ligand development, and have shown that PREP ligands have multitargeting effect on toxic protein aggregation, degradation of protein aggregates and cellular stress. PREP ligands have shown disease-modifying effect in Parkinson’s disease models, and aim to continue to test them further in other models of neurodegenerative diseases. However, novel targets and disease paradigms are under investigation as well.
Novel models and treatment concepts for neuropsychiatric disorders
Multimodal brain pharmacology
Group members - UEF
Henri Leinonen Academy Research Fellow , Faculty of Health Sciences, School of Pharmacy
Timo Myöhänen Professor
Markus Forsberg Professor , Faculty of Health Sciences, School of Pharmacy
Timo Myöhänen Professor
Markus Forsberg Professor , Faculty of Health Sciences, School of Pharmacy
Aaro Jalkanen Senior Researcher , Faculty of Health Sciences, School of Pharmacy
Jouni Ihalainen Visiting Researcher , Faculty of Health Sciences, School of Pharmacy
Hengjing Cui Postdoctoral researcher
Katja Savolainen University Lecturer , Faculty of Health Sciences, School of Pharmacy
Ali Mohammed Project Researcher , Faculty of Health Sciences, School of Pharmacy
Umair Seemab Early Stage Researcher , Faculty of Health Sciences, School of Pharmacy
Katri Vainionpää Project Researcher , Faculty of Health Sciences, School of Pharmacy
Jaana Leskinen Laboratory Technician , Faculty of Health Sciences, School of Pharmacy
Sonja Holopainen Laboratory Assistant , Faculty of Health Sciences, School of Pharmacy
Markus Storvik University Lecturer , Faculty of Health Sciences, School of Pharmacy
Other group members
M.Sc. Students: Konsta Rintala, Niklas Kämppi
Collaboration with UEF research groups
2-Imidazole as a Substitute for the Electrophilic Group Gives Highly Potent Prolyl Oligopeptidase Inhibitors Pätsi, Henri T.; Kilpeläinen, Tommi P.; Auno, Samuli; Dillemuth, Pyry M. J.; Arja, Khaled; Lahtela-Kakkonen, Maija K.; Myöhänen, Timo T.; Wallén, Erik A. A.. 2021. 2-Imidazole as a Substitute for the Electrophilic Group Gives Highly Potent Prolyl Oligopeptidase Inhibitors Acs medicinal chemistry letters 12 10: 1578-1584. 2021
Prolyl oligopeptidase inhibition reduces alpha-synuclein aggregation in a cellular model of multiple system atrophy Cui, Hengjing; Kilpeläinen, Tommi; Zouzoula, Lydia; Auno, Samuli; Trontti, Kalevi; Kurvonen, Sampo; Norrbacka, Susanna; Hovatta, Iiris; Jensen, Poul Henning; Myöhänen, Timo T.. 2021. Prolyl oligopeptidase inhibition reduces alpha-synuclein aggregation in a cellular model of multiple system atrophy Journal of cellular and molecular medicine 25 20: 9634-9646. 2021
Prolyl oligopeptidase inhibition reduces oxidative stress via reducing NADPH oxidase activity by activating protein phosphatase 2A Eteläinen, T; Kulmala, V; Svarcbahs, R; Jäntti, M; Myohänen, T T. 2021. Prolyl oligopeptidase inhibition reduces oxidative stress via reducing NADPH oxidase activity by activating protein phosphatase 2A Free radical biology and medicine 169: 14-23. 2021
Restoration of visual function in adult mice with an inherited retinal disease via adenine base editing Suh, Susie; Choi, Elliot H; Leinonen, Henri; Foik, Andrzej T; Newby, Gregory A; Yeh, Wei-His; Dong, Zhiqian; Kiser, Philip D; Lyon, David C; Liu, David R; Palczewski, Krzysztof. 2021. Restoration of visual function in adult mice with an inherited retinal disease via adenine base editing Nature biomedical engineering 5 2: 169-178. 2021
Homeostatic plasticity in the retina is associated with maintenance of night vision during retinal degenerative disease Leinonen, Henri; Pham, Nguyen C; Boyd, Taylor; Santoso, Johanes; Palczewski, Krzysztof; Vinberg, Frans. 2020. Homeostatic plasticity in the retina is associated with maintenance of night vision during retinal degenerative disease eLife 9: e59422. 2020
A Mixture of U.S. Food and Drug Administration-Approved Monoaminergic Drugs Protects the Retina From Light Damage in Diverse Models of Night Blindness Leinonen H, Choi EH, Gardella A, Kefalov VJ, Palczewski K.. 2019. A Mixture of U.S. Food and Drug Administration-Approved Monoaminergic Drugs Protects the Retina From Light Damage in Diverse Models of Night Blindness Investigative ophthalmology and visual science 60 5: 1442-1453. 2019
Vision in laboratory rodents - Tools to measure it and implications for behavioral research Leinonen, H; Tanila, H. 2018. Vision in laboratory rodents - Tools to measure it and implications for behavioral research BEHAVIOURAL BRAIN RESEARCH 352: 172-182. 2018
Retinal Degeneration In A Mouse Model Of CLN5 Disease Is Associated With Compromised Autophagy Leinonen Henri, Keksa-Goldsteine Velta, Ragauskas Symantas, Kohlmann Philip, Signh Yajuvinder, Savchencko Ekaterina, Puranen Jooseppi, Malm Tarja, Kalesnykas Giedrius, Koistinaho Jari, Tanila Heikki, Kanninen Katja M. 2017. Retinal Degeneration In A Mouse Model Of CLN5 Disease Is Associated With Compromised Autophagy. Scientific Reports 7: 1597. 2017