Neuropharmacology and Drug Targets Consortium (NDTC)

01.01.2022 -

Research group

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.

Funder(s)

Main funder

Academy of Finland

Neuropharmacology and Drug Targets Consortium (NDTC) funder logo Neuropharmacology and Drug Targets Consortium (NDTC) funder logo

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:

  1. The eye as a window to the CNS
  2. Novel therapies targeting on common mechanisms in neurodegenerative and retinal degenerative diseases
  3. Novel models and treatment concepts for neuropsychiatric disorders
  4. Multimodal brain pharmacology – better understanding of drug effects on brain functions

Keywords

Time period

01.01.2022 -

    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:

    1. Precisely layered structure
    2. Hierarchical function and ease to precisely detect function by electroretinography (ERG) – Minimally invasive and same method in animals and humans (which is fast!)
    3. Transparency of the eye enables noninvasive anatomical imaging (structural images within minutes)
    4. Ease to dissect out without contamination quickly in disease models (~ 1 min)
    5. Direct connection to the mid-brain via ganglion cell axons
    6. Highly amenable tissue for local therapies, as exemplified by clinical anti-VEGF treatments
    7. Success of preclinical gene therapy easy and quick to image

    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

    • 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.

     

    • Models
      • 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

    Multimodal brain pharmacology

    • 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

Group members - UEF

Other group members

  • M.Sc. Students: Konsta Rintala, Niklas Kämppi
    M.Sc. Students: Konsta Rintala, Niklas Kämppi

Collaboration with UEF research groups

Publications