This preclinical study aims to assess if small-molecule mimics of the nerve growth factors MANF and CDNF are neuroprotective and able to slow Parkinson’s progression.
About the study
Nerve growth factors, or neurotrophic factors, are proteins that support the growth and development of nerve cells (neurons). Several of these factors have shown a potential protective effect in Parkinson’s; however, an ongoing challenge with these therapies is that they currently require neurosurgery. This is because most neurotrophic factors are too large to pass through the blood-brain-barrier (BBB) – the protective layer of cells surrounding the brain which controls what leaves and enters the brain. Therefore, an area of research that is of interest for researchers is finding ways to overcome this challenge.
To address this, Professor Mart Saarma at the University of Helsinki is evaluating four small molecules that mimic the action of two nerve growth factors associated with dopamine neurons – cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF) – in models of Parkinson’s. Both CDNF and MANF belong to a family of neurotrophic factors which have a protective effect by preventing premature cell death.
Unlike CDNF and MANF, these small molecule mimics can pass through the BBB, meaning if the results indicate they are neuroprotective, they could be tested in a clinical trial without the need for surgery. The main objective of this study will be to test whether the mimics are neuroprotective and affect progression in models of Parkinson’s. The secondary objectives are to determine which of the compounds have the most potential, and what the optimal dosing for this is.
Trial overview
- Researcher: Professor Mart Saarma
- Institution: University of Helsinki
- Project Type: Preclinical
- Status: Ongoing
- Start Date: Jan 2025
- Therapy Target: Nerve growth factors
More about the study
What are MANF and CDNF?
Cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF) belong to a unique family of neurotrophic factors that promote cell survival by regulating endoplasmic reticulum (ER) stress. The ER is a part of the cell that performs a variety of functions, most notably in facilitating protein folding. Proteins are made up of long chains of molecules called amino acids, which must be folded a specific way in order to carry out its intended function. You can think of this like folding a paper airplane – it will only fly when built properly.
Both MANF and CDNF are mainly found within the ER are are associated with something called an unfolded protein response (source). This is activated when there is a build-up of misfolded proteins in the ER; once active, the cell increases production of folding chaperones (helpers) and increases degredation of misfolded proteins to reduce stress. If the cell cannot reduce this stress after some time, it will initiate a cell death pathway. MANF and CDNF help regulate the unfolded protein response, keeping its activity at a level that reduces the likelihood of triggering cell death while also allowing the repair and recycling processes to continue. This response is especially relevant in Parkinson’s due to the accumulation of mis-folded alpha-synuclein – a hallmark and driver of Parkinson’s progression.
What do we mean by “mimics”?
Here, “mimics” refers to small molecules that are synthetically (artificially) made to replicate the action or effect of a naturally-occuring protein. In this case, these molecules would be mimicking the action of MANF and CDNF. Stucturally, they are not identical, but their intended effect is.
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