Landmark 250 · Lab study (cells or animals)
RET agonists: small-molecule GDNF mimics
In short
Helsinki groups found drug-like molecules (BT13, BT44) that switch on RET, GDNF's receptor, and helped dopamine neurons in dishes and rats; no human trial has been found.
- What it is
- Lab study (cells or animals)
- Outcome
- Still being studied
- When
- 2017–2021
- Approach
- Replace or repair what's lost
- Research lane
- Growth factors
- Last checked
- 20 Oct 2026
The research record
This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".
Who
Mart Saarma, Yulia Sidorova, Arun Mahato and colleagues, University of Helsinki, with Raimo Tuominen's group (animal work) and Mati Karelson. Key papers: Sidorova et al., Front Pharmacol 2017 (BT13, pain); Mahato et al., Mov Disord 2020 (BT13, dopamine neurons); Renko et al., J Parkinsons Dis 2021 (BT44). Funders named: EU FP7 grants, the Lundbeck Foundation, Sigrid Jusélius Foundation, Parkinson's UK (Innovation Grant K-1408), the Academy of Finland and Tekes. Gene Code Ltd also funded the work and owns the patents on the BT compounds, on which Karelson and Saarma are inventors (declared in the 2021 paper).
What happened
GDNF (landmark 213) is a large protein that must be infused into the brain through surgery, and infusion trials improved scans but not patients (landmark 146). RET is the receptor GDNF uses to signal.
- 2017. BT13 was found by screening 18,400 drug-like compounds. It acts on RET, spurred neurite growth in sensory neurons and eased nerve-injury pain in rats. This paper was not about Parkinson's.
- 2020. BT13 activated RET and its downstream signals (ERK and AKT). It supported cultured dopamine neurons and protected them from the toxins 6-OHDA and MPP+ only when RET was present. It entered the mouse brain and raised striatal dopamine release. (Mov Disord 35:245–255; online December 2019.)
- 2020, chapter. In a rat 6-OHDA model BT13 eased motor imbalance, though the GDNF protein used as positive control did not clearly protect the dopamine system either (Renko et al., PMID 33479704).
- 2021. A second-generation molecule, BT44, protected cultured dopamine neurons from MPP+ and reduced motor imbalance in 6-OHDA rats, and appeared to protect dopamine fibres. In 2023 a Würzburg group made an injectable nanoformulation of BT44 that reached the mouse brain better and showed no acute toxicity (Haider et al., Biomacromolecules).
Why it moved us toward a cure
GDNF's main obstacle in people is delivery. A small molecule that crosses the blood-brain barrier could be taken by mouth or injection. This sidesteps the surgical limits seen in landmark 146. It only helps if the original GDNF idea (landmark 213) works in people, which is not yet shown.
Outcome
Open and preclinical. All evidence is in cells, mice and rats. No clinical trial of a RET agonist for Parkinson's was found on ClinicalTrials.gov or in a Europe PMC search for 2022–26, and the same GDNF doubt (scans improved, patients did not) applies. No correction or retraction was found.
Sources
- Mahato et al., Mov Disord 2020, DOI 10.1002/mds.27943, PMID 31840869 (open full text, PMC7496767)
- Sidorova et al., Front Pharmacol 2017, DOI 10.3389/fphar.2017.00365
- Renko et al., J Parkinsons Dis 2021, DOI 10.3233/JPD-202400, PMID 34024778 (open full text, PMC8461720)
- Renko et al., chapter, 2020, PMID 33479704
- Haider et al., Biomacromolecules 2023, DOI 10.1021/acs.biomac.2c00761 (abstract via Europe PMC)
- Not yet verified: doses and group sizes; the title of the book series for the 2020 chapter; any unpublished clinical development by Gene Code Ltd.
How it connects
Built on
- builds on GDNF discovered · 1993
- responds to GDNF infusion trials (Amgen, Bristol) · 2006
Led to
None recorded.