GDNF: the growth-factor idea, from infusions to gene therapy

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

Early work by Steven Gill (Frenchay Hospital, Bristol), Clive Svendsen and colleagues; Anthony Lang's multicentre team; Alan Whone's single-centre trial; now AskBio, a Bayer subsidiary. The Phase 1b paper's authors are A. D. Van Laar, K. S. Bankiewicz and colleagues, with AskBio as the listed affiliation; the ClinicalTrials.gov sponsor is Brain Neurotherapy Bio and the paper's copyright is AskBio's. Funders of the early trials were not checked.

What happened

• 1993. GDNF (glial cell line-derived neurotrophic factor) was purified and shown to keep midbrain dopamine neurons alive in culture (Lin et al., Science 260:1130–1132, then at Synergen).
• 2003. Five patients received GDNF by pump into the putamen in a Phase 1 safety trial. After one year there were no serious side effects, the off-medication motor score had improved 39% and daily-living score 61%; PET dopamine storage in the putamen rose 28% after 18 months (Gill et al., Nature Medicine 9:589–595). It was not blinded.
• 2006 and 2019. Two placebo-controlled trials (34 and 35 people) found no clinical benefit, though PET uptake rose (landmark 146). I confirmed the 2006 one: 34 patients, off-motor score -10.0% against -4.5% on placebo (p = 0.53), and 32.5% more PET dopamine uptake (Lang et al., Ann Neurol 2006).
• AB-1005 (AAV2-GDNF). A harmless virus carries the GDNF gene into the putamen in one surgery, the same delivery approach as landmark 112. In the Phase 1b (NCT04167540, 11 people with mild or moderate disease, single-arm and open-label; registry start April 2020, estimated completion June 2027), all had expected surgery-related adverse events; six serious events in three people were judged unrelated to the gene therapy. At 18 months the mild group was stable and the moderate group's off-medication motor score (MDS-UPDRS Part III) fell by 20.4 points on average, without a control group (Van Laar et al., Movement Disorders 2025). The FDA gave it RMAT (a fast-track designation for cell and gene therapies) on 19 February 2025. The sham-controlled Phase 2 is in landmark 160.

Why it moved us toward a cure

GDNF had been discovered as a potent survival factor for dopamine neurons (landmark 213). It is the main attempt to rescue the surviving neurons rather than replace the lost ones, and would pair with cell grafts (what could unlock a cure).

Outcome

Open. No efficacy result for AB-1005 exists. The infusion trials (dead ends) are the warning: better scans did not mean better patients.

Sources

• Lin et al., Science, 21 May 1993 · Gill et al., Nat Med 2003, DOI 10.1038/nm850 · BioWorld report, Apr 2003
• Van Laar et al., Mov Disord 2025;40:1297–1306, DOI 10.1002/mds.30193, PMID 40395017 · sponsor release, 27 May 2025 · RMAT, CGTLive · NCT04167540
• Lin et al., Science 1993;260:1130–1132, DOI 10.1126/science.8493557, PMID 8493557 · Lang et al., Ann Neurol 2006;59:459–466, DOI 10.1002/ana.20737, PMID 16429411
• REGENERATE-PD sources are in landmark 160; the 2006 and 2019 trial sources in landmark 146.
• Not yet verified: the Phase 1b paper's full text (abstract read); the 2019 trial numbers (see landmark 146); funders of the 2003 and 2006 studies; the Bayer acquisition terms.