Peptides›Cognitive›GDNF (Glial Cell Line-Derived Neurotrophic Factor)

GDNF (Glial Cell Line-Derived Neurotrophic Factor)

/ Endogenous neurotrophin (TGF-beta superfamily; RET receptor signalling); recombinant

TIER 2 · TranslationalN = 0 · TESTING PENDINGMW 30000.00 g·mol⁻¹

ALIAS · Glial cell line-derived neurotrophic factor · Recombinant human GDNF · Liatermin · rhGDNF

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Research use onlyAny dose figures below describe what specific cited studies used, reported factually. Nothing on this page is guidance for human use.READ FIRST →

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§ A · Identity

Primary sequence— sequence not captured —

MW · 30000.00CLASS · Endogenous neurotrophin (TGF-beta superfamily; RET receptor signalling); recombinantCATEGORY · Cognitive

Tier 2. Multiple Phase 2 trials in Parkinson disease via intraputamenal infusion (Gill 2003 open-label positive; Lang 2006 randomised negative; Whone 2019 intermittent convection-enhanced delivery mixed). No regulatory approval. The preclinical biology — selective trophic support for midbrain dopaminergic neurons — remains compelling but has not produced an approved therapeutic.

§ B · Mechanism of action

Glial cell line-derived neurotrophic factor (GDNF) is a distant member of the TGF-beta superfamily, structurally and mechanistically distinct from the classical neurotrophins (NGF, BDNF, NT-3, NT-4). The biologically active form is a disulfide-linked homodimer (~30 kDa). GDNF signals through a heteromeric receptor complex consisting of the GFR-alpha-1 co-receptor and the RET receptor tyrosine kinase, activating Ras-MAPK and PI3K-Akt pathways. GDNF was originally identified as a survival factor for midbrain dopaminergic neurons — the cell population lost in Parkinson disease — and this selectivity drove substantial clinical interest.

§ C · Human clinical evidence

Tier 2. The Bristol open-label Phase 1 trial of intraputamenal GDNF infusion in Parkinson disease (Gill and colleagues, Nature Medicine 2003) reported motor function improvement that generated substantial interest. The subsequent randomised, double-blind, vehicle-controlled Phase 2 trial (Lang and colleagues, Annals of Neurology 2006) did not replicate efficacy and was halted early. The intermittent convection-enhanced-delivery Phase 2 trial in 2019 (Whone and colleagues, Brain) reported imaging signal but did not meet its primary clinical endpoint.

§ D · Primary literature

PubMed12669033Gill SS et al. — Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease · Nature Medicine · human-phase-1Open-label intraputamenal GDNF infusion in five Parkinson disease participants was associated with motor function improvement on UPDRS over 12 months.Limitations: Open-label, no controls, very small n; selected population; subsequently not replicated in randomised design.2003

PubMed16429411Lang AE et al. — Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease · Annals of Neurology · human-phase-2Bilateral intraputamenal GDNF infusion did not improve UPDRS motor scores versus placebo at six months; trial halted early for futility and safety.Limitations: Modest sample size; delivery method debated post hoc; sponsor terminated program.2006

PubMed30808022Whone A et al. — Randomized trial of intermittent intraputamenal glial cell line-derived neurotrophic factor in Parkinson's disease · Brain · human-phase-2Intermittent convection-enhanced intraputamenal GDNF over 40 weeks did not improve the primary clinical endpoint versus placebo, although 18F-DOPA PET imaging showed signal differences.Limitations: Phase 2; primary clinical endpoint negative; imaging signal interpretation contested.2019

§ F · Safety signal

Intraputamenal GDNF infusion has produced delivery-site complications including catheter-related events. Anti-GDNF antibody development was reported in some recipients. Cerebellar lesions observed in non-human primate toxicology with high systemic doses contributed to historical safety concerns; intraputamenal local delivery has not produced an analogous human signal in published reports.

§ H · Regulatory status

Regulatory status

FDA status:: Not FDA-approved

§ I · Notable gaps and controversies

The discrepancy between Gill 2003 (open-label, positive) and Lang 2006 (randomised, negative) is one of the field's most-cited cautionary lessons about open-label neurosurgical trials. Convection-enhanced delivery methodology has continued to develop, but no GDNF program has yet produced a positive pivotal trial. Vendor research-grade GDNF protein is preclinical-only and is not equivalent to clinical-grade material used in trials.