Neurotrophic factor therapies utilize endogenous proteins that support neuron survival, function, and plasticity to treat neurodegenerative diseases. These growth factors represent a disease-modifying approach rather than just symptomatic treatment[1]. The neurotrophic factor family includes several key proteins that have been extensively studied for their neuroprotective properties, including brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), nerve growth factor (NGF), ciliary neurotrophic factor (CNTF), and insulin-like growth factor (IGF-1)[2].
The rationale for neurotrophic factor therapy stems from the observation that many neurodegenerative diseases are characterized by decreased levels of endogenous neurotrophins or impaired signaling through their receptors. For example, BDNF levels are reduced in Alzheimer's disease brains, and GDNF expression is altered in Parkinson's disease. Restoring or enhancing neurotrophic support represents a logical therapeutic strategy to slow or halt disease progression[3].
The neurotrophin family comprises four structurally related proteins that signal through the Trk family of receptor tyrosine kinases and the p75NTR pan-neurotrophin receptor:
Brain-Derived Neurotrophic Factor (BDNF)
Nerve Growth Factor (NGF)
Neurotrophin-3 (NT-3)
Neurotrophin-4/5 (NT-4)
The GDNF family of ligands (GFLs) signal through a distinct receptor complex:
Glial Cell Line-Derived Neurotrophic Factor (GDNF)
Neurturin (NRTN)
Artemin (ARTN)
Persephin (PSPN)
Neurotrophin binding to Trk receptors triggers multiple intracellular signaling cascades:
PI3K/Akt Pathway
MAPK/ERK Pathway
PLCγ Pathway
The p75NTR receptor can signal independently or in concert with Trk receptors:
GDNF family ligands signal through a unique mechanism:
Neurotrophic factors play critical roles in Alzheimer's disease pathogenesis and treatment:
BDNF in AD
NGF in AD
IGF-1 in AD
Neurotrophic factors are particularly relevant for dopaminergic neuron survival:
GDNF in PD
BDNF in PD
CNTF in PD
Motor neuron survival is the primary target:
CNTF in ALS
IGF-1 in ALS
BDNF in ALS
Neurotrophic factors address multiple HD pathology features:
BDNF in HD
CNTF in HD
| Agent | Company | Mechanism | Delivery | Stage | Indication |
|---|---|---|---|---|---|
| 7,8-DHF | Various | TrkB agonist | Oral | Preclinical | AD, PD |
| TrkB agonists | BMS-986020 | TrkB agonist | Oral | Phase 1 | AD |
| AAV-BDNF | Various | Gene therapy | Intraparenchymal | Preclinical | AD, PD |
| r-BDNF | Various | Recombinant protein | Intranasal | Phase 1 | AD |
| Agent | Company | Mechanism | Delivery | Stage | Indication |
|---|---|---|---|---|---|
| AAV-GDNF | Various | Gene therapy | Intraputaminal | Phase 1/2 | PD |
| AAV2-NTN | Ceregene | Gene therapy | Intraputaminal | Phase 2 | PD |
| GDNF protein | Various | Native protein | Intraputaminal | Phase 2 | PD |
| Agent | Company | Mechanism | Delivery | Stage | Indication |
|---|---|---|---|---|---|
| CERE-110 (AAV2-NGF) | Ceregene | Gene therapy | Intraparenchymal | Phase 2 | AD |
| NGF protein | Various | Native protein | Intranasal | Phase 1 | AD |
| LAD-I | Various | NGF modulator | Various | Preclinical | AD |
Recombinant Proteins
Formulation Strategies
AAV Vectors
Non-Viral Vectors
Intranasal Delivery
Focused Ultrasound
Cellular Delivery
The BBB remains the primary challenge for neurotrophic factor delivery:
Nagahara AH, Tuszynski MH. Potential therapeutic uses of neurotrophic factors in CNS disorders. Nat Rev Neurol. 2011;7(1):39-50. 2011. ↩︎
Hefti FF. Development of effective therapy for Alzheimer's disease based on neurotrophic factors. Neurochem Res. 2008;33(12):2435-2444. 2008. ↩︎
Holtman IR, Chao JR, Heurtin C, et al. Neurotrophic factors in neurodegenerative disease. Nat Rev Drug Discov. 2022;21(7):477-498. 2022. ↩︎
Peng S, Wuu J, Mufson EJ, Fahnestock M. Increased proBDNF and reduced mature BDNF in prefrontal cortex in Alzheimer's disease. J Alzheimers Dis. 2020;76(3):1045-1058. 2020. ↩︎
Nagahara AH, Merrill DA, Coppola G, et al. Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease. Nat Med. 2009;15(3):331-337. 2009. ↩︎
Tuszynski MH, Thal L, Pay M, et al. A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nat Med. 2005;11(5):551-555. 2005. ↩︎
Rafii MS, Tuszynski MH, Thomas RG, et al. Adeno-associated virus delivery of nerve growth factor for Alzheimer disease: A randomized clinical trial. JAMA Neurol. 2023;80(9):958-966. 2023. ↩︎
Gill SS, Patel NK, Hotton GR, et al. Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. Nat Med. 2003;9(5):589-595. 2003. ↩︎
Lang AE, Gill S, Patel N, et al. Randomized controlled trial of intraputamenal GDNF infusion in Parkinson disease. Arch Neurol. 2006;63(7):978-985. 2006. ↩︎
Zuccato C, Tartari M, Crotti A, et al. Huntingtin interacts with REST/NRSF to modulate the expression of genes. Nat Genet. 2010;42(3):245-254. 2010. ↩︎