TABLE 1.

Neurotrophic factors (NTFs) used in PD patients.

NTF	Characterization
Nerve growth factor (NGF)	The first NTF discovered (Levi-Montalcini and Hamburger, 1951). NGF was tested in one PD patient as a supporting tool for adrenal chromaffin tissue grafts (Olson et al., 1991).
Glial cell line-derived neurotrophic factor (GDNF)	Most studied NTF in PD. GDNF was discovered by Lin et al. (1993). In 1994 the first in vivo study with GDNF demonstrated that intranigrally injected GDNF improved apomorphine-induced rotational behavior in 6-hydroxydopamine (6-OHDA)-injected rats (Hoffer et al., 1994). Six clinical trials were conducted with GDNF (Gill et al., 2003; Nutt et al., 2003; Slevin et al., 2005; Lang et al., 2006; Heiss et al., 2019; Whone et al., 2019). In these trials, GDNF was injected into the brain in the form of protein or in the form of gene therapy with viral vector.
Neurturin (NRTN)	NRTN demonstrated neurorestorative properties in the nigrostriatal neurons in animal models of PD (Kotzbauer et al., 1996). Intraputaminal adeno-associated type-2 viral vector (AAV2)–delivered gene of NRTN was not superior to sham surgery when assessed using the UPDRS motor scores in clinical trials (Marks et al., 2008; Warren Olanow et al., 2015).
Platelet-derived growth factor BB (PDGF-BB)	PDGF-BB demonstrated neurorestorative properties in the nigrostriatal neurons in animal models of PD (Zachrisson et al., 2011). No change in clinical rating scores in placebo-controlled clinical trial with PD patients (Paul et al., 2015).
Cerebral dopamine neurotrophic factor (CDNF)	CDNF was discovered in 2007 and demonstrated neurorestorative properties in the nigrostriatal neurons in animal models (Lindholm et al., 2007). CDNF achieved its primary endpoint of safety and tolerability in a recent phase I-II clinical trial (Herantis Pharma, 2020; ClinicalTrials.gov: NCT03295786, NCT03775538).