Table 5.

NHP trials and clinical trials utilizing NRTN

Author	Method	Subjects	Results	Reference
Kordower et al. (2006)	Unilateral infusion of AAV2-NRTN into the striatum, caudate nucleus and SN, 4 days after MTPT lesion.	Unilaterally MPTP-treated macaques (n = 20).	Therapy well tolerated. 88% reduction in CRS score. Antero- and retrograde transport of vector found. Preservation of nigral neurons and striatal terminals after 10 months.	[91]
Herzog et al. (2007)	Unilateral injection of AAV2-NRTN into the caudate nucleus and putamen.	Macaques aged >20 years (n = 3).	Well tolerated therapy at 8 months. ∼20% Increased striatal metabolism. Increased number of TH+ cells in striatum.	[92]
Herzog et al. (2008)	Bilateral injection of AAV2-NRTN in the caudate nucleus and putamen in high, medium and low dose.	Naive cynomolgus monkeys (n = 12).	No observed adverse effects. 60–65% increase in striatal TH+ density. No difference between high and medium titer. No increase in nigral TH+ at 3 months.	[83]
Marks et al. (2008)	Open label study. Bilateral intraputaminal injections of either high or low dose AAV2-NRTN.	PD-patients in Hoehn-Yahr stage 3-4 aged between 35–70 years.	No serious adverse events at 1 year. 36% improvement of UPDRS OFF-state motor scores. No change in striatal 18F-L-DOPA uptake from baseline.	[93]
Marks et al. (2010)	Double blind sham-surgery controlled randomized trial. Bilateral putaminal injection of AAV2-NRTN.	PD-patients aged 35–75 years scoring >30 in the motor part of UPDRS in OFF-state averaging at 3.03 in Hoehn Yahr scale (n = 58).	Vector not superior to sham surgery at 12 months. 6 subjects developed antibodies against vector. Several secondary endpoints met. Subpopulation with improved motor score at 18-months.	[9]
Bartus et al. (2013)	Open label study. Bilateral injection of AAV2-NRTN to SN, and either low- or high dose injection in putamen.	PD-patients in Hoehn-Yahr stage 3-4 aged between 35–70 years (n = 12).	No serious adverse events at 2-year follow-up. Approximately 5-point decrease in UPDRS-motor-score in OFF-periods. No change in ADL.	[85]
Warren Olanow et al. (2015)	Randomized double blinded sham-surgery controlled study. Bilateral injection of AAV2-NRTN into SN and putamen.	PD-patients in Hoehn-Yahr stage 3-4 aged between 35–70 years (n = 51).	Therapy did not prove superior to sham surgery in improving motor score at 15-24-month follow-up. Therapy well tolerated.	[84]

Clinical and preclinical studies with NRTN-gene therapy. UPDRS, United Parkinson Disease Rating Scale; ADL, Activities of daily living.