Table 2.
Summary of gene therapy clinical programs for Parkinson’s disease (Bartus et al., 2014).
| Treatment (approach) | Trial design | Year began | Subject # dosed | Highest total dose(vg) | Target(S) | Largest volume (μl)/site | Safety results | Efficacy outcomes |
|---|---|---|---|---|---|---|---|---|
| AAV2/GAD | Ph1-uncontrolleda | 2003 | 12 | 1 × 1012 | Subthal Nuc (unilat) | 50 | Acceptable | Advanced to Ph2 |
| Ph2-double-blindb | 2008 | 22/16* | 1 × 1012 | Subthal Kuc (Bilat) | 35 | Acceptable | Mixed results; program suspended | |
| AAV2/AADC | Ph1-uncontrolledc | 2004 | 10 | 0.3 × 1012 | Putamen (Bilat) | 50 | Acceptable | Program suspended; revised Ph1 recently announced |
| AAV2/AADC | Ph 1 -uncontrolledd | 2007 | 6 | 0.3 × 1012 | Putamen (Bilat) | 50 | Acceptable | No further testing; revised Ph1 recently announced by USA group |
| AAV2/ | Ph1-uncontrollede | 2005 | 12 | 0.54 × 1012 | Putamen (Bilat) | 5(10)** | Acceptable | Advanced to Ph2 |
| NRTN | Ph2A-double-blindf | 2006 | 38 | 0.54 × 1012 | Putamen (Bilat) | 5(10)** | Acceptable | Mixed results; revised Ph1 designed |
| Ph1-uncontrolledg | 2009 | 6 | 2.4 × 1012 | Put + SN (Bilat) | 50 | Acceptable | Advanced to Ph2 | |
| Ph2B-double-blindh | 2010 | 24 | 2.4 × 1012 | Put + SN (Bilat) | 50 | Acceptable | Program suspended | |
| LENTI/AADC- | Ph 1/2-uncontrolled# | 2008 | 15 | Lentivirus dosing is not comparable to that of AAV## | Putamen (Bilat) | Acceptable | Program suspended; additional work to optimize vector ongoing | |
| AAV2/GDNF | Ph1-uncontrolledk | 2013 | Ongoing | 0.7 × 1012 | Putamen (Bilat) | 150 | N/A | N/A |
| Synopsis | Total of seven phase 1 and three phase 2 trials | 2003–2013 | >139 | Tested up to 1 × 1012 vg AAV | Targets have included subthalamic nucleus, putamen and SN | 50 μl (most common); 150 μl (largest) | No safety issues or serious side effects noted | Efficacy outcomes generally disappointing |
AAV, adeno-associated virus; SN, substantia nigra. aKaplitt et al. (2007); bLeWitt et al. (2011); cChristine et al. (2009); dMuramatsu et al. (2010); eMarks et al. (2008); fMarks et al. (2010); gBartus (2013); hBartus et al. (2013); Palfi et al. (2014); and kLonser (2009). *Twenty-two subjects were dosed but six were eliminated from efficacy analysis due to mistargetirvg of cannula. **Two 5 μl volumes infused via single needle tract −4 mm apart. #Described as a Phase 1/2 trial, this open label (uncontrolled) study does not differ substantially from many dose-escalation Phase 1 safety studies that include secondary efficacy endpoints; thus, the distinction appears to be more a semantic preference than a reflection of a substantial difference in study design. ##A fivefold dose range was tested involving three dose levels (1.9 × 107 transducing units (TU); 4.0× 107 TU; 1.0× 108 TU).