Table 2.
Factors to consider in future clinical trials with GDNF and related factors in PD
| What form should the GDNF be given in? |
| •A gene therapy approach was favoured over protein infusions given the complexity of the neurosurgical intervention required for the former and the burden this places on the patients with Parkinson’s disease. |
| •Consider using mammalian cell produced GDNF and NRTN proteins. |
| Patient type |
| •Younger patients with marked L-dopa response and no major ventral striatal dopamine loss on dopamine imaging. |
| •Avoid certain genetic forms/variants associated with Parkinsonism (Parkin; GBA). |
| Disease stage |
| •Avoid late stage disease. |
| Dose given |
| •Depends on the neurotrophic factor that is being delivered, but probably need higher doses than have been trialed to date (with the exception of the first ICV trial of GDNF). |
| Volume given |
| •Depends on delivery system but need to give up to ∼1 ml per striatum treated. |
| Delivery device |
| •Several now in existence, e.g., Renishaw, Clearpoint system. |
| Need for adjunct therapies |
| •Not proven to be needed, although preclinical data suggests that Nurr 1 agonists may enhance the efficacy of GDNF—so perhaps this should be included as part of further trials. |
| Need for imaging? If so with what? |
| •F-dopa PET imaging seems to have provided useful information in trials to date, but need for other PET markers looking at DA turnover/release as well as network reconstruction. |
| Trial end points: What and when? |
| •Standard measures UPDRS part 2±PDCore scores at 18–24 month as the primary end point. |
| •Sample size currently undecided given lack of major effects seen to date which would allow one to power such a study. |
| Trial design |
| •Consider a delayed start design to the trial or a randomized double-blind placebo-controlled study. |
| •Keep the trial outcomes and measures simple. |
| •In postmortem samples, it is important to show that GDNF and NRTN have activated RET-dependent signalling pathways or to show direct RET receptor activation. |
| Health economics for this agent? |
| •Depends on where it is positioned |
| BUT although it works uniquely to restore the dopaminergic nigrostriatal, it will nevertheless have to compete with other “DA” therapies/interventions- new dopamine drugs; DuoDopa®; Deep Brain Stimulation etc and the newer dopaminergic gene or cell-based therapies should they be shown to work. |
| •Currently it would not be competitive given the size of effects seen to date, but this may relate to suboptimal delivery, etc. |