Challenges for gene therapy of CNS disorders and implications for Parkinson's disease therapies.

The CNS poses significant challenges for effective gene therapy, including the presence of the blood–brain barrier, which prevents the entry of large molecules. Adenoassociated viral (AAV) vectors have been developed that demonstrate efficient and stable transgene expression in the CNS and are the most advanced vector class in clinical application, but limitations still manifest. One of them is the difficulty to achieve extensive transduction volumes. Bearing this in mind, anti-parkinsonian therapies with relatively restricted targets are particularly suited for initial clinical attempts. In this issue of Human Gene Therapy a long-term follow-up of one such AAV Parkinson’s disease (PD) clinical trial is presented (Mittermeyer et al., 2012, this issue). Several important implications of this work are discussed, including the need for more widespread transduction to achieve a clinical benefit. Results obtained with AAV9 demonstrating blood–brain barrier crossing and extensive CNS transduction have raised hopes for noninvasive delivery of viral vectors to wide CNS targets. A second study in this issue of Human Gene Therapy explores AAV9 efficiency in nonhuman primates and underscores the importance of delivery route, preexisting antibody response, and vector tropism (Samaranch et al., 2012, this issue). Taken together, these two studies showcase progress and current challenges in clinical and nonhuman primate CNS gene therapy. Degeneration of the substantia nigra pars compacta and subsequent loss of striatal dopamine content is believed to underpin the cardinal motor symptoms of PD, namely tremor, rigidity, and bradykinesia. Although current pharmacotherapies are initially effective, they are associated with a decline in efficacy as the disease progresses and have a number of side effects, including hallucinations and uncontrollable motor movements (dyskinesias), that may effectively limit the dose of l-DOPA patients can tolerate (Obeso et al., 2000). Hence the search for alternative treatment, which needs to be safe and ideally requires a single administration, provides effective symptomatic relief, and even potentially halts or reverses the disease process. One way in which this may be achieved is through the use of gene therapy. The majority of current gene therapy approaches for the treatment of CNS disorders have focused on the use of AAV vectors, as they offer stable, long-term gene expression (McCown, 2011). Such vectors have been administered directly into the target sites of the CNS through stereotaxic surgery (Christine et al., 2009; Marks et al., 2010). However, this invasive approach requires specialist surgical facilities and accounts for some of the undesirable side effects of gene therapy reported in the literature (e.g., intracranial hemorrhage and edema; Christine et al., 2009). Nevertheless, localized infusions of vector can efficiently target specific brain regions, with the associated reduced risk of adverse events not directly related to vector delivery. The results of several phase I/II gene therapy trials for Parkinson’s have thus far been encouraging, with vectors showing good safety profiles and being well tolerated in patients. Current trials can be subdivided into three main strategies: increasing striatal dopamine content, using aromatic l-amino acid decarboxylase (rAAV2-hAADC; Genzyme, Cambridge, MA) alone or a combination of hAADC, tyrosine hydroxylase, and guanosine 5¢-triphosphate cyclohydrolase I (carried by equine infectious anemia virus-derived lentiviral vector ProSavin; Oxford BioMedica, Oxford, UK); changing basal ganglia circuitry by inhibiting the subthalamic nucleus, using the gene for glutamic acid decarboxylase (AAV-GAD; Neurologix, Fort Lee, NJ); or a trophic factor (neurturin) approach aiming to improve the nigrostriatal pathway (AAV2-NTN, CERE-120; Ceregene, San Diego, CA) (Witt and Marks, 2011). In this issue of Human Gene Therapy, Mittermeyer and colleagues report a long-term evaluation of a phase I study of AADC gene therapy for PD (Mittermeyer et al., 2012, this issue). AADC is the rate-limiting enzyme for the conversion of l-DOPA to dopamine, and loss of AADC may be associated with the wearing off of l-DOPA responsiveness in patients (Ichinose et al., 1994). Thus, restoration of AADC capacity within the putamen should result in elevated dopamine levels in response to exogenous l-DOPA. This study is a continuation of previous work by this group, who initially reported findings based on a 6-month follow-up of 10 patients who received either a low dose (9 · 10 vector genome copies [VG]) or a high dose (3· 10 VG) of AADC