Moving Forward Toward a Cure for Parkinson's: Neuropathology of the Nigrostriatal Pathway Determines the Location of Growth Factor Delivery
Authors: Terence R Flotte, Robert M Frederickson, Pedro R Lowenstein, Christian Mueller
Journal: Molecular Therapy (2011)

Vectors based on recombinant adeno-associated virus (rAAV) have been used successfully in the clinic to treat humans with Leber congenital amaurosis,1Cideciyan AV Aleman TS Boye SL Schwartz SB Kaushal S Roman AJ et al.Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics.Proc Natl Acad Sci USA. 2008; 105: 15112-15117Crossref PubMed Scopus (593) Google Scholar,2Maguire AM Simonelli F Pierce EA Pugh Jr, EN Mingozzi F Bennicelli J et al.Safety and efficacy of gene transfer for Leber's congenital amaurosis.N Engl J Med. 2008; 358: 2240-2248Crossref PubMed Scopus (1739) Google Scholar,3Bainbridge JW Smith AJ Barker SS Robbie S Henderson R Balaggan K et al.Effect of gene therapy on visual function in Leber's congenital amaurosis.N Engl J Med. 2008; 358: 2231-2239Crossref PubMed Scopus (1642) Google Scholar a single-gene disorder affecting the function of photoreceptor cells of the retina, and there are ongoing clinical studies evaluating similar vectors in several disorders of the brain, including Canavan disease,4Leone P Janson CG Bilaniuk L Wang Z Sorgi F Huang L et al.Aspartoacylase gene transfer to the mammalian central nervous system with therapeutic implications for Canavan disease [see comments] [erratum appears in Ann Neurol 48: 398, 2000].Ann Neurol. 2000; 48: 27-38Crossref PubMed Scopus (137) Google Scholar Batten disease,5Crystal RG Sondhi D Hackett NR Kaminsky SM Worgall S Stieg P et al.Clinical protocol. Administration of a replication-deficient adeno-associated virus gene transfer vector expressing the human CLN2 cDNA to the brain of children with late infantile neuronal ceroid lipofuscinosis.Hum Gene Ther. 2004; 15: 1131-1154Crossref PubMed Google Scholar and Parkinson's disease (PD).6Eberling JL Jagust WJ Christine CW Starr P Larson P Bankiewicz KS et al.Results from a phase I safety trial of hAADC gene therapy for Parkinson disease.Neurology. 2008; 70: 1980-1983Crossref PubMed Scopus (310) Google Scholar Despite these promising results, the daunting complexity of the anatomical organization of the brain challenges our capacity to deliver gene products to the precise anatomical locations where they are needed to mediate a therapeutic effect. In addition, damage to specific brain regions and the neuroanatomical pathways that connect them—such as occurs in various degenerative diseases—can further compromise our ability to deliver vectors and their therapeutic payloads. In this issue of Molecular Therapy, Ciesielska et al.7Ciesielska A Mittermeyer G Hadaczek P Kells AP Forsayeth J Bankiewicz KS Anterograde axonal transport of AAV2-GDNF in rat basal ganglia.Mol Ther. 2011; 19: 922-927Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar demonstrate that degeneration of the nigrostriatal pathway in models of PD renders unfeasible therapeutic strategies based on vector delivery to the substantia nigra and instead supports a strategy based on delivery to the striatum and subsequent anterograde transport toward the substantia nigra. rAAV vectors have been shown to mediate safe, long-term gene transfer to cells and tissues of neuroectodermal origin. In particular, “first-generation” rAAV vectors—those packaged in AAV serotype 2—are quite efficient at transducing neurons in vivo. The organization of the central nervous system (CNS), comprising nuclei (neuron cell body clusters) projecting their axons along specific neuroanatomical pathways to much broader brain regions, has raised the possibility that single directed injections into confined areas might serve as “nodes” for broader and/or targeted distribution of vector or vector-expressed proteins throughout the brain. Indeed, transduction of neurons by gene transfer vectors leads to distribution of transgene and/or its gene product throughout both the dendritic arbor and axon terminals of transduced neurons. Evidence has been provided for rAAV transport along neural pathways in both the anterograde and retrograde directions.8Hollis 2nd, ER Kadoya K Hirsch M Samulski RJ Tuszynski MH Efficient retrograde neuronal transduction utilizing self-complementary AAV1.Mol Ther. 2008; 16: 296-301Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar,9Chamberlin NL Du B de Lacalle S Saper CB Recombinant adeno-associated virus vector: use for transgene expression and anterograde tract tracing in the CNS.Brain Res. 1998; 793: 169-175Crossref PubMed Scopus (187) Google Scholar Anterograde transport is mediated by axonal transport from a neuronal cell body down the axon to the nerve terminals where axons synapse with the next neuron in the pathway. Retrograde transport denotes a process whereby vector is taken up by distal axonal termini and trafficked backward to the cell body, in the direction opposite from nerve conduction and neurotransmitter flow. PD is a progressive degenerative disorder of the CNS resulting from the death of the nigrostriatal dopamine-containing neurons of the substantia nigra. The nigrostriatal pathway, which connects the substantia nigra with the striatum, is a key pathway involved in motor control. Because this pathway degenerates in PD, the main approach to the treatment of this disorder has been to deliver neurotrophic factors such as glial cellderived neurotrophic factor (GDNF) directly to the affected striatum. GDNF is known to support the survival of dopaminergic nigrostriatal neurons, as well as others, such as motor neurons. The intent of this strategy is twofold. Any GDNF delivered to the striatum would provide therapeutic benefit to the striatal neurons themselves but could also rescue any remaining nigrostriatal dopaminergic neurons still projecting to the striatum from the substantia nigra. This is because GDNF is secreted and will benefit diseased neurons located both close to the site of viral vector delivery in the striatum and in distant regions following retrograde axonal transport. Indeed, in the healthy brain, neurons normally make use of such retrograde transport to respond to growth factors secreted by downstream targets so as to effect neuronal cell survival and growth. Although either retrograde or anterograde transport of rAAV could be useful in devising a therapeutic strategy for PD, it is crucial to know whether transport via these pathways is feasible, because the PD brain will already have suffered much damage at the time of therapeutic intervention. Of course, neither this strategy nor any other would be likely to regrow axons of neurons that have already degenerated. However, in recent years clinical trials for PD have been put forward that propose to transduce the substantia nigra with vectors expressing growth factors. This contradicts the large body of knowledge gained over many decades indicating that such an approach is unlikely to provide a clinical benefit. To address this specific issue, Ciesielska et al. made use of both rodent and nonhuman primate models in which the nigrostriatal pathway has been chemically damaged, creating a state that mimics what would be expected in the brains of humans suffering from PD. The authors found that infusion of rAAV2-GDNF vector directly into either the striatum or the substantia nigra resulted in efficient GDNF delivery directly to both sites. However, transport of GDNF to the substantia nigra occurred only via anterograde transport after striatal delivery. Direct injection of vector to the substantia nigra was not successful at delivering either vector or GDNF protein to the striatum, even though the neuron cell bodies in the reticularis portion of the substantia nigra were still intact. The findings suggest that the retrograde pathway had degenerated to such an extent that it could not transport the therapeutic toward the striatum (Figure 1). In addition, anterograde transport achieved after direct striatal delivery offers a wider distribution of GDNF to other circuitry within the basal ganglia and pallidus that is also affected in PD and ultimately may benefit from GDNF therapy as well. Thus, with this new evidence for GDNF localization to the substantia nigra and other areas of the basal ganglia after direct striatal delivery, there is little rationale for AAV2-GDNF delivery directly to the substantia nigra in PD patients who present with a degenerated nigrostriatal pathway upon diagnosis. Aside from providing key information about the therapeutic strategy for delivering neurotrophic factors to CNS sites, and specifically for confirming the gene therapy approach needed for PD, this study provides a broader lesson. Gene delivery strategies must take into account the effects of the disease state on potential target cell populations. There are numerous cases, such as in PD, in which a gene delivery strategy that could work very effectively in an uninjured organ might face significant additional barriers due to loss of cells, alteration of tissue architecture, or lack of normal organ-system function. Altered airway surface secretions in the lungs of patients with cystic fibrosis and preexisting immune cell infiltration in the livers of patients with hepatitis C virus infection are but two other examples. In any case, asking a well-designed question is vital for the success of any series of experiments, and the complex landscape of in vivo gene therapy is no exception.