PMC

Diagrams of the genomes of various viral vectors used in gene therapy approaches. Each diagram depicts the genome of the virus along with that of the corresponding viral vector, showing viral structural genes, viral genes involved in replication, and genes essential or non-essential (accessory) for virus replication or growth. Viral genes that are transcribed in the 5’ to 3’ direction (rightward arrow) are depicted above the viral genome, and those transcribed in the opposite direction (leftward arrow) are depicted below the genome. Genes or regulatory elements deleted from viral vectors are shown in red and common locations for introduction of the therapeutic gene in the vector genome are depicted in green. Abbreviations: ds, double-stranded; ITR, inverted terminal repeat; IRL, inverted repeat long; IRS, inverted repeat short; LTR, long terminal repeat; TRS, terminal repeat short.

Gene therapy for pain using an HSV vector. a,b | Pain signalling is mediated by primary sensory afferents that connect via synapses in the spinal cord to release neurotransmitters and peptides, including glutamate, substance P and CGRP. After injection into the skin, the HSV vector is delivered to the cell bodies of primary afferents by retrograde axonal transport, enabling production and release of the transgene product (in this case ENK) from nerve terminals in the dorsal horn. c | ENK released from the transduced primary afferents inhibits nociceptive neurotransmission through binding to opioid receptors at presynaptic and postsynaptic sites Abbreviations: CGRP, calcitonin gene-related peptide; ENK, enkephalin; GAD, glutamic acid decarboxylase; GLU, glutamate; HSV, herpes simplex virus; SP, substance P.

Gene therapy targets in Parkinson disease. Excitatory connections from the cortex stimulate striatal neurons. Dopamine release regulates two populations of striatal neurons inversely: neurons that project directly to the GPi from the striatum are stimulated, and neurons that project to the GPi via the globus pallidus pars externa and STN are inhibited. Therefore, dopamine inhibits thalamic activity, which disinhibits the cortex and allows movement to occur. In PD, loss of dopaminergic neurons eliminates this cortical activation and inhibits movement. a | Vector injection into the caudate for the expression of dopamine producing enzymes replaces PD-related dopamine loss. b | Neurturin expression in the striatum and substantia nigra might preserve dopamine neurons, and enhance their function. c | Delivery of GAD to the STN induces GABA production, changing the STN input to the GPi from excitatory to inhibitory. GAD expression, therefore, reverses the abnormal increase in STN activity that occurs in PD, reducing the abnormally high GPi activity that prevents movement. Abbreviations: AADC, aromatic amino acid decarboxylase; GCH1, GTP cyclohydrolase 1; GABA, γ-aminobutyric acid; GAD, glutamic acid decarboxylase; GPi, globus pallidus pars interna; PD, Parkinson disease; STN, subthalamic nucleus; TH, tyrosine hydroxylase.

Vector-delivery strategies for gene therapy of neurogenetic diseases. Most inherited neurological diseases have global brain pathology, which requires widespread distribution of the vector for effective treatment. Certain properties of a therapeutic gene product can enhance its therapeutic effect; for example, in diseases of lysosomal enzyme deficiency, a cell corrected by transduction with the vector can secrete the previously missing enzyme, which can then be endocytosed by neighbouring cells. Some proteins can also be transported via neural pathways within the brain, providing wide distribution. a | Multiple, distributed injection tracks into the brain parenchyma with multiple deposits of vector along each track. b | Vector transport via axonal pathways is dependent on the specific neural system and on vector design. c | Injection into the cerebrospinal fluid (ventricles, cisterna magna or spinal cord) produces variable patterns and amounts of vector distribution. d | Vector entry into the brain via administration of herpes simplex virus to the PNS, intravenous infusion of adeno-associated virus serotypes, transplantation of lentivirus-transduced haematopoietic stem cells, or temporary osmotic opening of the blood–brain barrier.