Gene therapy

Abstract

A vector comprising an astrocyte-specific promoter operably linked to a nucleotide sequence encoding brain-derived neurotrophic factor (BDNF), or a precursor thereof.

Description

[0001]GENE THERAPY FIELD OF THE INVENTION The present invention relates to compounds for use in the treatment of neurological diseases. More specifically, the invention relates to polynucleotides comprising a nucleotide sequence encoding brain derived-neurotrophic factor (BDNF) and uses thereof, for example in the treatment of Rett syndrome. BACKGROUND TO THE INVENTION Rett syndrome (RTT) is a severe neurological disorder and a leading cause of intellectual disabilities in girls, with an incidence of 1 in 10,000-20,000 live births. RTT is characterised by a period of 6-12 months of overtly normal development followed by rapid regression with the loss of the purposeful motor skills and the onset of repetitive and autistic behaviours. In the vast majority of cases RTT is caused by loss-of-function mutations in the MECP2 gene, which encodes the methyl-CpG binding protein 2 (MECP2), a global chromatin regulator highly expressed in neurons. Recent studies have revealed that the MECP2 loss significantly alters neuronal activity leading to a progressive imbalance of the excitatory-inhibitory synaptic activity across the brain with divergent modalities occurring between different circuits and regions of the brain. MECP2 is involved in transcriptional regulation, specifically in transcriptional repression via recruitment of SIN3a and histone deacetylases (HDACs). One of the targets of MECP2 is the brain-derived neurotrophic factor (BDNF) gene. The expression of BDNF is repressed by MECP2 in the absence of neuronal activity (Chen W. et al. (2003) Science 302: 885-889). MECP2-depleted neurons have been shown to have a reduction in neuronal activity. Increased expression of BDNF in the brain of Mecp2 mutant mice has been shown to ameliorate pathology of the Mecp2 mutation. However, BDNF protein half-life is very short and it does not cross the blood-brain barrier (Bazzari, A. H. & Bazzari, F. H. (2022), Int. J. Mol. Sci. 23). Accordingly, there remains a significant need for improved and effective approaches for treating Rett syndrome. SUMMARY OF THE INVENTION The inventors have developed a therapeutic vector that enables specific expression of a BDNF transgene in astrocyte cells. The inventors demonstrated the efficacy of their approach in a mouse model of Rett syndrome. In particular, the inventors observed amelioration of pathological RTT phenotype, for example with amelioration in locomotor activity after treatment as assessed by three independent behavioural tests: the beam balance test, the open-field arena and the rotarod. The inventors also showed that their BDNF treatment promoted a wide recovery of mTOR / AKT activity (the functions of which are important for correct neuronal maturation and synaptic plasticity) in Mecp2-KO mice. In one aspect, the invention provides a polynucleotide (e.g. a vector) comprising a nucleotide sequence encoding brain-derived neurotrophic factor (BDNF), or a precursor thereof. In one aspect, the invention provides a polynucleotide (e.g. a vector) comprising an astrocyte-specific promoter and a nucleotide sequence encoding brain-derived neurotrophic factor (BDNF), or a precursor thereof. In one aspect, the invention provides a vector comprising an astrocyte-specific promoter operably linked to a nucleotide sequence encoding brain-derived neurotrophic factor (BDNF), or a precursor thereof. In some embodiments, the BDNF or precursor thereof is mature BDNF (mBDNF), pro-protein BDNF (proBDNF), or pre-pro-protein BDNF (preproBDNF). In some embodiments, the BDNF or precursor thereof is mature BDNF (mBDNF). In some embodiments, the BDNF or precursor thereof is pro-protein BDNF (proBDNF). In some embodiments, the BDNF or precursor thereof is pre-pro-protein BDNF (preproBDNF). In some embodiments, the nucleotide sequence encoding BDNF, or precursor thereof comprises or consists of a nucleotide sequence encoding an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 1, 6 or 7. In some embodiments, the nucleotide sequence encoding BDNF, or precursor thereof comprises or consists of a nucleotide sequence encoding an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 1. In some embodiments, the nucleotide sequence encoding BDNF, or precursor thereof comprises or consists of the nucleotide sequence of SEQ ID NO: 1, 6 or 7. In some embodiments, the nucleotide sequence encoding BDNF, or precursor thereof comprises or consists of the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the nucleotide sequence encoding BDNF, or precursor thereof comprises or consists of a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 5, 8 or 9. In some embodiments, the nucleotide sequence encoding BDNF, or precursor thereof comprises or consists of the nucleotide sequence of SEQ ID NO: 5, 8 or 9. In some embodiments, the nucleotide sequence encoding BDNF, or precursor thereof comprises or consists of a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 5. In some embodiments, the nucleotide sequence encoding BDNF, or precursor thereof comprises or consists of the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the promoter is selected from the group consisting of a Glial Fibrillary Acidic Protein (GFAP) promoter and an aldehyde dehydrogenase family 1, member L1 (ALDH1L1) promoter. In some embodiments, the astrocyte-specific promoter is a Glial Fibrillary Acidic Protein (GFAP) promoter. In some embodiments, the astrocyte-specific promoter comprises or consists of a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 2. In some embodiments, the astrocyte-specific promoter comprises or consists of the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the vector is a viral vector. In preferred embodiments, the vector is an adeno-associated virus (AAV) vector. In some embodiments, the vector further comprises a 5’ inverted terminal repeat (ITR) and a 3’ inverted terminal repeat (ITR). Suitably, the 5’ and the 3’ ITRs are AAV ITRs. In some embodiments, the 5’ and the 3’ ITRs are independently selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, or AAV13 ITRs. In some embodiments, the 5’ ITR comprises or consists of a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 3, and / or the 3’ ITR comprises or consists of a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 4. In preferred embodiments, the vector is in the form of a viral particle. Suitably, the viral particle is an AAV particle. In some embodiments, the viral particle is pseudotyped to confer central nervous system (CNS) tropism. In some embodiments, the viral particle comprises AAV-PHP.eB, AAV-PHP.B or AAV9 capsid proteins. In preferred embodiments, the viral particle comprises AAV-PHP.eB capsid proteins. In one aspect, the invention provides a kit for the production of a vector according to the invention. Suitably, the kit comprises a polynucleotide encoding the genome of the vector of the invention. The kit may further comprise a population of cells for the production of a vector according to the invention. In one aspect, the invention provides a method of producing a vector according to the invention. The method may comprise introducing a polynucleotide encoding the genome of the vector into a population of cells. Suitably, the method comprises culturing a population of cells under conditions for producing a vector according to the invention. In one aspect, the invention provides a cell comprising a vector according to the invention. The cell may be part of a populations of cells comprising a vector according to the invention. In one aspect, the invention provides a population of cells comprising a vector according to the invention. In one aspect, the invention provides a pharmaceutical composition comprising a vector or a cell according to the invention and a pharmaceutically acceptable carrier, diluent or excipient. In one aspect, the invention provides a vector, a cell, or a pharmaceutical composition according to the invention for use as a medicament. In one aspect, the invention provides the use of a vector, a cell, or a pharmaceutical composition according to the invention for the manufacture of a medicament. In one aspect, the invention provides a method comprising administering a vector, a cell, or a pharmaceutical composition according to the invention, to a subject in need thereof. Suitably, the use or method is for treating or preventing Rett Syndrome. In one aspect, the invention provides a vector, a cell, or a pharmaceutical composition according to the invention for use in treating or preventing a BDNF-associated disease. In one aspect, the invention provides a method for treating or preventing a BDNF-associated disease comprising administering a vector, a cell, or a pharmaceutical composition according to the invention, to a subject in need thereof. In some embodiments, the BDNF-associated disease is selected from the group consisting of Rett syndrome, infantile cognitive disabilities, autism spectrum disorder and age-related neurodegenerative disorders. In some embodiments, the BDNF-associated disease is Rett syndrome. DESCRIPTION OF THE DRAWINGS FIGURE 1 Specificity of GFAP-derived promoter in vivo A) Illustration of the experimental setting to test the GFAP-derived promoter in vivo. B) Upper, low magnification of GFP (green) and Sox9 (red) immunostaining in brains derived from control and GFAPp-GFP-treated mice (Scale bar: 100um). Bottom, high magnification immunostaining for GFP (green) and Sox9 (red) in the cortex of GFAPp-GFP-treated mice. Pie chart showing the fraction of GFP+ Sox9+ (gray) and GFP+ Sox9- (black) cells. FIGURE 2 High dose treatment with GFAPp-BDNF A) Illustration of the experimental setting for treating neonatal wild-type and Mecp2-KO mice with 1010vg / mouse dose of the AAV_PHP.eB-GFAPp-BDNF. B) Mouse body weight curve for wild-type (WT) and Mecp-KO (KO) mice controls (GFP) and treated with BDNF (BDNF). C) Representative photo of wild-type mice at P9 treated with BDNF (left) or control (GFP, right). D) Bar graphs showing blood glucose measurement in wild-type and Mecp2-KO control and BDNF treated animals. Dashed lines represent the physiological blood glucose range of wild- type mice. Error bars, SD. ** p < 0.01 as compared to WT mice (ANOVA-one way with Tukey’s post hoc test). FIGURE 3 Treatment with GFAPp-BDNF improves motor behavior of Mecp2-KO animals A) Illustration of the experimental setting for treating neonatal wild-type and Mecp2-KO mice with 109vg / mouse dose of the AAV_PHP.eB GFAPp-BDNF. B) Mouse body weight curve for wild-type (WT) and Mecp-KO (KO) mice controls (GFP) and treated with BDNF (BDNF). C) Kaplan-Meier survival plot for wild-type and Mecp-KO mice controls and treated with BDNF. D) Evaluation of motor coordination through the beam balance test quantified as crossing time (Upper, * p < 0.05 versus KO-BDNF and KO-GFP) and number of errors (Bottom, * p < 0.05 versus KO-BDNF and KO-GFP). E-F) Evaluation of the latency to fall from the Rotarod analysis (E) and the distance of the spontaneous locomotor activity in a field arena (F) in 6 weeks-old control and BDNF treated mice. Error bars, SD. ANOVA-two way (D) or ANOVA- one way (E, F) with Tukey’s post hoc test. FIGURE 4 GFAPp-BDNF treatment increases mTOR / AKT signaling pathway A) Low magnification of GFP (green) and Sox9 (red) immunostaining in brains derived from AAV-GFAPp-GFP-treated mice with 109and 1010vg / mouse (Scale bar 100um). B) Left, illustration of the ELISA anti-BDNF performed on brain lysates. Right, bar graphs showing BDNF amount measured by ELISA in brain lysates. The results were reported as the fold change relative to control Mecp2-KO (KO GFP) animals. C) Representative Western blot and quantitative analysis for the ribosomal protein S6, its phosphorylated form (pS6) and a normalizer (β-Actin) from cortical tissues of wild-mice (WT) and Mecp2 KO transduced control (KO GFP) or BDNF-treated (KO BDNF). Error bars, SD. * p < 0.05, ** p < 0.01, *** p < 0.01 (ANOVA-one way with Tukey’s post hoc test). DETAILED DESCRIPTION OF THE INVENTION The terms “comprising”, “comprises” and “comprised of” as used herein are synonymous with “including” or “includes”; or “containing” or “contains”, and are inclusive or open-ended and do not exclude additional, non-recited members, elements or steps. The terms “comprising”, “comprises” and “comprised of” also include the term “consisting of”. RETT SYNDROME Rett syndrome (RTT) is a severe neurological disorder and a leading cause of intellectual disabilities in girls. RTT is characterised by a period of 6-12 months of overtly normal development followed by rapid regression with the loss of the purposeful motor skills and the onset of repetitive and autistic behaviours. In the vast majority of cases RTT is caused by loss-of-function mutations in the MECP2 gene, which encodes the methyl-CpG binding protein 2 (MeCP2). Studies have revealed that the Mecp2 loss is associated with a reduction of BDNF in the central nervous system. BDNF stimulates neuronal maturation and synaptic plasticity through the activation of the AKT / mTOR signalling pathway, which is dysregulated in Mecp2-depleted animals (Ricciardi, S. et al. (2011) Hum. Mol. Genet.20, 1182–1196). BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) Brain-derived neurotrophic factor (BDNF) is a neurotrophin found in the central nervous system (CNS). In some embodiments, the BDNF is a mammalian BDNF. In preferred embodiments, the BDNF is a human BDNF. BDNF may be expressed as a precursor form, preproBDNF, which undergoes maturation cleavage steps, initially to form a proneurotrophin form of BDNF, proBDNF, and then further to form mature BDNF, mBDNF. In some embodiments, the polynucleotide or vector of the invention encodes a precursor of BDNF. In some embodiments the BDNF precursor is preproBDNF or proBDNF. Preferably, the BDNF precursor is preproBDNF. An example BDNF precursor sequence is: MTILFLTMVISYFGCMKAAPMKEANIRGQGGLAYPGVRTHGTLESVNGPKAGSRGLTSLADTFEHVIE ELLDEDQKVRPNEENNKDADLYTSRVMLSSQVPLEPPLLFLLEEYKNYLDAANMSMRVRRHSDPARRG ELSVCDSISEWVTAADKKTAVDMSGGTVTVLEKVPVSKGQLKQYFYETKCNPMGYTKEGCRGIDKRHW NSQCRTTQSYVRALTMDSKKRIGWRFIRIDTSCVCTLTIKRGR (SEQ ID NO: 1; human preproBDNF) A further example BDNF precursor sequence is: APMKEANIRGQGGLAYPGVRTHGTLESVNGPKAGSRGLTSLADTFEHVIEELLDEDQKVRPNEENNKD ADLYTSRVMLSSQVPLEPPLLFLLEEYKNYLDAANMSMRVRRHSDPARRGELSVCDSISEWVTAADKK TAVDMSGGTVTVLEKVPVSKGQLKQYFYETKCNPMGYTKEGCRGIDKRHWNSQCRTTQSYVRALTMDS KKRIGWRFIRIDTSCVCTLTIKRGR (SEQ ID NO: 6; human proBDNF) An example mature BDNF sequence is: HSDPARRGELSVCDSISEWVTAADKKTAVDMSGGTVTVLEKVPVSKGQLKQYFYETKCNPMGYTKEGC RGIDKRHWNSQCRTTQSYVRALTMDSKKRIGWRFIRIDTSCVCTLTIKRGR (SEQ ID NO: 7; human mBDNF) In some embodiments, the BDNF precursor is preproBDNF, proBDNF, or a variant or fragment thereof. In some embodiments, the BDNF is mBDNF. In some embodiments, the BDNF or precursor thereof comprises or consists of an amino acid sequence selected from any one of SEQ ID NOs: 1, 6, or 7. In some embodiments, the BDNF or precursor thereof comprises or consists of an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to any one of SEQ ID NOs: 1, 6, or 7. In preferred embodiments, the BDNF or precursor thereof comprises or consists of an amino acid sequence of SEQ ID NO: 1, or a sequence having at least 80% sequence identity to the sequence of SEQ ID NO: 1. In some embodiments, the nucleotide sequence encoding BDNF, or precursor thereof comprises or consists of a nucleotide sequence encoding an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 1. In some embodiments, the nucleotide sequence encoding BDNF, or precursor thereof comprises or consists of the nucleotide sequence of SEQ ID NO: 1. In some embodiments, the nucleotide sequence encoding BDNF, or precursor thereof comprises or consists of a nucleotide sequence encoding an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 6. In some embodiments, the nucleotide sequence encoding BDNF, or precursor thereof comprises or consists of the nucleotide sequence of SEQ ID NO: 6. Suitably, the precursor protein encoded by the nucleotide sequence retains the natural function of a BDNF precursor, for example the natural function of SEQ ID NO: 1 or 6. In some embodiments, the nucleotide sequence encoding BDNF, or precursor thereof comprises or consists of a nucleotide sequence encoding an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 7. In some embodiments, the nucleotide sequence encoding BDNF, or precursor thereof comprises or consists of the nucleotide sequence of SEQ ID NO: 7. Suitably, the mature protein encoded by the nucleotide sequence retains the natural function of BDNF, for example the natural function of SEQ ID NO: 7. An example nucleotide sequence encoding a BDNF precursor is: ATGACCATCCTTTTCCTTACTATGGTTATTTCATACTTTGGTTGCATGAAGGCTGCCCCCATGAAAGA AGCAAACATCCGAGGACAAGGTGGCTTGGCCTACCCAGGTGTGCGGACCCATGGGACTCTGGAGAGCG TGAATGGGCCCAAGGCAGGTTCAAGAGGCTTGACATCATTGGCTGACACTTTCGAACACGTGATAGAA GAGCTGTTGGATGAGGACCAGAAAGTTCGGCCCAATGAAGAAAACAATAAGGACGCAGACTTGTACAC GTCCAGGGTGATGCTCAGTAGTCAAGTGCCTTTGGAGCCTCCTCTTCTCTTTCTGCTGGAGGAATACA AAAATTACCTAGACGCTGCAAACATGTCCATGAGGGTCCGGCGCCACTCTGACCCTGCCCGCCGAGGG GAGCTGAGCGTGTGTGACAGTATTAGTGAGTGGGTAACGGCGGCAGACAAAAAGACTGCAGTGGACAT GTCGGGCGGGACGGTCACAGTCCTTGAAAAGGTCCCTGTATCAAAAGGCCAACTGAAGCAATACTTCT ACGAGACCAAGTGCAATCCCATGGGTTACACAAAAGAAGGCTGCAGGGGCATAGACAAAAGGCATTGG AACTCCCAGTGCCGAACTACCCAGTCGTACGTGCGGGCCCTTACCATGGATAGCAAAAAGAGAATTGG CTGGCGATTCATAAGGATAGACACTTCTTGTGTATGTACATTGACCATTAAAAGGGGAAGATAG (SEQ ID NO: 5; human preproBDNF) A further example of a nucleotide sequence encoding a BDNF precursor is: GCCCCCATGAAAGAAGCAAACATCCGAGGACAAGGTGGCTTGGCCTACCCAGGTGTGCGGACCCATGG GACTCTGGAGAGCGTGAATGGGCCCAAGGCAGGTTCAAGAGGCTTGACATCATTGGCTGACACTTTCG AACACGTGATAGAAGAGCTGTTGGATGAGGACCAGAAAGTTCGGCCCAATGAAGAAAACAATAAGGAC GCAGACTTGTACACGTCCAGGGTGATGCTCAGTAGTCAAGTGCCTTTGGAGCCTCCTCTTCTCTTTCT GCTGGAGGAATACAAAAATTACCTAGACGCTGCAAACATGTCCATGAGGGTCCGGCGCCACTCTGACC CTGCCCGCCGAGGGGAGCTGAGCGTGTGTGACAGTATTAGTGAGTGGGTAACGGCGGCAGACAAAAAG ACTGCAGTGGACATGTCGGGCGGGACGGTCACAGTCCTTGAAAAGGTCCCTGTATCAAAAGGCCAACT GAAGCAATACTTCTACGAGACCAAGTGCAATCCCATGGGTTACACAAAAGAAGGCTGCAGGGGCATAG ACAAAAGGCATTGGAACTCCCAGTGCCGAACTACCCAGTCGTACGTGCGGGCCCTTACCATGGATAGC AAAAAGAGAATTGGCTGGCGATTCATAAGGATAGACACTTCTTGTGTATGTACATTGACCATTAAAAG GGGAAGATAG An example of a nucleotide sequence encoding mature BDNF is: (SEQ ID NO: 8; human proBDNF) CACTCTGACCCTGCCCGCCGAGGGGAGCTGAGCGTGTGTGACAGTATTAGTGAGTGGGTAACGGCGGC AGACAAAAAGACTGCAGTGGACATGTCGGGCGGGACGGTCACAGTCCTTGAAAAGGTCCCTGTATCAA AAGGCCAACTGAAGCAATACTTCTACGAGACCAAGTGCAATCCCATGGGTTACACAAAAGAAGGCTGC AGGGGCATAGACAAAAGGCATTGGAACTCCCAGTGCCGAACTACCCAGTCGTACGTGCGGGCCCTTAC CATGGATAGCAAAAAGAGAATTGGCTGGCGATTCATAAGGATAGACACTTCTTGTGTATGTACATTGA CCATTAAAAGGGGAAGATAG (SEQ ID NO: 9; human mBDNF) In some embodiments, the BDNF or precursor thereof is encoded by a nucleotide sequence comprising or consisting of a sequence selected from any one of SEQ ID NOs: 5, 8, or 9. In a preferred embodiment, the BDNF precursor is encoded by a nucleotide sequence comprising or consisting of SEQ ID NO: 5. In some embodiments, the nucleotide sequence encoding BDNF, or precursor thereof comprises or consists of a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 5. In some embodiments, the nucleotide sequence encoding BDNF, or precursor thereof comprises or consists of the nucleotide sequence of SEQ ID NO: 5. In some embodiments, the nucleotide sequence encoding BDNF, or precursor thereof comprises or consists of a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 8. In some embodiments, the nucleotide sequence encoding BDNF, or precursor thereof comprises or consists of the nucleotide sequence of SEQ ID NO: 8. In some embodiments, the nucleotide sequence encoding BDNF, or precursor thereof comprises or consists of a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 9. In some embodiments, the nucleotide sequence encoding BDNF, or precursor thereof comprises or consists of the nucleotide sequence of SEQ ID NO: 9. BLOOD-BRAIN BARRIER (BBB) The term “blood brain barrier” (BBB) as used herein means the highly selective semi- permeable membrane barrier which separates the circulating blood from the brain and extracellular fluid in the central nervous system. It is formed by the selectivity of tight junctions between endothelial cells. The blood-brain barrier occurs along all capillaries of the brain and consists of tight junctions. Overcoming the difficulty of delivering therapeutic agents to specific regions of the brain presents a major challenge to treatment of most brain disorders. In particular, BDNF protein is generally not able to cross the blood-brain barrier following intravenous administration. Preferably, the vector particle of the invention (e.g. the AAV vector particle) is adapted for crossing an intact blood brain barrier. Preferably the vector particle (e.g. the AAV vector particle) does not impair blood-brain barrier integrity and / or selectivity and / or affect permeability. In other words, the vector particle is preferably adapted to cross a blood-brain barrier which has not been compromised or weakened, i.e. which maintains tight junctions between endothelial cells. Methods are known in the art which can determine whether or not a blood brain barrier is intact. For example, the permeability of the blood-brain barrier can be detected by perfusion of Evan’s blue dye. Alternatively a fluorescent-conjugated cadaverine dye can be used as a blood-brain barrier permeability marker, together with the AAV particle carrying a fluorescent marker. Preferably, the vector particle (e.g. the AAV vector particle) does not cause microgliosis. Suitably, the vector particle (e.g. the AAV vector particle) does not cause sustained inflammation in the central nervous system. The “central nervous system” as used herein means the nervous system consisting of the brain and spinal cord. The “peripheral nervous system” as used herein means the components of the nervous system outside of the central nervous system. The peripheral nervous system consists of the nerves and ganglia outside of the brain and spinal cord. PROMOTERS AND REGULATORY SEQUENCES The polynucleotides and vectors of the invention include elements allowing for the expression of BDNF or a precursor thereof. These may be referred to as expression control sequences. Thus, the polynucleotides and vectors typically comprise expression control sequences (e.g. comprising a promoter sequence) operably linked to a transgene (e.g. the nucleotide sequence encoding the BDNF or precursor thereof). Suitably, the promoter is active only in a specific host cell environment, thus allowing for targeted expression of the transgene in a particular cell type (e.g. a tissue-specific promoter such as an astrocyte-specific promoter). The promoter may show inducible expression in response to presence of another factor, for example a factor present in a host cell. In any event, where the polynucleotide or vector is administered for therapy, it is preferred that the promoter should be functional in the target cell background. In preferred embodiments, the promoter is astrocyte specific. Astrocytes are star-shaped glial cells that are typically found in the brain and spinal cord. They perform functions including biochemical control of endothelial cells that form the blood–brain barrier, provision of nutrients to nervous tissue, maintenance of extracellular ion balance and regulation of cerebral blood flow. Astrocytes may be characterised by expression of the Sox9 marker. Suitably, the astrocytes are Sox9+. An astrocyte-specific promoter may refer to a promoter that specifically promotes transgene expression in astrocytes. In some embodiments, astrocyte specific transgene expression may result in greater than 50% of transgene expression occurring in astrocytes. In some embodiments, astrocyte specific transgene expression may result in greater than 60%, 70%, 80%, 85%, 90%, 95%, 97%, 98% or 99% (preferably, 99% or greater) of transgene expression occurring in astrocytes. In some embodiments, astrocyte specific transgene expression may result in greater than 50% of cells expressing transgene being astrocytes. In some embodiments, astrocyte specific transgene expression may result in greater than 60%, 70%, 80%, 85%, 90%, 95%, 97%, 98% or 99% (preferably, 99% or greater) of cells expressing transgene being astrocytes. Specificity of expression of transgene may be determined by any suitable method known in the art, for example as disclosed herein. For example, a marker, such as GFP, may be encoded by a transgene, and expression of the marker in different cell types may be determined using a suitable assay, such as immunofluorescence. Expression of the marker may be compared against expression of Sox9 as a marker of astrocytes to analyse astrocyte specificity of expression. In some embodiments, the promoter is selected from the group consisting of a Glial Fibrillary Acidic Protein (GFAP) promoter and an aldehyde dehydrogenase family 1, member L1 (ALDH1L1) promoter. In some embodiments, the promoter is a Glial Fibrillary Acidic Protein (GFAP) promoter. An example GFAP promoter is: AACATATCCTGGTGTGGAGTAGGGGACGCTGCTCTGACAGAGGCTCGGGGGCCTGAGCTGGCTCTGTG AGCTGGGGAGGAGGCAGACAGCCAGGCCTTGTCTGCAAGCAGACCTGGCAGCATTGGGCTGGCCGCCC CCCAGGGCCTCCTCTTCATGCCCAGTGAATGACTCACCTTGGCACAGACACAATGTTCGGGGTGGGCA CAGTGCCTGCTTCCCGCCGCACCCCAGCCCCCCTCAAATGCCTTCCGAGAA (SEQ ID NO: 2; GFAP promoter) In some embodiments, the astrocyte-specific promoter comprises or consists of a nucleotide sequence that has at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 2. In some embodiments, the astrocyte-specific promoter comprises or consists of the nucleotide sequence of SEQ ID NO: 2. In some embodiments, the promoter is an ALDH1L1 promoter. An example ALDH1L1 promoter is: ACCCTTTGGGTTCTTTGTTCTATTCCCCAAGTCATCCCTTCTTTTCCATGAAATGCAGCCCAGGTTCA TATCCGTATAGTTTCTCAGCTTGCTTCCTCCCAGAATTTGGGGGAGTCTAGAGGTCTCTTTTCATTTT ATATTGTCTCTGACCCTTTCAGTCCAAGTCTACACTGTTTTGCTCATATAATTCTTTTAAAAATGTTG CATGTCTCCTGTAGATCTCACTGAGGTTCATGCCTTTAGACAACTGTCAAACCCACACATCTCTTTGA GAAAAGCCCTTCTCTCTCTTGGGCTTCTGCTGAGACTGCTGTCAAGGACAACTGTAAGCTTCTTAGAA ATCCTACTATTTAACAAAATATTCTGAGGTGTCCCTTTGTTCTCTTTGAAGATTTTACAAAAGATCTC ATGACCACACTCTTGGCTTCATCTTTAGGCCATCTTCCTTGCACTGGCCTGCATTTGCTCTTTGCCTG GAAGCCATTTGTTAGTTTTAGCATCATATGACATCTGGAGAAGCTGGACATTTTCACAGCCCAAGTTA TGGTTCCTTTTTATTTAACAATCCTTCCTTTGGCTTATGTCCCTTCTCTCACATTTTAGTATAAGCAG CAAGAAGAAGCCAGGAGGAGGCACCTTCAACAATCTCCTTAATGAGATCCCCCAGTTCATCTGGTACA TTTTCTACTTTCCACATGATTTCGGAACACTTTCTGCTTAAAATTCCCTCCTCTCCTGCTCCATACCT CTAAGAGTATGGATTCCTCTCTGATTTCCTAATACATCTTTTTGGGGTGTCTAACCTCCAAGCCATTG TTCAGTGGTTCCTGTCGCCCATCTGCCTTCTCAATTTTAACTCCCAAGTTCAGAACACACCACTTTCC CATTGCAGGCCCCTAACACTCAGCCAGTTTTCCTACAGATTATATGGCACACCTTCCACACACAGGGC ATGCATTCAGCCCTGGGGACTTCCCAGGAGAATAAGCTAGTCTTCGCCATCATTGTCCAGAGACATGT TAATCAAGCAATCCCAGAAGCAGTGATAAAATTGCAGTTGAAGGCAGGGTGCAGTGGCTCATGCCTGT AATCTCAGCACTTTGGGAGGCTGAGGTAGGTGGATCATCTGACGTCAGGAGTTTGAGACCAGCCTGGC CAACATGGTGAAACCCCGGTGAAACGTCTACTAAAAATACAAAAATTAGCTGGGTGTGGTGGCGCATG CCTGTAATCCCAGCTACTCAGGAGGCTAAGGCAGGAGAATCGCTTGAACCTAGGAGGTGGAGGGTCCA TTGAGCTG (SEQ ID NO: 20; ALDH1L1 promoter) In some embodiments, the astrocyte-specific promoter comprises or consists of a nucleotide sequence that has at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 20. In some embodiments, the astrocyte-specific promoter comprises or consists of the nucleotide sequence of SEQ ID NO: 20. Without wishing to be bound by theory, the targeting of transgene expression to astrocytes may provide beneficial advantages to the therapeutic uses of the vectors, cells or pharmaceutical compositions of the present invention. Astrocytes have a natural ability to produce and release neurotrophins, and are able to act as a “factory” to produce BDNF. Furthermore, in BDNF-associated diseases, such as Rett syndrome, neurons often have reduced functionality, and accordingly may be less able to express BDNF. In some embodiments, the vectors of the present invention may comprise a Woodchuck Hepatitis Virus Post-transcriptional regulatory Element (WPRE). Suitably, the nucleotide sequence encoding brain-derived neurotrophic factor (BDNF), or a precursor thereof, is operably linked to a WPRE. Suitable WPRE sequences will be well known to those of skill in the art (see e.g. Zufferey, R., et al., 1999. Journal of virology, 73(4), pp.2886-2892; and Zanta-Boussif, M.A. et al., 2009. Gene therapy, 16(5), pp.605-619). Suitably, the WPRE is a wild-type WPRE or is a mutant WPRE. For example, the WPRE may be mutated to abrogate translation of the woodchuck hepatitis virus X protein (WHX) e.g. by mutating the WHX ORF translation start codon. In some embodiments, the WPRE comprises or consists of a nucleotide sequence which has at least 80% sequence identity to SEQ ID NO: 10 or a fragment thereof. Suitably, the WPRE comprises or consists of a nucleotide sequence which has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to SEQ ID NO: 10 or a fragment thereof. In some embodiments, the WPRE comprises or consists of the nucleotide sequence SEQ ID NO: 10 or a fragment thereof. AATCAACCTCTGGATTACAAAATTTGTGAAAGATTGACTGGTATTCTTAACTATGTTGCTCCTTTTAC GCTATGTGGATACGCTGCTTTAATGCCTTTGTATCATGCTATTGCTTCCCGTATGGCTTTCATTTTCT CCTCCTTGTATAAATCCTGGTTGCTGTCTCTTTATGAGGAGTTGTGGCCCGTTGTCAGGCAACGTGGC GTGGTGTGCACTGTGTTTGCTGACGCAACCCCCACTGGTTGGGGCATTGCCACCACCTGTCAGCTCCT TTCCGGGACTTTCGCTTTCCCCCTCCCTATTGCCACGGCGGAACTCATCGCCGCCTGCCTTGCCCGCT GCTGGACAGGGGCTCGGCTGTTGGGCACTGACAATTCCGTGGTGTTGTCGGGGAAGCTGACGTCCTTT CCATGGCTGCTCGCCTGTGTTGCCACCTGGATTCTGCGCGGGACGTCCTTCTGCTACGTCCCTTCGGC CCTCAATCCAGCGGACCTTCCTTCCCGCGGCCTGCTGCCGGCTCTGCGGCCTCTTCCGCGTCTTCGCC TTCGCCCTCAGACGAGTCGGATCTCCCTTTGGGCCGCCTCCCCGC (SEQ ID NO: 10; WPRE) In some embodiments, the vectors of the present invention may comprise an Internal Ribosome Entry Site (IRES). IRES sites are cis-acting RNA sequences that allow for ribosome recruitment and initiation of protein synthesis from mRNA transcripts in a cap-independent manner. An example IRES sequence is: ACGTTACTGGCCGAAGCCGCTTGGAATAAGGCCGGTGTGCGTTTGTCTATATGTTATTTTCCACCATA TTGCCGTCTTTTGGCAATGTGAGGGCCCGGAAACCTGGCCCTGTCTTCTTGACGAGCATTCCTAGGGG TCTTTCCCCTCTCGCCAAAGGAATGCAAGGTCTGTTGAATGTCGTGAAGGAAGCAGTTCCTCTGGAAG CTTCTTGAAGACAAACAACGTCTGTAGCGACCCTTTGCAGGCAGCGGAACCCCCCACCTGGCGACAGG TGCCTCTGCGGCCAAAAGCCACGTGTATAAGATACACCTGCAAAGGCGGCACAACCCCAGTGCCACGT TGTGAGTTGGATAGTTGTGGAAAGAGTCAAATGGCTCTCCTCAAGCGTATTCAACAAGGGGCTGAAGG ATGCCCAGAAGGTACCCCATTGTATGGGATCTGATCTGGGGCCTCGGTGCACATGCTTTACATGTGTT TAGTCGAGGTTAAAAAAACGTCTAGGCCCCCCGAACCACGGGGACGTGGTTTTCCTTTGAAAAACACG ATGATAATAC (SEQ ID NO: 18; IRES sequence) Without wishing to be bound by theory, IRES sequences may, for example, allow translation of two separate proteins from a single mRNA molecule. This may be beneficial for coexpression of more than one protein. VECTORS A vector is a tool that allows or facilitates the transfer of an entity from one environment to another. In accordance with the invention, and by way of example, some vectors used in recombinant nucleic acid techniques allow entities, such as a segment of nucleic acid (e.g. a heterologous DNA segment, such as a heterologous cDNA segment), to be transferred into a target cell. The vector may serve the purpose of maintaining the heterologous nucleic acid (DNA or RNA) within the cell, facilitating the replication of the vector comprising a segment of nucleic acid and / or facilitating the expression of the protein encoded by a segment of nucleic acid. In one aspect, the invention provides a vector wherein the vector comprises an astrocyte- specific promoter and a nucleotide sequence encoding brain-derived neurotrophic factor (BDNF), or a precursor thereof Vectors of the invention may be introduced into cells using a variety of techniques known in the art, such as transfection, transduction and transformation. Transfection may refer to a general process of incorporating a nucleic acid into a cell and includes a process using a non-viral vector to deliver a polynucleotide to a cell. Transduction may refer to a process of incorporating a nucleic acid into a cell using a viral vector. Preferably, the vectors used to transduce cells in the invention are viral vectors. The vectors of the invention are preferably adeno-associated viral (AAV) vectors, although it is contemplated that other viral vectors may be used. The vector may be, for example, an adeno- associated viral (AAV) vector, a lentiviral vector, a retroviral vector or an adenoviral vector. Preferably, the viral vector for use according to the present invention is in the form of a viral vector particle. In some embodiments, the viral vector particle is adapted for crossing the blood-brain barrier. In some embodiments, the viral vector particle adapted for crossing the blood-brain barrier for use according to the invention is an adeno-associated viral (AAV), retroviral, lentiviral, or adenoviral vector particle. Preferably, the viral vector particle is a lentiviral or AAV vector particle, more preferably an AAV vector particle. Although, some embodiments of the invention have been described with respect to AAV vector particles, it will be appreciated that some embodiments may apply mutatis mutandis to other viral vectors disclosed herein. The vector may be an mRNA vector. Transfection of cells with mRNA vectors can be achieved, for example, using nanoparticles, such as liposomes. In some embodiments, the vector is comprised in a nanoparticle. In some embodiments, the nanoparticle is a polymeric nanoparticle, inorganic nanoparticle or lipid nanoparticle. In some embodiments, the nanoparticle is a liposome. The nanoparticle may be targeted to a specific cell type(s) using one or more ligand displayed on its surface. In some embodiments, polynucleotide delivery is transposon mediated. ADENO-ASSOCIATED VIRAL (AAV) VECTORS In one aspect, the invention provides an AAV vector, wherein the AAV vector comprises an astrocyte specific promoter and a nucleotide sequence encoding brain-derived neurotrophic factor (BDNF), or a precursor thereof. In some embodiments, the AAV vector is an AAV vector particle. Suitably, the AAV vector particle is adapted for crossing the blood-brain barrier. Methods of preparing and modifying viral vectors and viral vector particles, such as those derived from AAV, are well known in the art. The AAV vector may comprise an AAV genome or a fragment or derivative thereof. An AAV genome is a polynucleotide sequence, which may encode functions needed for production of an AAV particle. These functions include those operating in the replication and packaging cycle of AAV in a host cell, including encapsidation of the AAV genome into an AAV particle. Naturally occurring AAVs are replication-deficient and rely on the provision of helper functions in trans for completion of a replication and packaging cycle. Accordingly, the AAV genome of the AAV vector of the invention is typically replication-deficient. The AAV genome may be in single-stranded form, either positive or negative-sense, or alternatively in double-stranded form. The use of a double-stranded form allows bypass of the DNA replication step in the target cell and so can accelerate transgene expression. The AAV genome may be from any naturally derived serotype, isolate or clade of AAV. Thus, the AAV genome may be the full genome of a naturally occurring AAV. As is known to the skilled person, AAVs occurring in nature may be classified according to various biological systems. Commonly, AAVs are referred to in terms of their serotype. A serotype corresponds to a variant subspecies of AAV which, owing to its profile of expression of capsid surface antigens, has a distinctive reactivity which can be used to distinguish it from other variant subspecies. Typically, a virus having a particular AAV serotype does not efficiently cross-react with neutralising antibodies specific for any other AAV serotype. AAV serotypes include AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10 and AAV11, and also recombinant serotypes, such as Rec2 and Rec3, recently identified from primate brain. Several rAAV vectors have been reported to efficiently cross the blood-brain barrier and transduce neurons and astrocytes in the neonatal mouse central nervous system (Zhang et al., Molecular Therapy 19: 1440-1448). It has been reported that neuronal tropism of AAVs is not preserved in primates, with the capability of neuronal targeting decreasing. However, glial targeting is generally less affected (Huang, Q. et al. (2019) PLoS One, 14, e0225206; Hordeaux, J. et al. (2019) Mol. Ther.27, 912-921; O’Carroll, S. J., Cook, W. H. & Young D. (2020) Front. Mol. Neurosco.13, 618020). In some embodiments, the AAV is an AAV1, AAV6, AAV6.2, AAV7, AAV9, rh10, rh39 or rh43 serotype. In some embodiments, the AAV vector particle comprises an AAV1, AAV6, AAV6.2, AAV7, AAV9, rh10, rh39 or rh43 serotype capsid protein. In some embodiments, the AAV vector particle is an AAV1, AAV6, AAV6.2, AAV7, AAV9, rh10, rh39 or rh43 vector particle. In some embodiments, the AAV is an AAV9; AAV9 PHP.B; or AAV9 PHP.eB serotype. In some embodiments, the AAV vector particle comprises an AAV9; AAV9 PHP.B; or AAV9 PHP.eB serotype capsid protein. In preferred embodiments, the AAV is an AAV-PHP.eB serotype comprising an AAV-PHP.eB serotype capsid protein. The capsid protein may be an artificial or mutant capsid protein. The term “artificial capsid” as used herein means that the capsid particle comprises an amino acid sequence which does not occur in nature or which comprises an amino acid sequence which has been engineered (e.g. modified) from a naturally occurring capsid amino acid sequence. In other words the artificial capsid protein comprises a mutation or a variation in the amino acid sequence compared to the sequence of the parent capsid from which it is derived where the artificial capsid amino acid sequence and the parent capsid amino acid sequences are aligned. Methods of sequence alignment are well known in the art and referenced herein. The term “adapted for crossing the blood brain barrier” as used herein means that the vector particle has the ability to cross the blood brain barrier, for example the vector particle may comprise a mutation or modification relative to the wild type vector particle which improves the ability to cross the blood brain barrier relative to an unmodified or wild type viral particle. Improved ability to cross the blood brain barrier may be measured for example by measuring the expression of a transgene, e.g. GFP, carried by the vector particle, wherein expression of the transgene in the brain correlates with the ability of the viral particle to cross the blood brain barrier. In some embodiments, the AAV vector particle comprises an artificial capsid amino acid sequence which enables the viral particle to cross the blood-brain barrier. In some embodiments, the AAV vector particle capable of crossing the blood-brain barrier comprises a VP1 capsid protein comprising an amino acid sequence comprising at least four contiguous amino acids from the sequence TLAVPFK (SEQ ID NO: 16) or KFPVALT (SEQ ID NO: 17). In some embodiments, the AAV vector particle capable of crossing the blood-brain barrier comprises a VP1 capsid protein comprising an amino acid sequence comprising at least five contiguous amino acids from the sequence TLAVPFK (SEQ ID NO: 16) or KFPVALT (SEQ ID NO: 17). In some embodiments, the AAV vector particle capable of crossing the blood-brain barrier comprises a VP1 capsid protein comprising an amino acid sequence comprising at least six contiguous amino acids from the sequence TLAVPFK (SEQ ID NO: 16) or KFPVALT (SEQ ID NO: 17). In some embodiments, the AAV vector particle capable of crossing the blood-brain barrier comprises a VP1 capsid protein comprising an amino acid sequence comprising the sequence TLAVPFK (SEQ ID NO: 16) or KFPVALT (SEQ ID NO: 17). In some embodiments, the nucleic acid sequence encoding the at least four, at least five, at least six or all seven contiguous amino acids from the sequence TLAVPFK (SEQ ID NO: 16) or KFPVALT (SEQ ID NO: 17) is inserted at a position corresponding to the position between a sequence encoding for amino acids 588 and 589 of AAV9 (SEQ ID NO: 15). The terms “corresponding to”, “reference to” and “relative to” when used in the context of the numbering of a given amino acid or polynucleotide sequence may refer to the numbering of the residues of a specified reference sequence when the given amino acid or polynucleotide sequence is compared to the reference sequence. In other words, the residue number or residue position of a given polymer is designated with respect to the reference sequence rather than by the actual numerical position of the residue within the given amino acid or polynucleotide sequence. For example, a given amino acid sequence, such as that of an AAV capsid protein, can be aligned to a reference sequence by introducing gaps to optimise residue matches between the two sequences. In these cases, although the gaps are present, the numbering of the residue in the given amino acid or polynucleotide sequence is made with respect to the reference sequence to which it has been aligned. In some embodiments, the AAV vector particle capable of crossing the blood-brain barrier comprises a VP1 capsid protein comprising an amino acid sequence comprising the sequence DGTLAVPFKAQ (SEQ ID NO: 13). In preferred embodiments, the AAV vector particle capable of crossing the blood-brain barrier is AAV9 PHP.eB. In some embodiments, the amino acid sequence of the AAV-PHP.eB capsid VP1 protein is: MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGPGNGLDKGEPVNAADAAALEH DKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSFGGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSP QEPDSSAGIGKSGAQPAKKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSSS GNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPWGYFDFNRFHCHFSPRDWQR LINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANNLTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIP QYGYLTLNDGSQAVGRSSFYCLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKT INGSGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNSEFAWPGASSWALNGRNSLMNPGPAMA SHKEGEDRFFPLSGSLIFGKQGTGRDNVDADKVMITNEEEIKTTNPVATESYGQVATNHQSDGTLAVPFKAQAQT GWVQNQGILPGMVWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTAFNKDKLN SFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTEGVYSEPRPIGTRYLTRNL (SEQ ID NO: 12; AAV-PHP.eB VP1 protein) In some embodiments, the AAV vector particle comprises a capsid comprising an amino acid sequence that has at least 70%, 75%, 80%, 85% or 90% identity to SEQ ID NO: 12, more preferably at least 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 12, wherein the AAV vector particle is capable of crossing the blood-brain barrier. The AAV-PHP.eB vector is described in WO 2017 / 100671, which is incorporated herein by reference. In some embodiments, the AAV vector particle comprises a AAV9 PHP.B capsid, preferably the AAV-PHP.B VP1 capsid protein. In some embodiments, the AAV vector particle capable of crossing the blood-brain barrier is AAV9 PHP.B. In some embodiments, the amino acid sequence of the AAV-PHP.B capsid VP1 protein is: MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGPGNGLDKGEPVNAADAAALEH DKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSFGGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSP QEPDSSAGIGKSGAQPAKKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSSS GNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPWGYFDFNRFHCHFSPRDWQR LINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANNLTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIP QYGYLTLNDGSQAVGRSSFYCLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSRT INGSGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNSEFAWPGASSWALNGRNSLMNPGPAMA SHKEGEDRFFPLSGSLIFGKQGTGRDNVDADKVMITNEEEIKTTNPVATESYGQVATNHQSAQTLAVPFKAQAQT GWVQNQGILPGMVWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTAFNKDKLN SFITQYSTGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTEGVYSEPRPIGTRYLTRNL (SEQ ID NO: 14 AAV-PHP.B) In some embodiments, the AAV vector particle comprises a capsid comprising an amino acid sequence that has at least 70%, 75%, 80%, 85% or 90% identity to SEQ ID NO: 14, more preferably at least 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 14, wherein the AAV vector particle is capable of crossing the blood-brain barrier. The AAV-PHP.B vector is described in Deverman et al. (2016) Nat Biotechnol 34: 204-209 and WO 2015 / 038958, which are incorporated herein by reference. An example amino acid sequence of the (wild-type) AAV9 capsid is: MAADGYLPDWLEDNLSEGIREWWALKPGAPQPKANQQHQDNARGLVLPGYKYLGPGNGLDKGEPVNAADAAALEH DKAYDQQLKAGDNPYLKYNHADAEFQERLKEDTSFGGNLGRAVFQAKKRLLEPLGLVEEAAKTAPGKKRPVEQSP QEPDSSAGIGKSGAQPAKKRLNFGQTGDTESVPDPQPIGEPPAAPSGVGSLTMASGGGAPVADNNEGADGVGSSS GNWHCDSQWLGDRVITTSTRTWALPTYNNHLYKQISNSTSGGSSNDNAYFGYSTPWGYFDFNRFHCHFSPRDWQR LINNNWGFRPKRLNFKLFNIQVKEVTDNNGVKTIANNLTSTVQVFTDSDYQLPYVLGSAHEGCLPPFPADVFMIP QYGYLTLNDGSQAVGRSSFYCLEYFPSQMLRTGNNFQFSYEFENVPFHSSYAHSQSLDRLMNPLIDQYLYYLSKT INGSGQNQQTLKFSVAGPSNMAVQGRNYIPGPSYRQQRVSTTVTQNNNSEFAWPGASSWALNGRNSLMNPGPAMA SHKEGEDRFFPLSGSLIFGKQGTGRDNVDADKVMITNEEEIKTTNPVATESYGQVATNHQSAQAQAQTGWVQNQG ILPGMVWQDRDVYLQGPIWAKIPHTDGNFHPSPLMGGFGMKHPPPQILIKNTPVPADPPTAFNKDKLNSFITQYS TGQVSVEIEWELQKENSKRWNPEIQYTSNYYKSNNVEFAVNTEGVYSEPRPIGTRYLTRNL (SEQ ID NO: 15 AAV9 wt) Reviews of AAV serotypes may be found in Choi et al. (2005) Curr. Gene Ther.5: 299-310 and Wu et al. (2006) Molecular Therapy 14: 316-27. The sequences of AAV genomes or of elements of AAV genomes including ITR sequences, rep or cap genes for use in the invention may be derived from the following accession numbers for AAV whole genome sequences: Adeno-associated virus 1 NC_002077, AF063497; Adeno-associated virus 2 NC_001401; Adeno-associated virus 3 NC_001729; Adeno-associated virus 3B NC_001863; Adeno- associated virus 4 NC_001829; Adeno-associated virus 5 Y18065, AF085716; Adeno- associated virus 6 NC_001862; Avian AAV ATCC VR-865 AY186198, AY629583, NC_004828; Avian AAV strain DA-1 NC_006263, AY629583; Bovine AAV NC_005889, AY388617. AAV may also be referred to in terms of clades or clones. This refers to the phylogenetic relationship of naturally derived AAVs, and typically to a phylogenetic group of AAVs which can be traced back to a common ancestor, and includes all descendants thereof. Additionally, AAVs may be referred to in terms of a specific isolate, i.e. a genetic isolate of a specific AAV found in nature. The term genetic isolate describes a population of AAVs which has undergone limited genetic mixing with other naturally occurring AAVs, thereby defining a recognisably distinct population at a genetic level. The skilled person can select an appropriate serotype, clade, clone or isolate of AAV for use in the invention on the basis of their common general knowledge. The AAV serotype determines the tissue specificity of infection (or tropism) of an AAV virus. Typically, the AAV genome of a naturally derived serotype, isolate or clade of AAV comprises at least one inverted terminal repeat sequence (ITR). An ITR sequence acts in cis to provide a functional origin of replication and allows for integration and excision of the vector from the genome of a cell. In preferred embodiments, one or more ITR sequences flank the nucleotide sequences encoding the BDNF or precursor thereof. The AAV genome may also comprise packaging genes, such as rep and / or cap genes which encode packaging functions for an AAV particle. The rep gene encodes one or more of the proteins Rep78, Rep68, Rep52 and Rep40 or variants thereof. The cap gene encodes one or more capsid proteins such as VP1, VP2 and VP3 or variants thereof. These proteins make up the capsid of an AAV particle. A promoter will be operably linked to each of the packaging genes. Specific examples of such promoters include the p5, p19 and p40 promoters (Laughlin et al. (1979) Proc. Natl. Acad. Sci. USA 76: 5567-5571). For example, the p5 and p19 promoters are generally used to express the rep gene, while the p40 promoter is generally used to express the cap gene. As discussed above, the AAV genome used in the AAV vector of the invention may therefore be the full genome of a naturally occurring AAV. For example, a vector comprising a full AAV genome may be used to prepare an AAV vector or vector particle in vitro. However, while such a vector may in principle be administered to patients, this will rarely be done in practice. Preferably the AAV genome will be derivatised for the purpose of administration to patients. Such derivatisation is standard in the art and the invention encompasses the use of any known derivative of an AAV genome, and derivatives which could be generated by applying techniques known in the art. Derivatisation of the AAV genome and of the AAV capsid are reviewed in Coura and Nardi (2007) Virology Journal 4: 99, and in Choi et al. and Wu et al., referenced above. Derivatives of an AAV genome include any truncated or modified forms of an AAV genome which allow for expression of a transgene from an AAV vector of the invention in vivo. Typically, it is possible to truncate the AAV genome significantly to include minimal viral sequence yet retain the above function. This is preferred for safety reasons to reduce the risk of recombination of the vector with wild-type virus, and also to avoid triggering a cellular immune response by the presence of viral gene proteins in the target cell. Typically, a derivative will include at least one inverted terminal repeat sequence (ITR), preferably more than one ITR, such as two ITRs or more. One or more of the ITRs may be derived from AAV genomes having different serotypes, or may be a chimeric or mutant ITR. A preferred mutant ITR is one having a deletion of a trs (terminal resolution site). This deletion allows for continued replication of the genome to generate a single-stranded genome which contains both coding and complementary sequences, i.e. a self-complementary AAV genome. This allows for bypass of DNA replication in the target cell, and so enables accelerated transgene expression. In some embodiments, the AAV vector comprises at least one, such as two, AAV1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 ITRs. In some embodiments, the AAV vector comprises at least one AAV9 ITR. In some embodiments, the AAV vector comprises two AAV9 ITRs. The one or more ITRs will preferably flank the nucleotide sequence encoding BDNF or a precursor thereof at either end. The inclusion of one or more ITRs is preferred to aid concatamer formation of the vector of the invention in the nucleus of a host cell, for example following the conversion of single-stranded vector DNA into double-stranded DNA by the action of host cell DNA polymerases. The formation of such episomal concatamers protects the vector construct during the life of the host cell, thereby allowing for prolonged expression of the transgene in vivo. In some embodiments, the 5’ ITR comprises or consists of a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 3, and / or the 3’ ITR comprises or consists of a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 4. CTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAGAG AGGGAGTGGCCAACTCCATCACTAGGGGTTCCT (SEQ ID NO: 3) AGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGG TCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAG (SEQ ID NO: 4) In preferred embodiments, ITR elements will be the only sequences retained from the native AAV genome in the derivative. Thus, a derivative will preferably not include the rep and / or cap genes of the native genome and any other sequences of the native genome. This is preferred for the reasons described above, and also to reduce the possibility of integration of the vector into the host cell genome. Additionally, reducing the size of the AAV genome allows for increased flexibility in incorporating other sequence elements (such as regulatory elements) within the vector in addition to the transgene. The following portions could therefore be removed in a derivative of the invention: one inverted terminal repeat (ITR) sequence, the replication (rep) and capsid (cap) genes. However, in some embodiments, derivatives may additionally include one or more rep and / or cap genes or other viral sequences of an AAV genome. Naturally occurring AAV integrates with a high frequency at a specific site on human chromosome 19, and shows a negligible frequency of random integration, such that retention of an integrative capacity in the vector may be tolerated in a therapeutic setting. Where a derivative comprises capsid proteins i.e. VP1, VP2 and / or VP3, the derivative may be a chimeric, shuffled or capsid-modified derivative of one or more naturally occurring AAVs. In particular, the invention encompasses the provision of capsid protein sequences from different serotypes, clades, clones or isolates of AAV within the same vector (i.e. a pseudotyped vector). Thus, in one embodiment the AAV vector is in the form of a pseudotyped AAV vector particle. Chimeric, shuffled or capsid-modified derivatives will be typically selected to provide one or more desired functionalities for the AAV vector. Thus, these derivatives may display increased efficiency of gene delivery, decreased immunogenicity (humoral or cellular), an altered tropism range and / or improved targeting of a particular cell type compared to an AAV vector comprising a naturally occurring AAV genome, such as that of AAV2. Increased efficiency of gene delivery may be effected by improved receptor or co-receptor binding at the cell surface, improved internalisation, improved trafficking within the cell and into the nucleus, improved uncoating of the viral particle and improved conversion of a single-stranded genome to double- stranded form. Increased efficiency may also relate to an altered tropism range or targeting of a specific cell population, such that the vector dose is not diluted by administration to tissues where it is not needed. Chimeric capsid proteins include those generated by recombination between two or more capsid coding sequences of naturally occurring AAV serotypes. This may be performed for example by a marker rescue approach in which non-infectious capsid sequences of one serotype are co-transfected with capsid sequences of a different serotype, and directed selection is used to select for capsid sequences having desired properties. The capsid sequences of the different serotypes can be altered by homologous recombination within the cell to produce novel chimeric capsid proteins. Chimeric capsid proteins also include those generated by engineering of capsid protein sequences to transfer specific capsid protein domains, surface loops or specific amino acid residues between two or more capsid proteins, for example between two or more capsid proteins of different serotypes. Shuffled or chimeric capsid proteins may also be generated by DNA shuffling or by error-prone PCR. Hybrid AAV capsid genes can be created by randomly fragmenting the sequences of related AAV genes e.g. those encoding capsid proteins of multiple different serotypes and then subsequently reassembling the fragments in a self-priming polymerase reaction, which may also cause crossovers in regions of sequence homology. A library of hybrid AAV genes created in this way by shuffling the capsid genes of several serotypes can be screened to identify viral clones having a desired functionality. Similarly, error prone PCR may be used to randomly mutate AAV capsid genes to create a diverse library of variants which may then be selected for a desired property. The sequences of the capsid genes may also be genetically modified to introduce specific deletions, substitutions or insertions with respect to the native wild-type sequence. In particular, capsid genes may be modified by the insertion of a sequence of an unrelated protein or peptide within an open reading frame of a capsid coding sequence, or at the N- and / or C-terminus of a capsid coding sequence. The unrelated protein or peptide may advantageously be one which acts as a ligand for a particular cell type, thereby conferring improved binding to a target cell or improving the specificity of targeting of the vector to a particular cell population (e.g. to astrocytes). The unrelated protein may also be one which assists purification of the viral particle as part of the production process, i.e. an epitope or affinity tag. The site of insertion will typically be selected so as not to interfere with other functions of the viral particle e.g. internalisation, trafficking of the viral particle. The skilled person can identify suitable sites for insertion based on their common general knowledge. The invention additionally encompasses the provision of sequences of an AAV genome in a different order and configuration to that of a native AAV genome. The invention also encompasses the replacement of one or more AAV sequences or genes with sequences from another virus or with chimeric genes composed of sequences from more than one virus. Such chimeric genes may be composed of sequences from two or more related viral proteins of different viral species. The AAV vector of the invention may take the form of a nucleotide sequence comprising an AAV genome or derivative thereof and a sequence encoding the BDNF or a precursor thereof. The AAV particles of the invention include transcapsidated forms wherein an AAV genome or derivative having an ITR of one serotype is packaged in the capsid of a different serotype. The AAV particles of the invention also include mosaic forms wherein a mixture of unmodified capsid proteins from two or more different serotypes makes up the viral capsid. The AAV particle also includes chemically modified forms bearing ligands adsorbed to the capsid surface. For example, such ligands may include antibodies for targeting a particular cell surface receptor. Thus, for example, the AAV particles of the invention include those with an AAV2 genome and AAV9 capsid proteins (AAV2 / 9), or AAV9 PHP.B or PHP.eB capsid proteins. The AAV vector may comprise multiple copies (e.g. 2, 3 etc.) of the nucleotide sequence referred to herein. VARIANTS, DERIVATIVES, ANALOGUES, HOMOLOGUES AND FRAGMENTS In addition to the specific proteins and nucleotides mentioned herein, the invention also encompasses variants, derivatives, analogues, homologues and fragments thereof. In the context of the invention, a “variant” of any given sequence is a sequence in which the specific sequence of residues (whether amino acid or nucleic acid residues) has been modified in such a manner that the polypeptide or polynucleotide in question retains at least one of its endogenous functions. A variant sequence can be obtained by addition, deletion, substitution, modification, replacement and / or variation of at least one residue present in the naturally occurring polypeptide or polynucleotide. The term “derivative” as used herein in relation to proteins or polypeptides of the invention includes any substitution of, variation of, modification of, replacement of, deletion of and / or addition of one (or more) amino acid residues from or to the sequence, providing that the resultant protein or polypeptide retains at least one of its endogenous functions. The term “analogue” as used herein in relation to polypeptides or polynucleotides includes any mimetic, that is, a chemical compound that possesses at least one of the endogenous functions of the polypeptides or polynucleotides which it mimics. Typically, amino acid substitutions may be made, for example from 1, 2 or 3, to 10 or 20 substitutions, provided that the modified sequence retains the required activity or ability. Amino acid substitutions may include the use of non-naturally occurring analogues. Proteins used in the invention may also have deletions, insertions or substitutions of amino acid residues which produce a silent change and result in a functionally equivalent protein. Deliberate amino acid substitutions may be made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity and / or the amphipathic nature of the residues as long as the endogenous function is retained. For example, negatively charged amino acids include aspartic acid and glutamic acid; positively charged amino acids include lysine and arginine; and amino acids with uncharged polar head groups having similar hydrophilicity values include asparagine, glutamine, serine, threonine and tyrosine. Conservative substitutions may be made, for example according to the table below. Amino acids in the same block in the second column and preferably in the same line in the third column may be substituted for each other: ALIPHATIC Non-polar G A P I L V Polar - uncharged C S T M N Q Polar - charged D E K R H AROMATIC F W Y The term “homologue” as used herein means an entity having a certain homology with the wild type amino acid sequence or the wild type nucleotide sequence. The term “homology” can be equated with “identity”. In the present context, a homologous sequence is taken to include an amino acid sequence which may be at least 50%, 55%, 65%, 75%, 85% or 90% identical, preferably at least 95%, 96% or 97% or 98% or 99% identical to the subject sequence. Typically, the homologues will comprise the same active sites etc. as the subject amino acid sequence. Although homology can also be considered in terms of similarity (i.e. amino acid residues having similar chemical properties / functions), in the context of the present invention it is preferred to express homology in terms of sequence identity. In the present context, a homologous sequence is taken to include a nucleotide sequence which may be at least 50%, 55%, 65%, 75%, 85% or 90% identical, preferably at least 95%, 96% or 97% or 98% or 99% identical to the subject sequence. Although homology can also be considered in terms of similarity, in the context of the present invention it is preferred to express homology in terms of sequence identity. Preferably, reference to a sequence which has a percent identity to any one of the SEQ ID NOs detailed herein refers to a sequence which has the stated percent identity over the entire length of the SEQ ID NO referred to. Homology comparisons can be conducted by eye, or more usually, with the aid of readily available sequence comparison programs. These commercially available computer programs can calculate percent homology or identity between two or more sequences. Percent homology may be calculated over contiguous sequences, i.e. one sequence is aligned with the other sequence and each amino acid or nucleotide in one sequence is directly compared with the corresponding amino acid or nucleotide in the other sequence, one residue at a time. This is called an “ungapped” alignment. Typically, such ungapped alignments are performed only over a relatively short number of residues. Although this is a very simple and consistent method, it fails to take into consideration that, for example, in an otherwise identical pair of sequences, one insertion or deletion in the amino acid or nucleotide sequence may cause the following residues or codons to be put out of alignment, thus potentially resulting in a large reduction in percent homology when a global alignment is performed. Consequently, most sequence comparison methods are designed to produce optimal alignments that take into consideration possible insertions and deletions without penalising unduly the overall homology score. This is achieved by inserting “gaps” in the sequence alignment to try to maximise local homology. However, these more complex methods assign “gap penalties” to each gap that occurs in the alignment so that, for the same number of identical amino acids or nucleotides, a sequence alignment with as few gaps as possible, reflecting higher relatedness between the two compared sequences, will achieve a higher score than one with many gaps. “Affine gap costs” are typically used that charge a relatively high cost for the existence of a gap and a smaller penalty for each subsequent residue in the gap. This is the most commonly used gap scoring system. High gap penalties will of course produce optimised alignments with fewer gaps. Most alignment programs allow the gap penalties to be modified. However, it is preferred to use the default values when using such software for sequence comparisons. For example when using the GCG Wisconsin Bestfit package the default gap penalty for amino acid sequences is -12 for a gap and -4 for each extension. Calculation of maximum percent homology therefore firstly requires the production of an optimal alignment, taking into consideration gap penalties. A suitable computer program for carrying out such an alignment is the GCG Wisconsin Bestfit package (University of Wisconsin, USA; Devereux et al. (1984) Nucleic Acids Research 12: 387). Examples of other software that can perform sequence comparisons include, but are not limited to, the BLAST package (see Ausubel et al. (1999) ibid – Ch.18), FASTA (Atschul et al. (1990) J. Mol. Biol. 403-410) and the GENEWORKS suite of comparison tools. Both BLAST and FASTA are available for offline and online searching (see Ausubel et al. (1999) ibid, pages 7-58 to 7-60). However, for some applications, it is preferred to use the GCG Bestfit program. Another tool, BLAST 2 Sequences, is also available for comparing protein and nucleotide sequences (FEMS Microbiol. Lett. (1999) 174(2):247-50; FEMS Microbiol. Lett. (1999) 177(1):187-8). Although the final percent homology can be measured in terms of identity, the alignment process itself is typically not based on an all-or-nothing pair comparison. Instead, a scaled similarity score matrix is generally used that assigns scores to each pairwise comparison based on chemical similarity or evolutionary distance. An example of such a matrix commonly used is the BLOSUM62 matrix (the default matrix for the BLAST suite of programs). GCG Wisconsin programs generally use either the public default values or a custom symbol comparison table if supplied (see the user manual for further details). For some applications, it is preferred to use the public default values for the GCG package, or in the case of other software, the default matrix, such as BLOSUM62. Once the software has produced an optimal alignment, it is possible to calculate percent homology, preferably percent sequence identity. The software typically does this as part of the sequence comparison and generates a numerical result. “Fragments” are also variants and the term typically refers to a selected region of the polypeptide or polynucleotide that is of interest either functionally or, for example, in an assay. “Fragment” thus refers to an amino acid or nucleic acid sequence that is a portion of a full- length polypeptide or polynucleotide. Such variants may be prepared using standard recombinant DNA techniques such as site- directed mutagenesis. Where insertions are to be made, synthetic DNA encoding the insertion together with 5’ and 3’ flanking regions corresponding to the naturally-occurring sequence either side of the insertion site may be made. The flanking regions will contain convenient restriction sites corresponding to sites in the naturally-occurring sequence so that the sequence may be cut with the appropriate enzyme(s) and the synthetic DNA ligated into the cut. The DNA is then expressed in accordance with the invention to make the encoded protein. These methods are only illustrative of the numerous standard techniques known in the art for manipulation of DNA sequences and other known techniques may also be used. Codon optimisation The polynucleotides used in the invention may be codon-optimised. Codon optimisation has previously been described in WO 1999 / 41397 and WO 2001 / 79518. Different cells differ in their usage of particular codons. This codon bias corresponds to a bias in the relative abundance of particular tRNAs in the cell type. By altering the codons in the sequence so that they are tailored to match with the relative abundance of corresponding tRNAs, it is possible to increase expression. By the same token, it is possible to decrease expression by deliberately choosing codons for which the corresponding tRNAs are known to be rare in the particular cell type. Thus, an additional degree of translational control is available. Codon usage tables are known in the art for mammalian cells, as well as for a variety of other organisms. EXEMPLARY VECTORS In one aspect of the invention, there is provided a vector comprising an astrocyte-specific promoter operably linked to a nucleotide sequence encoding brain-derived neurotrophic factor (BDNF), or a precursor thereof. In some embodiments, there is provided a vector comprising an AAV 5’ ITR, an astrocyte- specific promoter, a nucleotide sequence encoding BDNF, or a precursor thereof, and an AAV 3’ ITR, wherein the astrocyte-specific promoter is operably linked to the nucleotide encoding BDNF, or a precursor thereof. In some embodiments, there is provided a vector comprising an AAV 5’ ITR, an astrocyte- specific promoter, a nucleotide sequence encoding BDNF, or a precursor thereof, a WPRE, and an AAV 3’ ITR, wherein the astrocyte-specific promoter is operably linked to the nucleotide encoding BDNF, or a precursor thereof. In some embodiments, there is provided a vector comprising an AAV 5’ ITR, a GFAP promoter, a nucleotide sequence encoding BDNF, or a precursor thereof, and an AAV 3’ ITR, wherein the GFAP promoter is operably linked to the nucleotide encoding BDNF, or a precursor thereof. In some embodiments, there is provided a vector comprising an AAV 5’ ITR, a GFAP promoter, a nucleotide sequence encoding BDNF, or a precursor thereof, a WPRE, and an AAV 3’ ITR, wherein the GFAP promoter is operably linked to the nucleotide encoding BDNF, or a precursor thereof. In some embodiments, there is provided a vector comprising an AAV 5’ ITR, a GFAP promoter, a nucleotide sequence encoding preproBDNF, or a precursor thereof, and an AAV 3’ ITR, wherein the GFAP promoter is operably linked to the nucleotide encoding BDNF, or a precursor thereof. In some embodiments, there is provided a vector comprising an AAV 5’ ITR, a GFAP promoter, a nucleotide sequence encoding preproBDNF, or a precursor thereof, a WPRE, and an AAV 3’ ITR, wherein the GFAP promoter is operably linked to the nucleotide encoding BDNF, or a precursor thereof. In some embodiments, the vector comprises a nucleotide sequence encoding a reporter. In some embodiments, there is provided a vector comprising an AAV 5’ ITR, an astrocyte-specific promoter, a nucleotide sequence encoding BDNF, or a precursor thereof, a nucleotide sequence encoding a reporter, and an AAV 3’ ITR, wherein the astrocyte-specific promoter is operably linked to the nucleotide encoding BDNF, or a precursor thereof. In some embodiments, the vector comprises an AAV 5’ ITR, an astrocyte-specific promoter, a nucleotide sequence encoding BDNF, or a precursor thereof, an internal ribosome-entry site (IRES), a nucleotide sequence encoding a reporter, a WPRE, and an AAV 3’ ITR. In some embodiments, the vector comprises an AAV 5’ ITR, a GFAP promoter, a nucleotide sequence encoding preproBDNF, an IRES, a nucleotide sequence encoding GFP, a WPRE element, and an AAV 3’ ITR. In some embodiments, the vector of the invention comprises or consists of a nucleotide sequence that has at least 70% sequence identity to SEQ ID NO: 11 or a fragment thereof. Suitably, the vector of the invention comprises or consists of a nucleotide sequence that has at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity to SEQ ID NO: 11 or a fragment thereof. In some embodiments, the vector of the invention comprises or consists of the nucleotide sequence SEQ ID NO: 11 or a fragment thereof. CTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGGCCTCAGTGAGCGAGCGAGCG CGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTactagtAACATATCCTGGTGTGGAGTAG GGGACGCTGCTCTGACAGAGGCTCGGGGGCCTGAGCTGGCTCTGTGAGCTGGGGAGGAGGCAGACAGC CAGGCCTTGTCTGCAAGCAGACCTGGCAGCATTGGGCTGGCCGCCCCCCAGGGCCTCCTCTTCATGCC CAGTGAATGACTCACCTTGGCACAGACACAATGTTCGGGGTGGGCACAGTGCCTGCTTCCCGCCGCAC CCCAGCCCCCCTCAAATGCCTTCCGAGAAGCCCATTGAGCAGGGGGCTTGCATTGCACCCCAGCCTGA CAGCCTGGCATCTTGGGATAAAAGCAGCACAGCCCCCTAGGGGCTGCCCTTGCTGTGTGGCGCCACCG GCGGTGGAGAACAAGGCTCTATTCAGCCTGTGCCCAGGAAAGGGGATCAGGGGATGCCCAGGCATGGA CAGTGGGTGGCAGGGGGGGAGAGGAGGGCTGTCTGCTTCCCAGAAGTCCAAGGACACAAATGGGTGAG GGGAGAGCTCTCCCCATAGCTGGGCTGCGGCCCAACCCCACCCCCTCAGGCTATGCCAGGGGGTGTTG CCAGGGGCACCCGGGCATCGCCAGTCTAGCCCACTCCTTCATAAAGCCCTCGTATCCCAGGAGCGAGC AGAGCCAGAGCAGGTTGGAGAGGAGACGCATCACCTCtgctgcttgccaccATGACCATCCTTTTCCT TACTATGGTTATTTCATACTTTGGTTGCATGAAGGCTGCCCCCATGAAAGAAGCAAACATCCGAGGAC AAGGTGGCTTGGCCTACCCAGGTGTGCGGACCCATGGGACTCTGGAGAGCGTGAATGGGCCCAAGGCA GGTTCAAGAGGCTTGACATCATTGGCTGACACTTTCGAACACGTGATAGAAGAGCTGTTGGATGAGGA CCAGAAAGTTCGGCCCAATGAAGAAAACAATAAGGACGCAGACTTGTACACGTCCAGGGTGATGCTCA GTAGTCAAGTGCCTTTGGAGCCTCCTCTTCTCTTTCTGCTGGAGGAATACAAAAATTACCTAGACGCT GCAAACATGTCCATGAGGGTCCGGCGCCACTCTGACCCTGCCCGCCGAGGGGAGCTGAGCGTGTGTGA CAGTATTAGTGAGTGGGTAACGGCGGCAGACAAAAAGACTGCAGTGGACATGTCGGGCGGGACGGTCA CAGTCCTTGAAAAGGTCCCTGTATCAAAAGGCCAACTGAAGCAATACTTCTACGAGACCAAGTGCAAT CCCATGGGTTACACAAAAGAAGGCTGCAGGGGCATAGACAAAAGGCATTGGAACTCCCAGTGCCGAAC TACCCAGTCGTACGTGCGGGCCCTTACCATGGATAGCAAAAAGAGAATTGGCTGGCGATTCATAAGGA TAGACACTTCTTGTGTATGTACATTGACCATTAAAAGGGGAAGATAGGAATTCGATATCAAGCTTATC GCGATACCGTCGACAATCAACCTCTGGATTACAAAATTTGTGAAAGATTGACTGGTATTCTTAACTAT GTTGCTCCTTTTACGCTATGTGGATACGCTGCTTTAATGCCTTTGTATCATGCTATTGCTTCCCGTAT GGCTTTCATTTTCTCCTCCTTGTATAAATCCTGGTTGCTGTCTCTTTATGAGGAGTTGTGGCCCGTTG TCAGGCAACGTGGCGTGGTGTGCACTGTGTTTGCTGACGCAACCCCCACTGGTTGGGGCATTGCCACC ACCTGTCAGCTCCTTTCCGGGACTTTCGCTTTCCCCCTCCCTATTGCCACGGCGGAACTCATCGCCGC CTGCCTTGCCCGCTGCTGGACAGGGGCTCGGCTGTTGGGCACTGACAATTCCGTGGTGTTGTCGGGGA AGCTGACGTCCTTTCCATGGCTGCTCGCCTGTGTTGCCACCTGGATTCTGCGCGGGACGTCCTTCTGC TACGTCCCTTCGGCCCTCAATCCAGCGGACCTTCCTTCCCGCGGCCTGCTGCCGGCTCTGCGGCCTCT TCCGCGTCTTCGCCTTCGCCCTCAGACGAGTCGGATCTCCCTTTGGGCCGCCTCCCCGCCAATTCTGC ATACTTCTTTACATTCCAGATATCTGCATCAAACACCATTGTCACACTCCATCGCGATCACGCGAGCC GAACGAACAAACCCAACAACATGAAACTACCTAGCGCTTCTATTCAGCATGATGTCTTTCGTATACAC AAATTCGGTTCTACAGGGTAACCTAGGCTGCATGTTTAAACATACATACTTCTTTACATTCCAGATAT CTGCATCAAACACCATTGTCACACTCCATCGCGATCACGCGAGCCGAACGAACAAACCCAACAACATG AAACTACCTAGCGCTTCTATTCAGCATGATGTCTTTCGTATACACAAATTCGGTTCTACAGGGTAACC TAGGCTGCATGTTTAAACATACATACTTCTTTACATTCCAGATATCTGCATCAAACACCATTGTCACA CTCCATCGCGATCACGCGAGCCGAACGAACAAACCCAACAACATGAAACTACCTAGCGCTTCTATTCA GCATGATGTCTTTCGTATACACAAATTCGGTTCTACAGGGTAACCTAGGCTGCAGGTACCTTCGAGCA GACATGATAAGATACATTGATGAGTTTGGACAAACCACAACTAGAATGCAGTGAAAAAAATGCTTTAT TTGTGAAATTTGTGATGCTATTGCTTTATTTGTAACCATTATAAGCTGCAATAAACAAGTTAACAACA ACAATTGCATTCATTTTATGTTTCAGGTTCAGGGGGAGATGTGGGAGGTTTTTTAAAGCAAGTAAAAC CTCTACAAATGTGGTAAAATCAAGCTTAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGC GCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTC AGTGAGCGAGCGAGCGCGCAG (SEQ ID NO: 11; AAV GFAPp-BDNF) In some embodiments, the vector of the invention comprises or consists of a nucleotide sequence that has at least 70% sequence identity to SEQ ID NO: 19 or a fragment thereof. Suitably, the vector of the invention comprises or consists of a nucleotide sequence that has at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity to SEQ ID NO: 19 or a fragment thereof. In some embodiments, the vector of the invention comprises or consists of the nucleotide sequence SEQ ID NO: 19 or a fragment thereof. CTGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGGCCTCAGTGAGCGAGCGAGCG CGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTactagtAACATATCCTGGTGTGGAGTAG GGGACGCTGCTCTGACAGAGGCTCGGGGGCCTGAGCTGGCTCTGTGAGCTGGGGAGGAGGCAGACAGC CAGGCCTTGTCTGCAAGCAGACCTGGCAGCATTGGGCTGGCCGCCCCCCAGGGCCTCCTCTTCATGCC CAGTGAATGACTCACCTTGGCACAGACACAATGTTCGGGGTGGGCACAGTGCCTGCTTCCCGCCGCAC CCCAGCCCCCCTCAAATGCCTTCCGAGAAGCCCATTGAGCAGGGGGCTTGCATTGCACCCCAGCCTGA CAGCCTGGCATCTTGGGATAAAAGCAGCACAGCCCCCTAGGGGCTGCCCTTGCTGTGTGGCGCCACCG GCGGTGGAGAACAAGGCTCTATTCAGCCTGTGCCCAGGAAAGGGGATCAGGGGATGCCCAGGCATGGA CAGTGGGTGGCAGGGGGGGAGAGGAGGGCTGTCTGCTTCCCAGAAGTCCAAGGACACAAATGGGTGAG GGGAGAGCTCTCCCCATAGCTGGGCTGCGGCCCAACCCCACCCCCTCAGGCTATGCCAGGGGGTGTTG CCAGGGGCACCCGGGCATCGCCAGTCTAGCCCACTCCTTCATAAAGCCCTCGTATCCCAGGAGCGAGC AGAGCCAGAGCAGGTTGGAGAGGAGACGCATCACCTCtgctgcttgccaccATGACCATCCTTTTCCT TACTATGGTTATTTCATACTTTGGTTGCATGAAGGCTGCCCCCATGAAAGAAGCAAACATCCGAGGAC AAGGTGGCTTGGCCTACCCAGGTGTGCGGACCCATGGGACTCTGGAGAGCGTGAATGGGCCCAAGGCA GGTTCAAGAGGCTTGACATCATTGGCTGACACTTTCGAACACGTGATAGAAGAGCTGTTGGATGAGGA CCAGAAAGTTCGGCCCAATGAAGAAAACAATAAGGACGCAGACTTGTACACGTCCAGGGTGATGCTCA GTAGTCAAGTGCCTTTGGAGCCTCCTCTTCTCTTTCTGCTGGAGGAATACAAAAATTACCTAGACGCT GCAAACATGTCCATGAGGGTCCGGCGCCACTCTGACCCTGCCCGCCGAGGGGAGCTGAGCGTGTGTGA CAGTATTAGTGAGTGGGTAACGGCGGCAGACAAAAAGACTGCAGTGGACATGTCGGGCGGGACGGTCA CAGTCCTTGAAAAGGTCCCTGTATCAAAAGGCCAACTGAAGCAATACTTCTACGAGACCAAGTGCAAT CCCATGGGTTACACAAAAGAAGGCTGCAGGGGCATAGACAAAAGGCATTGGAACTCCCAGTGCCGAAC TACCCAGTCGTACGTGCGGGCCCTTACCATGGATAGCAAAAAGAGAATTGGCTGGCGATTCATAAGGA TAGACACTTCTTGTGTATGTACATTGACCATTAAAAGGGGAAGATAGGAATTCCTGAGATCCGCCCCT CTCCCTCCCCCCCCCCTAACGTTACTGGCCGAAGCCGCTTGGAATAAGGCCGGTGTGCGTTTGTCTAT ATGTTATTTTCCACCATATTGCCGTCTTTTGGCAATGTGAGGGCCCGGAAACCTGGCCCTGTCTTCTT GACGAGCATTCCTAGGGGTCTTTCCCCTCTCGCCAAAGGAATGCAAGGTCTGTTGAATGTCGTGAAGG AAGCAGTTCCTCTGGAAGCTTCTTGAAGACAAACAACGTCTGTAGCGACCCTTTGCAGGCAGCGGAAC CCCCCACCTGGCGACAGGTGCCTCTGCGGCCAAAAGCCACGTGTATAAGATACACCTGCAAAGGCGGC ACAACCCCAGTGCCACGTTGTGAGTTGGATAGTTGTGGAAAGAGTCAAATGGCTCTCCTCAAGCGTAT TCAACAAGGGGCTGAAGGATGCCCAGAAGGTACCCCATTGTATGGGATCTGATCTGGGGCCTCGGTGC ACATGCTTTACATGTGTTTAGTCGAGGTTAAAAAAACGTCTAGGCCCCCCGAACCACGGGGACGTGGT TTTCCTTTGAAAAACACGATGATAATACCGGTCGCCACCATGGTGAGCAAGGGCGAGGAGCTGTTCAC CGGGGTGGTGCCCATCCTGGTCGAGCTGGACGGCGACGTAAACGGCCACAAGTTCAGCGTGTCCGGCG AGGGCGAGGGCGATGCCACCTACGGCAAGCTGACCCTGAAGTTCATCTGCACCACCGGCAAGCTGCCC GTGCCCTGGCCCACCCTCGTGACCACCCTGACCTACGGCGTGCAGTGCTTCAGCCGCTACCCCGACCA CATGAAGCAGCACGACTTCTTCAAGTCCGCCATGCCCGAAGGCTACGTCCAGGAGCGCACCATCTTCT TCAAGGACGACGGCAACTACAAGACCCGCGCCGAGGTGAAGTTCGAGGGCGACACCCTGGTGAACCGC ATCGAGCTGAAGGGCATCGACTTCAAGGAGGACGGCAACATCCTGGGGCACAAGCTGGAGTACAACTA CAACAGCCACAACGTCTATATCATGGCCGACAAGCAGAAGAACGGCATCAAGGTGAACTTCAAGATCC GCCACAACATCGAGGACGGCAGCGTGCAGCTCGCCGACCACTACCAGCAGAACACCCCCATCGGCGAC GGCCCCGTGCTGCTGCCCGACAACCACTACCTGAGCACCCAGTCCGCCCTGAGCAAAGACCCCAACGA GAAGCGCGATCACATGGTCCTGCTGGAGTTCGTGACCGCCGCCGGGATCACTCTCGGCATGGACGAGC TGTACAAGTCCGGACTCAGATCTCGACTAGCTAGTAGCTAGGTCGACAATCAACCTCTGGATTACAAA ATTTGTGAAAGATTGACTGGTATTCTTAACTATGTTGCTCCTTTTACGCTATGTGGATACGCTGCTTT AATGCCTTTGTATCATGCTATTGCTTCCCGTATGGCTTTCATTTTCTCCTCCTTGTATAAATCCTGGT TGCTGTCTCTTTATGAGGAGTTGTGGCCCGTTGTCAGGCAACGTGGCGTGGTGTGCACTGTGTTTGCT GACGCAACCCCCACTGGTTGGGGCATTGCCACCACCTGTCAGCTCCTTTCCGGGACTTTCGCTTTCCC CCTCCCTATTGCCACGGCGGAACTCATCGCCGCCTGCCTTGCCCGCTGCTGGACAGGGGCTCGGCTGT TGGGCACTGACAATTCCGTGGTGTTGTCGGGGAAGCTGACGTCCTTTCCATGGCTGCTCGCCTGTGTT GCCACCTGGATTCTGCGCGGGACGTCCTTCTGCTACGTCCCTTCGGCCCTCAATCCAGCGGACCTTCC TTCCCGCGGCCTGCTGCCGGCTCTGCGGCCTCTTCCGCGTCTTCGCCTTCGCCCTCAGACGAGTCGGA TCTCCCTTTGGGCCGCCTCCCCGCCAATTCTGCATACTTCTTTACATTCCAGATATCTGCATCAAACA CCATTGTCACACTCCATCGCGATCACGCGAGCCGAACGAACAAACCCAACAACATGAAACTACCTAGC GCTTCTATTCAGCATGATGTCTTTCGTATACACAAATTCGGTTCTACAGGGTAACCTAGGCTGCATGT TTAAACATACATACTTCTTTACATTCCAGATATCTGCATCAAACACCATTGTCACACTCCATCGCGAT CACGCGAGCCGAACGAACAAACCCAACAACATGAAACTACCTAGCGCTTCTATTCAGCATGATGTCTT TCGTATACACAAATTCGGTTCTACAGGGTAACCTAGGCTGCATGTTTAAACATACATACTTCTTTACA TTCCAGATATCTGCATCAAACACCATTGTCACACTCCATCGCGATCACGCGAGCCGAACGAACAAACC CAACAACATGAAACTACCTAGCGCTTCTATTCAGCATGATGTCTTTCGTATACACAAATTCGGTTCTA CAGGGTAACCTAGGCTGCAGGTACCTTCGAGCAGACATGATAAGATACATTGATGAGTTTGGACAAAC CACAACTAGAATGCAGTGAAAAAAATGCTTTATTTGTGAAATTTGTGATGCTATTGCTTTATTTGTAA CCATTATAAGCTGCAATAAACAAGTTAACAACAACAATTGCATTCATTTTATGTTTCAGGTTCAGGGG GAGATGTGGGAGGTTTTTTAAAGCAAGTAAAACCTCTACAAATGTGGTAAAATCAAGCTTAGGAACCC CTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGACCAAAGGT CGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCAG (SEQ ID NO: 19; AAV GFAPp-BDNF-IRES-GFP) PHARMACEUTICAL COMPOSITIONS AND INJECTED SOLUTIONS Although the agents for use in the invention can be administered alone, they will generally be administered in admixture with a pharmaceutical carrier, excipient or diluent, particularly for human therapy. The medicaments, for example vector particles, of the invention may be formulated into pharmaceutical compositions. These compositions may comprise, in addition to the medicament, a pharmaceutically acceptable carrier, diluent, excipient, buffer, stabiliser or other materials well known in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other material may be determined by the skilled person according to the route of administration, e.g. intravenous or intra-arterial. The pharmaceutical composition is typically in liquid form. Liquid pharmaceutical compositions generally include a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, magnesium chloride, dextrose or other saccharide solution, or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included. In some cases, a surfactant, such as pluronic acid (PF68) 0.001% may be used. In some cases, serum albumin may be used in the composition. For injection, the active ingredient may be in the form of an aqueous solution which is pyrogen- free, and has suitable pH, isotonicity and stability. The skilled person is well able to prepare suitable solutions using, for example, isotonic vehicles such as Sodium Chloride Injection, Ringer's Injection or Lactated Ringer's Injection. Preservatives, stabilisers, buffers, antioxidants and / or other additives may be included as required. For delayed release, the medicament may be included in a pharmaceutical composition which is formulated for slow release, such as in microcapsules formed from biocompatible polymers or in liposomal carrier systems according to methods known in the art. Handling of the cell therapy products is preferably performed in compliance with FACT-JACIE International Standards for cellular therapy. SUBJECT AND USE The term “subject” as used herein refers to either a human or non-human animal. Examples of non-human animals include vertebrates, for example mammals, such as non- human primates (particularly higher primates), dogs, rodents (e.g. mice, rats or guinea pigs), pigs and cats. The non-human animal may be a companion animal. Preferably, the subject is human. In some embodiments, the subject may have a BDNF-associated disease, for example Rett syndrome, infantile cognitive disabilities, autism spectrum disorder and age-related neurodegenerative disorders. In some embodiments, the subject may be at risk of developing a BDNF-associated disease. In preferred embodiments, the subject may have or is at risk of developing Rett syndrome. The subject may be diagnosed with a BDNF-associated disease or have been identified as being at risk of developing a BDNF-associated disease by any suitable method known in the art. The skilled person would be aware of symptoms of a BDNF-associated disease, for example aware of symptoms such as slowing development, loss of hand function and mobility, slowed brain and head growth, issues with walking, walking with a wide-based gait, walking on the toes, seizures, cognitive problems, digestive problems, issues with motor function, and breathing issues while awake as symptoms of Rett syndrome. The skilled person would be aware of genetic markers and risk factors associated with a BDNF-associated disease, for example mutations in the MECP2 gene as markers of Rett syndrome. In one embodiment the subject is a mouse model of Rett syndrome. In one aspect, there is provided a vector, a cell, or a pharmaceutical composition according to the invention for use as a medicament. In one aspect, there is provided a vector, a cell, or a pharmaceutical composition according to the invention for use in the treatment or prevention of a BDNF-associated disease. In another aspect, there is provided the use of a vector, a cell, or a pharmaceutical composition according to the invention in the manufacture of a medicament for treating or preventing a BDNF-associated disease. In one aspect, there is provided a method for treating or preventing a BDNF-associated disease, wherein a vector, a cell, or a pharmaceutical composition according to the invention is administered to a subject in need thereof. In some embodiments, the use in treatment or the method of treatment provides BDNF to the central nervous system of a subject. In some embodiments, the use in treatment or the method of treatment provides BDNF to the cortex and cerebellum of a subject. In some embodiments, the use in treatment or the method of treatment provides BDNF to the somatosensory cortex and / or striatum of a subject. In some embodiments, the use in treatment or the method of treatment provides BDNF to neuronal cells. In some embodiments, the use in treatment or the method of treatment provides an improvement in motor function in a subject. Methods for measuring motor function are known to those skilled in the art, for example, the beam balance test, the open-field arena, and the rotarod. In some embodiments, the use in treatment or the method of treatment provides an improvement in learning and / or cognitive function in a subject. Methods for measuring learning and / or cognitive function are known to those skilled in the art. For example, in humans the General Practitioner Assessment of Cognition (GPCOG) test may be used. Alternative cognitive tests include but are not limited to the Mini Mental State Examination (MMSE), The Six-item Cognitive Impairment Test (6CIT), Abbreviated Mental Test (AMT) and Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). In some embodiments, the use in treatment or the method of treatment may provide a rescue of a slowed development in a subject. In some embodiments, the use in treatment or the method of treatment may provide an extension of lifespan in a subject. In some embodiments, the use in treatment or the method of treatment further comprises the additional step of carrying out blood tests at, during, or after administration of the vector, cell or pharmaceutical composition of the invention. In some embodiments, the subject’s blood glucose concentration is monitored at, during or after administration of the vector, cell or pharmaceutical composition of the invention. In some embodiments, the use in treatment or the method of treatment further comprises administration of a high-calorie diet, for example in response to a fall in the subject’s blood glucose concentration following administration of the vector, cell or pharmaceutical composition of the invention. ADMINISTRATION In some embodiments, the vector, cell or pharmaceutical composition is administered to a subject systemically. In some embodiments, the vector, cell or pharmaceutical composition is administered to a subject locally. In some embodiments, the vector, cell or pharmaceutical composition is administered to a subject intracranially, intracerebrally or intraparenchymally. The term “systemic delivery” or “systemic administration” as used herein means that the agent of the invention is administered into the circulatory system, for example to achieve broad distribution of the agent. In contrast, topical or local administration restricts the delivery of the agent to a localised area, e.g. intracerebral administration entails direct injection into the brain. In some embodiments, the vector, cell or pharmaceutical composition is administered intravascularly, intravenously or intra-arterially. Suitably, in some embodiments the vector, cell or pharmaceutical composition is administered to the internal carotid artery. As used herein, the term “agent” may refer to the vector, cell or pharmaceutical composition of the invention. In some embodiments, the vector, cell or pharmaceutical composition is administered simultaneously, sequentially or separately in combination with an immunosuppressant. In some embodiments, the immunosuppressant is cyclosporin A (CsA). In some embodiments, the vector, cell or pharmaceutical composition may be administered simultaneously, sequentially or separately in combination with a high-calorie diet. In some embodiments, the vector, cell or pharmaceutical composition may be administered prior to administration of a high-calorie diet. In some embodiments, a high-calorie diet may be administered following administration of the vector, cell or pharmaceutical composition of the present invention. In some embodiments, a high-calorie diet may be administered up to 1 day, up to 2 days, up to 3 days, up to 4 days, up to 5 days, up to 6 days, up to 7 days, up to 8 days, up to 9 days, up to 10 days, up to 11 days, up to 12 days, up to 13 days, up to 14 days, up to 3 weeks, up to 4 weeks, up to 5 weeks, up to 6 weeks, up to 7 weeks, up to 8 weeks, up to 3 months, up to 6 months, up to a year, or indefinitely following administration of the vector, cell or pharmaceutical composition of the present invention. In some embodiments, a subject’s blood glucose concentration may be monitored following administration of the vector, cell or pharmaceutical composition of the present invention, and a high-calorie diet administered if blood glucose concentration falls. The term “combination”, or terms “in combination”, “used in combination with” or “combined preparation” as used herein may refer to the combined administration of two or more agents or approaches simultaneously, sequentially or separately. The term “simultaneous” as used herein means that the agents or approaches are administered concurrently, i.e. at the same time. The term “sequential” as used herein means that the agents or approaches are administered one after the other. The term “separate” as used herein means that the agents or approaches are administered independently of each other but preferably within a time interval that allows the agents or approaches to show a combined, preferably synergistic, effect. Thus, administration “separately” may permit one agent or approach to be administered, for example, within 1 minute, 5 minutes or 10 minutes after the other. Dosage The skilled person can readily determine an appropriate dose of an agent of the invention to administer to a subject. Typically, a physician will determine the actual dosage which will be most suitable for an individual patient and it will depend on a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual undergoing therapy. There can of course be individual instances where higher or lower dosage ranges are merited, and such are within the scope of the invention. The therapeutic applications provided by the invention may comprise administration of a therapeutically effective amount of a vector, a cell, or a pharmaceutical composition according to the invention. The term “therapeutically effective amount”, as used herein, refers to an amount of a vector, a cell, or a pharmaceutical composition that is required to reduce in severity, ameliorate or prevent symptoms of a BDNF-associated disease, such as Rett Syndrome. In some embodiments, the therapeutically effective amount is an amount of a vector, a cell, or a pharmaceutical composition that is required to provide an improvement in motor function in a subject. In some embodiments, the therapeutically effective amount is an amount of a vector, a cell, or a pharmaceutical composition that is required to provide an improvement in learning and / or cognitive function in a subject. In some embodiments, the vector is administered at a dosage of 5×109to 5×1014vg per kilogram of body weight. In some embodiments, the vector is administered at a dosage of 5×1010to 5×1014vg per kilogram of body weight. In some embodiments, the vector is administered at a dosage of 5×1011to 5×1014vg per kilogram of body weight. In some embodiments, the vector is administered at a dosage of 5×1012to 5×1014vg per kilogram of body weight. In some embodiments, the vector is administered at a dosage of 5×1013to 5×1014vg per kilogram of body weight. In some embodiments, the vector is administered at a dosage of 5×1013to 2×1014vg per kilogram of body weight. In some embodiments, the vector is administered at a dosage of 6×1013to 2×1014vg per kilogram of body weight. In some embodiments, the vector is administered at a dosage of 6.7×1013to 2.0×1014vg per kilogram of body weight. The skilled person will understand that they can combine all features of the invention disclosed herein without departing from the scope of the invention as disclosed. Preferred features and embodiments of the invention will now be described by way of non- limiting examples. The practice of the present invention will employ, unless otherwise indicated, conventional techniques of chemistry, biochemistry, molecular biology, microbiology and immunology, which are within the capabilities of a person of ordinary skill in the art. Such techniques are explained in the literature. See, for example, Sambrook, J., Fritsch, E.F. and Maniatis, T. (1989) Molecular Cloning: A Laboratory Manual, 2nd Edition, Cold Spring Harbor Laboratory Press; Ausubel, F.M. et al. (1995 and periodic supplements) Current Protocols in Molecular Biology, Ch.9, 13 and 16, John Wiley & Sons; Roe, B., Crabtree, J. and Kahn, A. (1996) DNA Isolation and Sequencing: Essential Techniques, John Wiley & Sons; Polak, J.M. and McGee, J.O’D. (1990) In Situ Hybridization: Principles and Practice, Oxford University Press; Gait, M.J. (1984) Oligonucleotide Synthesis: A Practical Approach, IRL Press; and Lilley, D.M. and Dahlberg, J.E. (1992) Methods in Enzymology: DNA Structures Part A: Synthesis and Physical Analysis of DNA, Academic Press. Each of these general texts is herein incorporated by reference. EXAMPLES EXAMPLE 1 Designing an astrocyte-specific transgene expression cassette To explore using astrocytes as a “factory” to produce neurotrophins, we tested an astrocyte- specific promoter (Chan, K. Y. et al. (2016) Nat. Biotechnol., 34, 204-209). This promoter derived from the natural promoter of the Glial Fibrillary Acidic Protein (GFAP) gene, which is expressed exclusively in astrocytes. To this end, we designed a construct carrying the GFP reporter gene under the GFAP-derived promoter (herein, GFAPp-GFP). Then, to exclude a possible mis-expression in neurons or other glia cells, we considered the AAV-PHP.eB to vehicle this transgene cassette in the brain of C57 / B6 neonatal mice (Figure 1A). The AAV- PHP.eB in fact targets with an equal efficiency both neurons and glia (in particular astrocytes) in rodents (Chan, K. Y. et al. (2016) Nat. Biotechnol., 34, 204-209). Thus, after four weeks from the injections, treated mice were sacrificed and the CNS transgene expression was analyzed by immunofluorescence (Figure 1A). Mice brains were stained with GFP and Sox9, an astrocyte-specific marker (Luoni, M. et al. (2020) Elife, 9), confirming that 99% of GFP+ cells were effectively Sox9+ astrocytes (Figure 1B). Neurons and other glia were only marginally targeted supporting the high specificity of this promoter. BDNF treatment with high dose After testing the GFAP promoter specificity, we generated a bicistronic vector that exploited the IRES sequence to express both the preproBDNF coding cassette and the GFP reporter (herein GFAPp-BDNF). We then treated either wild-type or Mecp2-null (heirein, Mecp2-KO (Guy, J., Hendrich, B., Holmes, M., Martin, J. E. & Bird, A., (2001) Nat. Genet.27, 322-326)) animals at neonatal stage with the dose of 1010vg / mouse, using the GFAPp-GFP construct as control (Figure 2A). After a few days from the injection, BDNF-treated mice started to lose weight (Figure 2B-C). Since BDNF is a known regulator of the endocrinological functions at hypothalamic level, acting in particular on glucose metabolism (Nakagawa, T. et al. (2002) Diabetes. Metab. Res. Rev.18, 185-191; Gotoh, K. et al. (2013) J. Neuroendocrinol.25, 302- 311), we decided to investigate the blood glucose levels of treated animals. As expected, glucose levels were around three times lower than control mice and below the lowest threshold of 100mg / dl (Figure 2D). Adjusting the dose of BDNF treatment induced a significant improvement of the pathological phenotype of Mecp2-KO mice We decided to adjust the dose, testing a 10-fold lower dosage (109vg / mouse, Figure 3A). With this treatment, we did not observe any adverse effects immediately after the injection and glucose levels were comparable to those of control GFP-treated mice (Figure 3B). Moreover, neither the growth curve nor the lifespan of wild-type treated animals were affected compared to controls after three months of life (Figure 3B-C). Regarding Mecp2-KO mice, we monitored these animals for their general condition and locomotor activity during the second month of life. Symptoms of Mecp2-KO animals generally occur and progress during this period and include tremors, respiratory abnormalities and a severe motor impairment. These symptoms rapidly lead to a sudden weight loss and a premature death in around 8-10 weeks of life. We observed that for mice administered the BDNF treatment their locomotor activity was clearly ameliorated after BDNF treatment as assessed by three independent behavioural tests: the beam balance test (Figure 3D), the open-field arena (Figure 3E) and the rotarod (Figure 3F). The growth curve and lifespan of Mecp2-KO treated mice also showed moderate improvement after the BDNF treatment (Figure 3B-C). Our results thus confirmed the effectiveness of the BDNF treatment in ameliorating the pathological RTT phenotype, particularly at locomotor level. BDNF treatment sustained a consistent the AKT / mTOR signaling pathway To compare the efficiency of transduction of astrocytes between the two dosages, we performed an immunofluorescence analysis using the GFP reporter. This confirmed that both dosages were able to efficiently target exclusively astrocytes in the cortex and other brain areas (Figure 4A). Then, to measure the BDNF amount in these brains we used an ELISA assay, observing an increase amount of this factor proportional to the viral dose (Figure 4A). Finally, since BDNF regulates the mTOR / AKT signaling pathway and since the alteration of this pathway is considered to be strictly involved in the pathological mechanism of Rett syndrome (Ricciardi, S. et al. (2011) Hum. Mol. Genet. 20, 1182-1196; Olson, C. O. et al. (2018) Front. Genet. 9, 1-17), we decided to investigate the effect of our treatment on this important protein complex. To do this, we performed a Western blot analysis to measure the amount of phosphorylated S6 (pS6) protein, a classic marker of mTOR activity (Biever, A., Valjent, E. & Puighermanal, E. (2015) Front. Mol. Neurosci. 8). We observed a significant increase in pS6 in the brains of BDNF-treated mice for both viral doses compared to control animals (Figure 4B). In summary, BDNF treatment promoted a wide recovery of mTOR / AKT activity in Mecp2-KO mice, whose functions are important for correct neuronal maturation and synaptic plasticity. DISCUSSION Herein, we proposed an alternative AAV-mediated gene therapy approach for RTT based on the overexpression of BDNF in the CNS of RTT mice. We set our transgene configuration to explore using astrocytes as a factory to diffuse BDNF throughout the brain parenchyma. We tested two viral doses and confirmed that the BDNF treatment could significantly improve the pathological phenotype of Mecp2-KO mice. In particular, we observed a remarkable amelioration of the locomotor activity and coordination. Finally, we correlated the beneficial effect of BDNF treatment with the increase of the mTOR / AKT signaling pathway. Indeed, this pathway is fundamental for cellular processes involved either in neuronal maturation, synaptic activity and plasticity (Bazzari, A. H. & Bazzari, F. H. (2022) Int. J. Mol. Sci.23). Dysregulation of mTOR / AKT pathway in Mecp2-KO mice has been shown to lead to a severe defect in protein synthesis that anticipated the symptoms onset (Ricciardi, S. et al. (2011) Hum. Mol. Genet. 20, 1182-1196). Thus, the improvement of the mTOR pathway mediated by BDNF treatment is important for restoring translational processes affected in Mecp2 deficient mice. With the lower dosage in wild-type mice we did not observe any significant alteration neither in the motor behaviour nor in the normal development and viability. In humans it will be possible to monitor glucose levelsthrough blood tests and counteract any depletions with higher-calorie diets. Overall, our approach is an alternative to the current pharmacological therapies for RTT patients. The “classic” gene therapy based on the restoration of Mecp2 function requires neuronal expression. However, to date, despite the fact that several preclinical studies in mice have demonstrated its efficacy (Luoni, M. et al. (2020) Elife, 9; Sinnett, S. E. et al. (2017) Mol. Ther. – Methods Clin. Dev.5, 180-190; Gadalla, K. K. E. et al. (2017) Mol. Ther. – Methods Clin. Dev.5, 180-190; Matagne, V. et al. (2017) Neurobiol. Dis.99, 1-11), there are no AAVs capable of efficiently transducing neurons in the brains of primates (Campos, L. J. et al. (2023) Curr. Res. Neurobiol. 4, 100086). On the contrary, our alternative approach, by taking advantage of astrocytes and their ability to release neurotrophins like BDNF, does not require an AAV with high neurotropism. Indeed, many AAVs, despite losing the ability to transduce neurons in the transition from rodents to primates, still maintain a good tropism for glia (Giannelli, S. G. (2023) bioRxiv 2023.06.27.546696; Campos, L. J. et al. (2023) Curr. Res. Neurobiol.4, 100086. MATERIALS AND METHODS Plasmid cloning The AAV plasmid carrying the GFAP-derived promoter was bought from Addgene (#99129) and the plasmid containing the entire human BDNF gene sequence were bought from Invivogen (NM_170735). Then, GFP or BDNF sequence was amplified by PCR to add the restriction site EcoNI and BamHI and cloned downstream the GFAP-derived promoter. The cassette carrying the IRES-GFP was subsequently cloned downstream the BDNF sequence through the addition of the restriction enzyme site EcorI and SalI by PCR. Mice Mice were maintained at San Raffaele Scientific Institute Institutional mouse facility (Milan, Italy) in micro-isolators under sterile conditions and supplied with autoclaved food and water. The Mecp2- / y mice (Guy et al., 2001) (The Jackson Laboratory stock #003890) were maintained on C57BL / 6J background. All procedures were performed according to protocols approved by the internal IACUC and reported to the Italian Ministry of Health according to the European Communities Council Directive 2010 / 63 / EU. AAVs production and purification AAV replication-incompetent, recombinant viral particles were produced 293T cells, cultured in Dulbecco Modified Eagle Medium – high glucose (Sigma-Aldrich) containing 10% fetal bovine serum (Sigma-Aldrich), 1% non-essential amino acids (Gibco), 1% sodium pyruvate (Sigma-Aldrich), 1% glutamine (Sigma-Aldrich) and 1% penicillin / streptomycin (Sigma- Aldrich). Cells were split every 3-4 days using Trypsin 0.25% (Sigma-Aldrich). Replication- incompetent, recombinant viral particles were produced in 293T cells by polyethylenimine (PEI) (Polyscience) co-transfection of three different plasmids: transgene-containing plasmid, packaging plasmid for rep and cap genes and pHelper (Agilent) for the three adenoviral helper genes. The cells and supernatant were harvested at 120 hrs. Cells were lysed in hypertonic buffer (40 mM Tris, 500 mM NaCl, 2 mM MgCl2, pH=8) containing 100U / ml Salt Active Nuclease (SAN, Arcticzymes) for 1h at 37°C, whereas the viral particles present in the supernatant were concentrated by precipitation with 8% PEG8000 (Polyethylene glycol 8000, Sigma-Aldrich) and then added to supernatant for an additional incubation of 30min at 37°C. In order to clarify the lysate cellular debris where separated by centrifugation (4000g, 30min). The viral phase was isolated by iodixanol step gradient (15%, 25%, 40%, 60% Optiprep, Sigma-Aldrich) in the 40% fraction and concentrated in PBS (Phosphate Buffer Saline) with 100K cut-off concentrator (Amicon Ultra15, MERCK-Millipore). Virus titers were determined using AAVpro© Titration Kit Ver2 (TaKaRa). AAV-PHP.eB vector injection, mouse phenotyping and tissue collection Mice were genotyped at P1 and the day after they were injected in the temporal vein with 30ul of AAV-PHP.eB particles in PBS from 1*109to 1*1010vg / mouse. Following injection, all mice were weighed three times a week. The balance and the motor coordination were assessed by the Beam Balance test, the Rotarod and the Open-field arena. For the first test, mice were placed on the tip of the beam at the “start-point” facing towards the beam. The number of foot- slips (error numbers) and total time on beam (crossing time) from “start” to “end” points were noted. If a mouse fell, the animal was returned to the site where it fell from, until completion of beam crossing. The Open Field test was performed in an arena of 50 × 50 cm. Mice were testing in a 10 minutes sessions measured as an index of anxiety and horizontal exploratory activity in a novel environment was assessed. For Rotarod (Ugo-Basile, Stoelting Co.) test, revolutions per minute (rpm) were set at an initial value of 4 with a progressive increase to a maximum of 40 rpm across the 5 minutes test session. The animals were given two days of training and three consecutive days of test, each session consisting of three trials. Latency to fall was measured by the rotarod timer. For blood glucose analysis, blood samples were collected from living animals using retro- orbital bleeding procedure with non-heparinized capillaries. Upon blood clothing cell fraction was pelleted (5min, 13000 rpm) and supernatant recovered. When the body loss reached 20% of total weight mice were sacrificed and tissues harvested. Briefly, mice were anesthetized with ketamine / xylazine and transcardially perfused with 0.1 M phosphate buffer (PB) at room temperature (RT) at pH 7.4. Upon this treatment the brain was collected. Brain hemispheres were separated: one half was post-fixed in 4% PFA for two days and then soaked in cryoprotective solution (30% sucrose in PBS) for immunofluorescence analysis the other further sectioned in different areas (cortex, striatum. cerebellum) quick frozen on dry-ice for Western blot and ELISA. Immunofluorescence Tissues were sectioned using cryostat after optimal cutting temperature compound (OCT) embedding in dry ice. Free-floating 50μm-thick coronal sections were rinsed in PBS and were incubated with 10% donkey serum (Sigma-Aldrich) and 3% Triton X-100 (Sigma-Aldrich) for 1 hr at RT to saturate the unspecific binding site before the overnight incubation at 4°C with the primary antibody (diluted in the blocking solution). Upon wash with PBS (3×), sections were incubated for 1 h at RT in blocking solution with DAPI (1:1000, Sigma-Aldrich) and with Alexa Fluor-488 and Alexa Fluor-594 anti-rabbit or anti-chicken secondary antibodies (1:1000, ThermoFisher Scientific). After PBS washes (3×), sections were mounted with fluorescent mounting medium (Dako). Tissues where stained with the following primary antibody: chicken anti-GFP (1:500; Dako), rabbit anti-Sox9 (1:500; Sugma-Aldrich). ELISA and Western Blot Brain protein extracts were prepared in RIPA buffer (10 mM Tris-HCl pH7.4, 150 mM NaCl, 1 mM EGTA, 0.5% Triton and complete 1% protease and phosphatase inhibitor mixture, Roche Diagnostics). Brain lysate samples (50 μg protein lysates) were used for ELISA anti- BDNF according to manufacturing guidelines. For Western Blot, 50ug of proteins were separated using 8% polyacrylamide gel and then transferred to PVDF membranes. Membranes were incubated overnight at 4°C with the following primary antibodies in 1X PBST with 5% w / v nonfat dry: rabbit anti-pS6235 / 236 (1:500, Cell Signaling), rabbit anti-S6 (1:500, Cell Signaling), mouse anti-β-Actin (1:50000; Sigma). Subsequently, membranes were incubated with the corresponding horseradish peroxidase (HRP)-conjugated secondary antibodies (1:10000; Dako). The signal was then revealed with a chemiluminescence solution (ECL reagent, RPN2232; GE Healthcare) and detected with the ChemiDoc imaging system (Bio-Rad). Statistics Values are expressed as mean ± standard deviation as indicated. All statistical analysis was carried out in GraphPad Prism 8.0, using one-way ANOVA, two-way ANOVA, Mantel-Cox test (survival curves). P-values below 0.05 were considered significant. In multi-group comparisons, multiple testing correction for pairwise tests among groups was applied using Tukey’s post hoc analysis.

Claims

CLAIMS 1. A vector comprising an astrocyte-specific promoter operably linked to a nucleotide sequence encoding brain-derived neurotrophic factor (BDNF), or a precursor thereof.

2. The vector of claim 1, wherein the BDNF or precursor thereof is mature BDNF (mBDNF), pro-protein BDNF (proBDNF) or pre-pro-protein BDNF (preproBDNF).

3. The vector of claim 1 or 2, wherein the nucleotide sequence encoding BDNF, or the precursor thereof, comprises or consists of: (a) a nucleotide sequence encoding an amino acid sequence having at least 70% sequence identity to SEQ ID NO: 1, 6 or 7; (b) a nucleotide sequence having at least 70% sequence identity to SEQ ID NO: 5, 8 or 9; or (c) the nucleotide sequence of SEQ ID NO: 5, 8 or 9.

4. The vector of any preceding claim, wherein the astrocyte-specific promoter is a Glial Fibrillary Acidic Protein (GFAP) promoter or an aldehyde dehydrogenase family 1, member L1 (ALDH1L1) promoter.

5. The vector of any preceding claim, wherein the astrocyte-specific promoter comprises or consists of: (a) a nucleotide sequence having at least 70% sequence identity to SEQ ID NO: 2; or (b) the nucleotide sequence of SEQ ID NO:

2.

6. The vector of any preceding claim, wherein the vector is a viral vector, optionally an adeno-associated virus (AAV) vector.

7. The vector of any preceding claim, wherein the vector further comprises a 5’ inverted terminal repeat (ITR) and a 3’ inverted terminal repeat (ITR), optionally wherein the 5’ and the 3’ ITRs are AAV ITRs.

8. The vector of claim 7, wherein the 5’ and the 3’ ITRs are independently selected from the group consisting of AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12 or AAV13 ITRs.

9. The vector of claim 7 or 8, wherein the 5’ ITR comprises or consists of a nucleotide sequence having at least 70% sequence identity to SEQ ID NO: 3, and / or wherein the 3’ ITR comprises or consists of a nucleotide sequence having at least 70% sequence identity to SEQ ID NO:

4.

10. The vector of any preceding claim, wherein the vector is in the form of a viral particle, optionally an AAV particle.

11. The vector of claim 10, wherein the viral particle is pseudotyped to confer central nervous system (CNS) tropism.

12. The vector of claim 10 or 11, wherein the viral particle comprises AAV-PHP.eB, AAV- PHP.B or AAV9 capsid proteins.

13. A cell comprising the vector of any preceding claim.

14. A pharmaceutical composition comprising the vector of any one of claims 1-12 or the cell of claim 13, and a pharmaceutically acceptable carrier, diluent or excipient.

15. The vector of any one of claims 1-12, the cell of claim 13 or the pharmaceutical composition of claim 14 for use as a medicament.

16. The vector of any one of claims 1-12, the cell of claim 13 or the pharmaceutical composition of claim 14 for use in treating or preventing a BDNF-associated disease.

17. The vector, cell or pharmaceutical composition for use according to claim 16, wherein the BDNF-associated disease is selected from the group consisting of Rett syndrome,infantile cognitive disabilities, autism spectrum disorder and age-related neurodegenerative disorders.

18. The vector, cell or pharmaceutical composition for use according to claim 16, wherein the BDNF-associated disease is Rett syndrome.

Images