EP4680752A1 - Gene therapy - Google Patents

Abstract

The present invention relates to nucleic acid constructs comprising granulin (GRN) promoter sequences. The present invention further relates to vectors, viral particles, host cells and pharmaceutical compositions comprising said nucleic acid constructs. The present invention also concerns the therapeutic use of said nucleic acid constructs, vectors, viral particles, and pharmaceutical compositions.

Description

GENE THERAPY FIELD OF THE INVENTION The present invention relates to nucleic acid constructs comprising granulin (GRN) promoter sequences. The present invention further relates to vectors, viral particles, host cells and pharmaceutical compositions comprising said nucleic acid constructs. The present invention also concerns the therapeutic use of said nucleic acid constructs, vectors, viral particles, and pharmaceutical compositions. BACKGROUND OF THE INVENTION Adeno-associated virus (AAV) vectors/particles are a commonly used vehicle to deliver molecular therapeutics for the treatment of clinical disorders. Many AAV-based therapies are gene replacement therapies. However, to provide robust AAV production and transgene expression, the AAV construct comprising the transgene of interest should be between 4.1 kb and 4.7 kb to allow for optimal packaging of the AAV. So-called ‘stuffer sequence’ or inert DNA can be added to the transgene or vector backbone to increase the overall length of the construct. However, vectors are sensitive to stuffer sequences which must therefore be chosen carefully so as not to negatively affect transgene expression, patient immune responses, and AAV packaging efficiency. Another approach to build length into AAV constructs is to modify the transgene sequence itself. However, this approach may not be suitable where it is desirable to use the native (wild type) transgene nucleotide sequence. A further approach to increase the overall length of AAV constructs is through the inclusion of an engineered promoter sequence. Such promoters must be chosen carefully to ensure suitable in vivo transgene expression levels. Moreover, where site-specific transgene expression is required, such as for the treatment of neurological disorders, selection of a promoter which provides targeted expression of the transgene of interest in the desired tissue or cell type is important. Among the various neurological disorders that could be treated via AAV-based gene therapy is Frontotemporal dementia (FTD). FTD is the second most common type of dementia after Alzheimer’s Disease (Olney et al., 2017). A mutation in one allele of the GRN gene, which encodes the protein progranulin (PGRN), is associated with the development of FTD (Baker et al., 2006). Homozygous mutations in GRN are associated with neuronal ceroid lipofuscinosis 11 (NCL11), which is characterized by cerebellar ataxia, seizures, retinitis pigmentosa, and cognitive disorders, usually beginning between 13 and 25 years of age (Faber et al., 2020). A variety of mutations can cause a loss of function of PGRN. In PGRN-deficient mouse models, driving neuronal expression of PGRN using an AAV gene therapy approach has been shown to correct behavioral deficits associated with FTD (Arrant et al., 2017). The link between PGRN deficiency and CNS disorders, including FTD and NCL11 is well established (Mole and Cotman, 2015; Chitramuthu et al.2017; ; Huin et al., 2020). Thus, there is a strong biological rationale for a therapeutic approach which increases levels of PGRN in tissues and cells of the central nervous system (CNS) to treat neurological diseases associated with PGRN deficiency. To date therapeutic approaches which increase levels of PGRN in the central nervous system to treat neurological diseases associated with PGRN deficiency, including FTD and NCL, have used nucleic acid constructs comprising traditional promoters that drive a strong and/or cell specific expression, such as UBC, CMV, CAG or chicken beta actin promoter. See for example US10,689,625 describes the generation of a construct where a CBA promoter is operably linked to transgene encoding PGRN, or Zin et al. (2021). However, no long-term data is available on the performance of traditionally active promoters driving the POI or PGRN expression, and it is hereby postulated that the use of endogenous or naturally occurring promoters that would maintain their natural transcriptional regulation may be advantageous. Bhandari et al. (1996) describe a structural and functional analysis of the human GRN promoter. This study identifies specific sequences with basal promoter activity (i.e., truncated promoter sequences), although strongest activity appears to be different across different cell types. Bhandari further identifies regulatory elements capable of modulating promoter activity. Sardiello et al. (2009) describe the presence of a number of CLEAR elements (used to designate coordinated lysosomal expression and regulation elements) in the GRN promoter, and the correlation between TFEB (“TFEB” as used herein means transcription factor EB) binding to these sequences and expression of lysosomal genes. She et al. (2017) further correlate TFEB occupancy in the GRN promoter with upregulation of PGRN expression. Typically, a nucleotide sequence encoding the PGRN coding sequence is about 1.8 kb in length, which is significantly shorter than the optimal length of 4.1 to 4.7 kb for packaging of a nucleic acid construct into an AAV. Thus, there remains a need for promoter sequences which can be used to increase the length of a viral vector construct while at the same time providing robust and CNS-targeted expression of protein of interests, such as PGRN. SUMMARY OF THE INVENTION It has been found that not only promoters derived from the granulin (GRN) gene can help to provide a transgene with a length between 4.1 kb and 4.7 kb but also that they are highly effective for driving central nervous system (CNS)-targeted expression of a protein of interest (POI), such as PGRN, in a gene therapy setting. Thus, the present invention provides a nucleic acid construct comprising a granulin (GRN) promoter operably linked to a nucleotide sequence encoding a protein of interest (POI), such as progranulin (PGRN) protein. Said promoter is preferably a truncated promoter. The present invention further discloses a vector comprising a nucleic acid construct of the invention. The vector may be a plasmid or a viral vector. The present invention also relates to viral particle comprising a capsid and a nucleic acid construct or a vector of the invention. Said viral particle can be an adeno-associated virus (AAV) particle or a viral particle which comprises an AAV genome, or a derivative thereof. Alternatively, it can be lentiviral particle or a viral particle which comprises a lentivirus genome or a derivative thereof. The present invention additionally provides a host cell which comprises a nucleic acid construct of the invention or a vector of the invention, and/or which produces a viral particle of the invention, optionally wherein the host cell is a HEK293 cell. Further provided by the present invention is a pharmaceutical composition comprising a nucleic acid construct of the invention, a vector of the invention, and/or a viral particle of the invention together with a pharmaceutically acceptable carrier, excipient, and/or diluent. Also disclosed in the present invention is a nucleic acid construct of the invention, a vector of the invention, a viral particle of the invention, and/or a pharmaceutical composition of the invention for use in a method of treating or preventing a disease characterized by deficiency of a POI, such as progranulin (PGRN) deficiency, in a patient in need thereof. The present invention further relates to a method of treating or preventing a disease characterized by deficiency of a POI, such as progranulin (PGRN) deficiency, in a patient in need thereof, said method comprising administering to the patient a therapeutically effective amount of a nucleic acid construct of the invention, a vector of the invention, a viral particle of the invention, and/or a pharmaceutical composition of the invention. The present invention also provides the use of a nucleic acid construct of the invention, a vector of the invention, a viral particle of the invention, and/or a pharmaceutical composition of the invention for the manufacture of a medicament for the treatment or prevention of a disease characterized by deficiency of a POI, such as progranulin (PGRN) deficiency, in a patient in need thereof. BRIEF DESCRIPTION OF THE FIGURES Figure 1. Evaluation of hPGRN expression in primary mice neurons and astrocytes for constructs pPG-41. Bar charts showing: A. mouse PGRN expression in non-transduced and transduced primary neurons from WT and GRN KO mice; B. human PGRN expression levels in transduced neurons; C Percentage of neurons expressing human PGRN following transduction with pPG41-D. Percentage of astrocytes expressing human PGRN following transduction with pPG41. E. expression levels of human PGRN in WT and KO neurons transduced with pPG41. Figure 2. Schematics showing organization of component nucleic acid sequences in AAV- 06164 construct, AAV-06262 construct and AAV-06263 construct.1801 residues long GRN1 promoter denotes a truncated form of the human granulin promoter of 1801 residues long. 632 residues long GRN2 promoter denotes a truncated form of the human granulin promoter of 632 residues long.489 residues long GRN3 promoter denotes a truncated form of the human granulin promoter of 489 residues long. KOZAK denotes the presence of a KOZAK sequence. Human PGRN denotes a polynucleotide sequence encoding human progranulin. SV40 polyA denotes a polynucleotide sequence comprising multiple Adenosine monophosphate residues. Figure 3. Evaluation of PGRN expression and secretion by Ad293 and N2A cells. A. Image of Western blot analysis of promoter activity in two different cells. B. Bar chart showing concentration of PGRN expressed (cell lysate) and secreted (supernatant). hPGRN expression was analysed for each of AAV9-06164, AAV9-06262 and AAV9-06263 constructs. Figure 4. Evaluation of human PGRN expression and secretion in GRN-/- mouse primary neurons. Bar charts showing PGRN mRNA levels (A.), PGRN protein expression (B.) and PGRN secretion (C.) by neuron cultures transduced with AAV9-06164, AAV9-06262, and AAV9-06263. An un-transduced control is also shown. Figure 5. Expression of human PGRN corrects lysosomal deficit in GRN^-/- mouse primary neurons. A. Image of western blot analysis performed to quantify the level of lysosomal protein cathepsin D in WT (GRN^+/+) and KO (GRN^-/-) primary neurons transduced with a lentiviral vector comprising the pPG41 construct. B-D. Bar charts showing levels of cathepsin D proteins (immature, mature heavy chain and mature light chain, respectively). Values for expression of cathepsin D are normalised to actin and GADPH expression level. Figure 6. Evaluation of expression of human PGRN (hPGRN) in wild-type rats following striatal injection of AAVTT-06164. A. IHC staining of hPGRN was observed in brain of wild-type rats that received striatal administration of AAVTT-06164. Elevated levels of hPGRN were detected mainly throughout the forebrain notably in the striatum, thalamus, hypothalamus, cerebral cortex and hippocampus, and in the midbrain in the substantia nigra of GRN^-/- KO mice. B. Quantification of hPGRN in the CSF of rats injected with AAVTT-06164 or control by ELISA. C. Western blot performed to analyze the levels of hPGRN expression and Cathepsin D maturation levels. Figure 7. Human PGRN expression impacts lysosomal gene expression in GRN^-/-neurons. Bar Chart showing measurement of mRNA levels of lysosomal genes in GRN^-/- neurons transduced with AAV9-06164, AAV9-06262 and AAV9-06263. Un-transduced wild-type and GRN^-/- neurons are shown as controls. DETAILED DESCRIPTION OF THE INVENTION As used in this specification and the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to “a nucleic acid” includes “nucleic acids”, and the like. The term “comprises” (including “comprise”, “comprising”) should be understood to have its normal meaning in the art, i.e., that the stated feature or group of features is included, but that the term does not exclude any other stated feature or group of features from also being present. For example, a promoter comprising a minimal promoter sequence may contain other components, such as one or more introns. The term “consists of” (including “consist of”, “consisting of”) should also be understood to have its normal meaning in the art, i.e., that the stated feature or group of features is included, to the exclusion of further features. For example, a promoter consisting of a minimal promoter sequence contains the minimal promoter sequence and no other components. For every embodiment in which “comprises” (or “comprising”) is used, we anticipate a further embodiment in which “consists of” (or “consisting of”) is used. Thus, every disclosure of “comprises” should be considered to also be a disclosure of “consists of”. The terms “protein” and “polypeptide” are used interchangeably herein and, in their broadest sense, refer to a compound of two or more subunit amino acids, amino acid analogs, or other peptidomimetics. The term “protein” thus includes short peptide sequences and also longer polypeptides. As used herein, the term “amino acid” refers to either natural and/or unnatural or synthetic amino acids, including both D or L optical isomers, and amino acid analogs and peptidomimetics. The term “AAV true type”, “AAVTT”, AAV-TT” or “AAVtt” relates to a capsid as defined in WO2015121501 and Tordo J. et al., 2018, both incorporated herein by reference, and comprising or consisting of SEQ ID NO: 1. A “r” in front of any of these terms stands for recombinant. The terms “inverted terminal repeat sequences”, “inverted terminal repeat” or “ITR” are sequences located at the 5’ and 3’ ends of the heterologous nucleic acid which allows the transgene and the one or more regulatory sequences located between the ITRs to be packaged within the rAAV capsid. Although typically full length ITRs from the same source as the one providing the rep function are used, as an alternative, ITRs from a different AAV source can be used, as well as truncated ITRs as long as they are still functional. The term “regulatory sequence” refers to one or more sequences that direct and/or are involved in the expression of a gene (herein of the transgene). Typically said one or more regulatory sequences are selected to direct, drive, assist and/or control the expression of the transgene in the target tissue, e.g., central nervous system (CNS). The term “transgene” refers to the nucleic acid sequence (typically encoding a protein) to be expressed in a primate once administered to the primate via the rAAV particles according to the invention, wherein said sequence which is not an AAV-derived sequence. It is typically of the same origin as the primate to be treated with the rAAV particle. The term “a transgene” should be construed as comprising one or more transgenes. The term “heterologous nucleic acid” refers to the nucleic acid sequence packaged inside the rAAV capsid which forms a viral particle. Such a nucleic acid sequence contains AAV inverted terminal repeat sequences (ITRs). In the examples herein, a heterologous nucleic acid contains, at a minimum, from 5’ to 3’, an AAV 5’ ITR, (a) sequence(s) encoding a transgene (i.e., a gene different from the gene encoding viral proteins), and an AAV 3’ ITR. The terms “patient” and “subject” are used interchangeably herein. Typically, the patient is a human. The term “nucleic acid construct” as used herein refers to an artificial (e.g., recombinantly produced or synthesized) nucleic acid comprising at least one control sequence (such as a promoter, allowing for expression of the protein of interest in vitro and/or in vivo) and at least one nucleotide sequence encoding a protein of interest (POI). Thus, a nucleic acid construct in the context of the present invention may be considered an expression cassette. The nucleic acid constructs may be isolated or substantially isolated. Nucleic acid constructs of the present invention may comprise appropriate promoters, enhancers, initiators, and other elements, such as for example polyadenylation (polyA) signals and/or a woodchuck hepatitis virus posttranscriptional regulatory element (WPRE) sequence. Nucleic acid constructs of the present invention may also comprise nucleotide sequences which facilitate their genetic manipulation, such as restriction sites. As used herein the term “operably linked” refers to a juxtaposition of two or more nucleotide sequences which allows each of said two or more sequences to perform their normal function. Typically, the term operably linked is used to refer to the juxtaposition of a regulatory element (e.g., a promoter, enhancer, polyA signal sequence, WPRE sequence, etc.) and a nucleotide sequence encoding a protein of interest (POI). For example, an operable linkage between a promoter and a protein-encoding nucleotide sequence permits the promoter to function to drive the expression of the POI in vitro and/or in vivo. The term “operably linked” does not preclude the existence of further sequences in between two or more nucleotide sequences operably linked as long as the two or more sequences can still to perform their normal function. Although sequence homology can also be considered in terms of functional similarity (i.e., amino acid residues having similar chemical properties/functions), in the context of the present document it is preferred to express homology in terms of sequence identity. Sequence comparisons can be conducted by eye or, more usually, with the aid of readily available sequence comparison programs. These publicly and commercially available computer programs can calculate percent homology (such as percent identity) between two or more sequences. Percent identity may be calculated over contiguous sequences, i.e., one sequence is aligned with the other sequence and each amino acid in one sequence is directly compared with the corresponding amino acid 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 (for example less than 50 contiguous amino acids). For comparison over longer sequences, gap scoring is used to produce an optimal alignment to accurately reflect identity levels in related sequences having insertion(s) or deletion(s) relative to one another. Examples of softwares/algorithms than can perform sequence comparisons include, but are not limited to, the BLAST package, FASTA and the GENEWORKS suite of comparison tools. Typically sequence comparisons are carried out over the length of the reference sequence. For example, if the user wished to determine whether a given sequence is 70 % identical to SEQ ID NO: 2, SEQ ID NO: 2 would be the reference sequence. For example, to assess whether a sequence is at least 90 % identical to SEQ ID NO: 2 (an example of a reference sequence), the skilled person would carry out an alignment over the length of SEQ ID NO: 2, and identify how many positions in the test sequence were identical to those of SEQ ID NO: 2. If at least 70 % of the positions are identical, the test sequence is at least 70 % identical to SEQ ID NO: 2. If the sequence is shorter than SEQ ID NO: 2, the gaps or missing positions should be considered to be non- identical positions. The term “fragment” as used herein refers to a contiguous portion of a reference sequence. For example, a fragment of SEQ ID NO: 2 of 50 nucleotides in length refers to 50 contiguous nucleotides of SEQ ID NO: 2. The term “functional variant” as used herein refers to a nucleic acid or amino acid sequence which has been modified relative to a reference sequence, but which retains the biological functions/ characteristics or at least one of the biological functions/ characteristics of said reference sequence. For example, a functional variant of an GRN promoter retains the ability to drive expression of a nucleotide sequence encoding a POI in cells of the CNS, such as neurons or astrocytes. Similarly, a functional variant of a PGRN protein retains the activities of the reference PGRN protein. The terms “polynucleotide” and “nucleic acid molecule” are used interchangeably herein and refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof. Non-limiting examples of polynucleotides include a gene, a gene fragment, messenger RNA (mRNA), cDNA, recombinant polynucleotides, synthetic polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes, and primers. A polynucleotide of the invention may be provided in isolated or substantially isolated form. By substantially isolated, it is meant that there may be substantial, but not total, isolation of the polypeptide from any surrounding medium. The polynucleotides may be mixed with carriers or diluents which will not interfere with their intended use and still be regarded as substantially isolated. A nucleic acid sequence which “encodes” a selected polypeptide is a nucleic acid molecule which is transcribed (in the case of DNA) and translated (in the case of mRNA) into a polypeptide in vivo when placed under the control of appropriate regulatory sequences, for example in an expression vector. The boundaries of the coding sequence are determined by a start codon at the 5' (amino) terminus and a translation stop codon at the 3' (carboxy) terminus. Polynucleotides can be synthesised according to methods well known in the art, as described by way of example in Sambrook et al (1989). The term “GRN promoter” refers to a nucleotide sequence of a GRN gene (e.g., a murine or a human GRN gene) which is capable of functioning as a promoter, i.e., capable of driving the transcription of a nucleotide sequence to which said GRN promoter is operably linked, thereby driving the expression of a protein encoded by said nucleotide sequence. Typically, a GRN promoter sequence as used in the context of the present invention will be specific for a particular tissue or cell type(s). Preferably, a GRN promoter used in the present invention will specifically drive expression of a protein of interest (POI), such as PGRN, in the neurons and/or the astrocytes. An exemplary sequence of a GRN promoter can be found as SEQ ID NO:1 (mouse origin) or as SEQ ID NO:2 (human origin). The term “intron” refers to an intragenic non-coding nucleotide sequence. Typically, introns are transcribed from the DNA into messenger RNA (mRNA) during transcription of a gene but are excised from the mRNA transcript by splicing prior to its translation. The term “enhancer element” refers to a short (50–1500 residues long) region of DNA that can be bound by proteins (typically referred to as transcription factors) to increase the likelihood that transcription of a particular gene will occur. Enhancer elements may for example be added to the promoter (Liu, B. et al., 2004). As vectors can be single strand (ss) or double strands (ds), nucleic acid sequences length is herein preferably expressed referring to the number of bases in length such as “bases”, “b”, “kilobases”, “kb” or as “residues length/long” (each of them being applicable to both ss and ds) rather than “base pairs” or “bp” more applicable to ds only. The terms “therapeutic amount” or “therapeutical effective amount” typically refer to the amount or the dose of a compound that is sufficient to exhibit a positive pharmacologic and/or physiologic effect on a disease and therefore to treat a disease, upon administration to a primate . The terms “treatment”, “treating” and the like, refer to obtaining a desired pharmacologic and/or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof to appear or to worthen and/or may be therapeutic in terms of a partial or complete cure for a disease and/or adverse effect attributable to the disease. Treatment thus covers any treatment of a disease in a primate, particularly in a human, and includes: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., causing regression of the disease. Progranulin (PGRN; also known as granulin-epithelin precursor, proepithelin, prostate cancer (PC) cell derived growth factor and acrogranin) is a secreted glycoprotein that is expressed by many cell types throughout the body. Encoded by a single gene (GRN; Gene ID: 2896) on chromosome 17q21, PGRN is a 593-amino acid, cysteine-rich protein with an estimated molecular weight of 68.5 kDa. It contains 7.5 granulin-like domains, each of which consist of highly conserved tandem repeats of a 12 cysteinyl motif. Proteolytic cleavage of PGRN by extracellular proteases, such as elastase, gives rise to smaller peptide fragments termed granulins or epithelins (e.g., granulin A, granulin B, granulin C, etc.). These fragments range in size from 6 to 25 kDa and have been implicated in a range of biological functions. An exemplary sequence of PGRN protein is reported in SEQ ID NO:14. An exemplary sequence of PGRN encoding sequence is reported in SEQ ID NO:13. The optimal length for packaging of a nucleic acid construct into an AAV is typically of 4.1 to 4.7 kilo bases (kb). However, it frequently happens that nucleic acid sequences encoding proteins of interest are too small to reach this optimal length even when considering the promoter length and additional sequences (such as regulatory sequences) length. It has been surprisingly found by the inventors that promoters derived from the granulin (GRN) gene can be used to increase/adjust the length of a nucleic acid construct while being highly effective for driving CNS-targeted expression of a protein of interest (POI), such as PGRN, in a gene therapy setting. In a first embodiment, the present invention provides a nucleic acid construct comprising a granulin (GRN) promoter operably linked to a nucleotide sequence encoding a protein of interest (POI). The promoter is preferably a truncated GRN promoter. In a non-limiting example, the POI is a progranulin (PGRN) protein. In a second embodiment, herein described is a nucleic acid construct comprising a granulin (GRN) promoter operably linked to a nucleotide sequence encoding a progranulin (PGRN) protein. The promoter is preferably a truncated GRN promoter. The GRN promoter to be used according to the present invention as a whole specifically drives expression of a protein of interest (POI), such as PGRN, in the neurons and/or the astrocytes. In the context of the present invention as a whole, the GRN promoter may be a full-length GRN promoter or a functional variant thereof. A functional variant of a GRN promoter is functional in the sense that it retains the characteristics of the corresponding non-variant GRN promoter. Thus, a functional variant of a GRN promoter retains the capacity to drive the transcription of a nucleotide sequence to which said functional variant is operably linked, thereby driving the expression of a protein encoded by said nucleotide sequence. A functional variant of a GRN promoter as described herein retains specificity for a particular tissue type. For example, a functional variant of a GRN promoter described herein will specifically drive expression of a protein of interest (POI), such as PGRN, in the neurons and/or the astrocytes. Non-limiting examples of GRN promoter sequences that can be used in the nucleic acid constructs described herein comprise or consist of SEQ ID NO: 1 or SEQ ID NO: 2 or a functional variant thereof having at least 90%, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 %, 99 %, 99.5 %, or 99.9 % identity to SEQ ID NO: 1 or SEQ ID NO: 2. Alternatively, the GRN promoter of the invention may be a truncated GRN promoter, i.e. a functional fragment of a full-length GRN promoter or of a functional variant thereof. A truncated GRN promoter should be a functional truncated GRN promoter (also named a functional GRN promoter fragment). It is functional in the sense that it retains the characteristics of the corresponding non-variant or full- length GRN promoter. Thus, a truncated GRN promoter according to the invention retains the capacity to drive the transcription of a nucleotide sequence to which said truncated GRN promoter is operably linked, thereby driving the expression of a protein encoded by said nucleotide sequence. A truncated GRN promoter as described herein retains specificity for a particular tissue type. For example, a truncated GRN promoter described herein will specifically drive expression of a protein of interest (POI), such as PGRN, in the neurons and/or the astrocytes. Such truncated promoter is a functional fragment of the promoter region of a GRN gene (or of a functional variant thereof) of sufficient length, and which comprises or consists at least of the minimal required elements to function as a GRN promoter, i.e., capable of driving the transcription of a nucleotide sequence to which said GRN promoter is operably linked, thereby driving the expression of a protein encoded by said nucleotide sequence. Non-limiting examples of such truncated GRN promoters to be used in the nucleic acid constructs of the present invention comprise or consist of: GRN1 (SEQ ID NO: 3). GRN2 ( SEQ ID NO: 4) or GRN3 (SEQ ID NO: 5). In the context of the present invention as a whole, the GRN promoter is preferably a truncated promoter and is preferably selected from the group consisting of: (a) A nucleotide sequence comprising or consisting of SEQ ID NO: 3; (b) A nucleotide sequence comprising or consisting of SEQ ID NO: 4; (c) A nucleotide sequence comprising or consisting of SEQ ID NO: 5; (d) A functional variant having at least 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 %, 99 %, 99.5 %, or 99.9 % identity to any one of SEQ ID NO: 3, 4 or 5; or (e) a functional fragment of any length of any one of (a), (b), (c) or (d), including minimal promoter sequences. A truncated promoter sequence which comprises or consists at least of the minimal required elements to function as a GRN promoter will be herein called “minimal promoter sequence“. Should a truncated promoter sequence or a minimal promoter sequence be used it is preferably about 300- 1000 residues long, such as about 350-900 residues long, about 400-800 residues long, about 450- 700 residues long, or yet about 485-630 residues long, such as having a length of any one of 485, 486, 487, 488, 489, 490, 491, 492, 493, 494 or 495 bases to 625, 626, 627, 628, 629, 630, 631, 632, 633, 634 or 635 bases. The nucleic acid constructs comprising the GRN promoters described herein provide enhanced expression of the protein of interest (POI) that they encode, for example PGRN. Said constructs also provide enhanced transcription efficiency. In certain embodiments, said enhanced expression is due to the transcriptional regulation of the GRN promoter. Thus, in certain embodiments, the expression of a POI, such as PGRN protein, from a nucleic acid construct of the invention comprising a GRN promoter may be increased relative to a construct having an alternative promoter said construct being otherwise identical. In certain aspects, the nucleic acid construct of the invention comprising a GRN promoter provides increased transcription efficiency relative to a construct having an alternative promoter said construct being otherwise identical. In the context of the present invention as a whole, the GRN promoter may comprise one or more introns and/or one or more enhancer elements. A GRN promoter which comprises a truncated promoter sequence and an intron and/or an added enhancer element is referred to herein as an “engineered GRN promoter”. In the context of the present invention as a whole, the protein or interest (POI) encoded by the nucleic acid construct is selected from the group consisting of (but not limited to): a secreted protein(including pre and/or pro-form of such secreted proteins), intracellular proteins, membrane-bound proteins and transmembrane proteins. Non-limiting examples of such POI include (but are not limited to) progranulin (PGRN), neuronal ceroid lipofuscinosis proteins type 1 to 14 (such as NCL type 2, 3, 6 or 11) or heparin-alpha-glucosaminide N-acetyl transferase (EC 2.3.1.78, alternatively known as HGSNAT). In a particular non-limiting example, the nucleotide sequence encoding the POI encodes a PGRN protein, such as a human PGRN protein. In another non-limiting example, the nucleotide sequence encoding the POI is a wild-type PGRN protein, such as a wild-type human PGRN protein. In another non-limiting example, the nucleotide sequence encoding the POI, such as PGRN, is not codon optimised. In the context of the present invention as a whole, a preferred nucleotide sequence encoding a PGRN protein or a functional variant thereof, comprises or consists of SEQ ID NO: 13 or a functional variant thereof having at least 70 %, 75 %, 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 %, 99 %, 99.5 %, or 99.9 % identity to SEQ ID NO: 13. Functional fragments of said nucleotide sequences may also be used. Such fragments may have a length of 1000-1781, 1200-1750, 1400-1700, or 1500-1600 bases. In the context of the present invention as a whole, a preferred nucleotide sequence encoding a PGRN protein encodes a PGRN protein which comprises or consists of SEQ ID NO: 14 or a functional variant thereof having at least 70 %, 75 %, 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 %, 99 %, 99.5 %, or 99.9 % identity to SEQ ID NO: 14. Nucleotides encoding functional fragments of said PGRN protein may also be used. Such PGRN protein fragments may have a length of 300-592, 350-490, 400-480, or 450-475 amino acid residues. In any protein or polypeptide described herein, the amino acid sequence may be modified by additions, deletions or substitutions, provided that a polypeptide having the modified sequence exhibits similar/same activity, as compared to a polypeptide having the unmodified sequence. By “similar” or “same” it is to be understood that the polypeptide of the modified sequence does not exhibit significantly reduced activity as compared to a polypeptide of the unmodified sequence. Such a modified protein or the nucleotide sequence which encodes said modified protein may be considered “functional variants”. For instance, PGRN has been observed to co-localize with the lysosomal marker protein LAMP-1 (lysosomal-associated membrane protein 1) and to play a role in the regulation of lysosomal function and biogenesis through acidification of lysosomes (Tanaka et al., 2017).Therefore, in order to identify functional variants and/or fragments of PGRN, the skilled person can assess the capability of said functional variants and/or fragments of PGRN to co-localize with LAMP-1 or to regulate lysosomal acidification. Co-localization of a PGRN protein and LAMP-1 may be evaluated and/or quantified using any suitable technique known in the art. For example, cultured cells deficient in PGRN (e.g., GRN^-/- cells, or cells in which expression PGRN expression has been down regulated by siRNA) may be transfected with a vector which comprises the nucleic acid construct comprising the functional variant or fragment of the nucleotide sequence encoding the PGRN protein. The cells may then be immuno-stained using a first fluorescently labelled (e.g., green) antibody specific for PGRN and a second fluorescently labelled (e.g., red) antibody specific for LAMP-1. Co-localization of the red and green staining can then be assessed using a fluorescence microscopy (see Tanaka et al., 2017). Co-localization of the variant of fragment of a PGRN protein and LAMP-1 may be at least about 50 %, 60 %, 70 %, 80 %, 85 %, 90 %, 95% or 99% of the co-localization between the corresponding non-variant or full-length PGRN protein under the same conditions. It can also be substantially the same as, or greater than, the co-localization between the corresponding non- variant or full-length PGRN protein under the same conditions. The effect of PGRN on lysosomal acidification may be evaluated using any suitable technique in the art. For example, cultured cells deficient in PGRN (e.g., GRN^-/- cells, or cells in which expression PGRN expression has been down regulated by siRNA) may be transfected with a vector which comprises the nucleic acid construct comprising the functional variant or fragment of the nucleotide sequence encoding the PGRN protein. The acidification of lysosomes in the transfected cells can then be assessed using cell permeable dyes, such as LysoSensor DND-189 or acridine orange (see Tanaka et al., 2017). LysoSensor DND-189 fluorescence increases dependently on lysosomal acidity. Acridine orange monomer emits green fluorescence, whereas its dimer and oligomers formed when it is protonated. Thus, the ratio of red/green fluorescence indicates the relative acidity of the lysosomes. The regulation of lysosomal acidification by the variant or fragment of a PGRN protein may be at least about 50 %, 60 %, 70 %, 80 %, 90 %, 95 % or 99 % of the regulation of lysosomal acidification by the corresponding non-variant or full-length PGRN protein under the same conditions. The regulation of lysosomal acidification by the variant or fragment of a PGRN protein may be substantially the same as, or greater than, the regulation of lysosomal acidification by the corresponding non-variant or full-length PGRN protein under the same conditions. Unless otherwise specified, modifications to a polypeptide sequence are preferably conservative amino acid modifications (or substitutions). Conservative substitutions replace amino acids with other amino acids of similar chemical structure, chemical properties and/or side-chain volume. The amino acids introduced may have similar polarity, hydrophilicity, hydrophobicity, basicity, acidity, neutrality or charge to the amino acids they replace. Alternatively, the conservative substitution may introduce another amino acid that is aromatic or aliphatic in the place of a pre-existing aromatic or aliphatic amino acid. Conservative amino acid changes are well-known in the art. In addition to a GRN promoter (or an engineered GRN promoter), the nucleic acid constructs according to the present invention may comprise one or more further regulatory elements. The one or more regulatory sequences that direct expression of said transgene is selected from the groups consisting of: a. one or more transcription initiation sequences (such as a promoter), b. one or more translation initiation sequences, c. one or more mRNA stability sequences, d. one or more transcription termination sequences (such as polyadenylation sequences), e. one or more secretory sequences, f. one or more enhancer sequences, g. one or more introns, h. one or more TATA boxes, i. one or more microRNA targeted sequences, j. one or more polylinker sequences facilitating the insertion of a DNA fragment within a vector, k. one or more splicing signal sequences, l. one or more posttranscriptional regulatory elements, or m. any combinations of any one or more of the groups a. to l. In the context of the present invention as a whole, preferred regulatory elements are those which function to stabilize an mRNA transcribed from the nucleic acid construct/vector and/or enhance the expression of the protein of interest (POI), such as PGRN, from the nucleic acid construct/vector. A non-limiting example of a regulatory element which may be used in the context of the present invention is a woodchuck hepatitis virus (WHP) posttranscriptional regulatory element (WPRE). A WPRE is a DNA sequence which, when transcribed into mRNA, creates tertiary structure in the mRNA transcript thereby enhancing the stability of the mRNA and also enhancing expression of the POI encoded by the nucleic acid construct. In the nucleic acid constructs (or vectors) of the present invention, the WPRE may be 3ʹ to the nucleotide sequence encoding the POI or the PGRN protein. The WPRE may comprise the nucleotide sequence of SEQ ID NO: 20 or a functional variant or fragment thereof having at least 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 %, 99 %, 99.5 %, or 99.9 % identity to the nucleotide sequence of SEQ ID NO: 20. The functional variant or fragment of the WPRE retains the characteristics of the corresponding non-variant or full-length WPRE. Thus, the variant or fragment WPRE may be capable of creating tertiary structure in an mRNA transcript and/or enhancing the stability of an mRNA transcript and/or enhancing expression of the POI encoded by the nucleic acid construct. The enhancement is relative to an mRNA not containing the variant or fragment WPRE. Another non-limiting example of a regulatory element which may be used in the context of the present invention is a polyadenylation (poly(A) or polyA) signal sequence. In eukaryotic cells, polyadenylation signal sequences within mRNA transcripts are recognized and processed to add a poly(A) tail consisting of multiple adenosine monophosphates at the 3ʹ end of the mRNA transcript. The poly(A) tail functions to promote export of the mRNA from the nucleus to the cytoplasm and prevents the degradation of the mRNA, thereby enhancing expressing of the POI encoded by the nucleic acid construct. In the nucleic acid constructs of the present invention, the polyadenylation signal sequence may be 3ʹ to the nucleotide sequence encoding the POI, such as PGRN. The polyadenylation signal sequence may comprise the nucleotide sequence SEQ ID NO: 21 or a functional variant or fragment thereof having at least 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 %, 99 %, 99.5 %, or 99.9 % identity to the nucleotide sequence of SEQ ID NO: 21. The functional variant or fragment of the polyadenylation sequence retains the characteristics of the corresponding non-variant or full-length polyadenylation signal sequence. In a further non- limiting example, the nucleic acid construct according to the invention comprises two or more regulatory elements such as a WPRE element and a polyadenylation signal sequence as herein described. Therefore, an example of nucleic acid construct as described herein may comprise, in the 5ʹ to 3ʹ direction, an GRN promoter (such as a truncated GRN promoter or an engineered truncated GRN promoter), a nucleotide sequence encoding the POI, such as a PGRN protein, an WPRE, and a polyadenylation signal sequence. Another example of sequences that can be further included in the nucleic acid construct of the invention is one or more restriction sites, such as a BamH1, Xba1 or yet EcoR1 restriction site. Examples of such restriction site sequences can be found as SEQ ID NOs: 15-17. In the context of the invention as a whole, the nucleic acid construct can be about 2100 to about 4500 residues long, such as 2100 to 4400 residues long, 2200 to 4000 residues long or 2400 to 3900 residues long. Examples of a nucleic acid construct according to the invention comprises or consists of in the 5ʹ to 3ʹ direction: (a) a GRN promoter sequence such as a truncated GRN promoter (engineered or not); (b) optionally a Kozak sequence; (c) a polynucleotide sequence encoding the POI, such as PGRN protein; and (d) optionally a posttranscriptional regulatory element such as WPRE and/or a poly(A) sequence such as an SV40 poly(A) sequence. In non-limiting examples, herein provided is a nucleic acid construct or vector comprising or consisting of: (a) SEQ ID NO: 7, (b) SEQ ID NO: 8, (c) SEQ ID NO: 9, or (d) functional variant or fragment thereof having at least 70 %, 75 %, 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 %, 99 %, 99.5 %, or 99.9 % identity to the nucleotide sequence of SEQ ID NO: 7, 8 or 9. The nucleic acid constructs of the present invention may be provided within vectors, such as plasmids or recombinant viral vectors. Therefore, in a third embodiment, herein provided is a vector comprising a nucleic acid construct of the invention. A suitable vector may be any vector which is capable of carrying a sufficient amount of genetic information and allowing expression of a POI in vivo. A vector comprising a nucleic acid construct of the invention may be administered directly to a patient in need thereof, or via a particle, such as a viral particle. Such vectors are routinely constructed in the art of molecular biology. By way of example in this regard we refer to Sambrook et al. (1989, Molecular Cloning - a laboratory manual; Cold Spring Harbor Press). The vector herein described can be of any type. For example, the vector may be a plasmid vector, a minicircle DNA or a viral vector. In the context of the present invention as a whole, the vector may be based on the herpes simplex virus, adenovirus or lentivirus. Alternatively, the vector may be an adeno-associated virus (AAV) vector or a derivative thereof. The vector of the invention can be single stranded or double stranded. In the context of the present invention as a whole, herein also described are vectors comprising a nucleic acid construct of the invention and further comprising at least one ITR flanking said nucleic acid construct in 5’ and/or 3’, preferably at least two ITRs (one at each end of the nucleic acid construct of the invention, i.e. a 5’ITR and a 3’ITR). An ITR sequence acts in cis to provide a functional origin of replication and allows for integration and excision of the nucleic acids construct from the genome of a cell. One or more of the ITRs may be obtained from viral genomes, such as AAV genomes, having different serotypes or may be a chimeric or mutant ITR. An example of a 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 viral genome (e.g., self-complementary AAV genome). This allows for bypass of DNA replication in the target cell, and so enables accelerated transgene expression. Preferred ITR sequences are those of from AAV genomes, such as AAV2, AAV9 and variants thereof. Non-limiting examples of such ITRs are disclosed as SEQ ID Nos: 25-26. The one or more ITRs will preferably flank the nucleic acid construct of the present invention, i.e., the nucleotide sequence comprising the GRN promoter and the nucleotide sequence encoding the POI, such as the PGRN protein. The inclusion of one or more ITRs is preferred to aid packaging of the nucleic acid construct of the invention (as such or included in a vector) into viral particles. In preferred aspects, ITR elements will be the only sequences retained from a native viral genome, e.g., from a native AAV genome. This is preferred for the reasons described above, and also to reduce the possibility of integration of the nucleic acid construct of the invention (as such or included in a vector) into a host cell genome. Additionally, when the nucleic acid construct (as such or included in a vector) contains an AAV genome, reducing the size of said AAV genome to only the ITRs allows for increased flexibility in incorporating other sequence elements (such as regulatory elements) within the nucleic acid construct in addition to the transgene. In the context of the invention as a whole, the vector preferably comprises (in the 5ʹ to 3ʹ direction): (a) a 5ʹ ITR; (b) a GRN promoter sequence such as a truncated GRN promoter (which can be engineered or not); (c) optionally a Kozak sequence; (d) a polynucleotide sequence encoding a POI (such as PGRN protein); (e) optionally a posttranscriptional regulatory element such as WPRE; (f) optionally a poly(A) sequence such as a SV40 poly(A) sequence; and (g) a 3ʹ ITR. In a non- limiting example, the vector of the invention comprises (in the 5ʹ to 3ʹ direction): (a) a 5ʹ ITR; (b) a truncated GRN promoter sequence; (c) a Kozak sequence; (d) a polynucleotide sequence encoding a POI (such as PGRN protein); (e) a WPRE and/or an SV40 poly(A) sequence; and (f) a 3ʹ ITR. In a further non-limiting example, the vector comprises (a) a 5ʹ ITR comprising or consisting of the nucleotide sequence of SEQ ID NO: 25 or a functional variant or fragment thereof having at least 70 % identity to SEQ ID NO: 25; (b) a truncated GRN promoter sequence comprising or consisting of the nucleotide sequence of SEQ ID NO: 3, SEQ ID NO: 4 or SEQ ID NO: 5 or a functional variant or fragment thereof having at least 70 % identity to SEQ ID NO: 3, SEQ ID NO: 4 or SEQ ID NO: 5; (c) optionally a Kozak sequence comprising or consisting of the nucleotide sequence of SEQ ID NO: 27; (d) a polynucleotide sequence encoding a POI, wherein the POI is PGRN protein comprising or consisting of the nucleotide sequence of SEQ ID NO: 13 or a functional variant or fragment thereof having at least 70 % identity to SEQ ID NO: 13; (e) a WPRE comprising or consisting of the nucleotide sequence of SEQ ID NO: 20 or a functional variant or fragment thereof having at least 70 % identity to SEQ ID NO: 20 and/or a SV40 poly(A) sequence comprising or consisting of the nucleotide sequence of SEQ ID NO: 21 or a functional variant or fragment thereof having at least 70 % identity to SEQ ID NO: 21; and (f) an 3ʹ ITR comprises or consists of the nucleotide sequence of SEQ ID NO: 26 or a functional variant or fragment thereof having at least 70 % identity to SEQ ID NO: 26. In a fourth embodiment, the present invention provides a viral particle comprising 1) a capsid (such as a viral capsid) and a nucleic acid construct of the invention or 2) a capsid (such as a viral capsid) and a vector of the invention. In the context of the present invention as a whole, the viral particle may be based on the herpes simplex virus, adenovirus or lentivirus. Alternatively, the viral particle may be an adeno-associated virus (AAV) particle or a derivative thereof. The viral particle derivative may be a chimeric, shuffled or capsid modified derivative. The preferred viral particle is a AAV particle (alternatively called rAAV particle for recombinant AAV particle). Wild-type AAV, containing viral genes, insert their genomic material into chromosome 19 of the host cell (Kotin, et al., 1990). The AAV serotype determines the tissue specificity of infection (or tropism) of an AAV virus. The AAV single-stranded DNA genome comprises two inverted terminal repeats (ITRs) and two open reading frames, containing structural (cap) and packaging (rep) genes (Hermonat et al., 1984). The AAV genome typically comprises 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 a viral particle such as an AAV particle. Naturally occurring AAV viruses are replication-deficient and rely on the provision of helper functions (such as adenovirus based) in trans for completion of a replication and packaging cycle. For therapeutic purposes, the only sequences required in cis, in addition to the gene coding for the POI, are the ITRs. Therefore, the vector (or viral vector) of the invention (i.e., the vector comprising a nucleic acid construct of the invention and ITRs sequences) preferably does not comprise the rep and cap genes. Most gene therapy nucleic acid constructs (as well as vector constructs and viral particles) are based on the AAV serotype 2 (AAV2). AAV2 binds to the target cells via the heparin sulphate proteoglycan receptor (Summerford and Samulski, 1998). The AAV2 genome, like those of all AAV serotypes, can be enclosed in a number of different capsid proteins. AAV2 can be packaged in its natural AAV2 capsid (AAV2/2), or it can be pseudotyped with other capsids (e.g., AAV2 genome in AAV1 capsid, named AAV2/1; AAV2 genome in AAV5 capsid, named AAV2/5; or yet AAV2 genome in AAV8 capsid, named AAV2/8). 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 or isolate or clade of AAV. As is known to the skilled person, AAV viruses occurring in nature may be classified according to various biological systems. Commonly, AAV viruses 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 neutralizing antibodies specific for any other AAV serotype. AAV serotypes include AAV1 (accession numbers e.g. NC_002077, AF063497), AAV2 (accession number e.g. NC_001401), AAV3 (accession numbers e.g. NC_001729, NC_001863), AAV4 (accession number e.g. NC_001829), AAV5 (accession number e.g. NC_006152), AAV6 (accession number e.g. NC_001862), AAV7 (accession number e.g. NC_006260), AAV8 (accession number e.g. NC_006261), AAV9 (accession number e.g. AY530579), and AAV10 (AAVrH10; accession number e.g. AY243015), as well as recombinant serotypes, such as Rec2 and Rec3 identified from primate brain. AAV viruses may also be referred to in terms of clades or clones. This refers to the phylogenetic relationship of naturally derived AAV viruses, and typically to a phylogenetic group of AAV viruses which can be traced back to a common ancestor and includes all descendants thereof. Additionally, AAV viruses may be referred to in terms of a specific isolate, i.e., a genetic isolate of a specific AAV virus found in nature. The term genetic isolate describes a population of AAV viruses which has undergone limited genetic mixing with other naturally occurring AAV viruses, thereby defining a recognizably distinct population at a genetic level. The skilled person can select an appropriate serotype, clade, clone or isolate of AAV for use in the present invention on the basis of their common general knowledge. The present invention encompasses viral particles comprising capsids (alternatively named capsid proteins or viral capsids) from various serotypes, clades, clones, or isolates of AAV. The genes encoding the capsids are typically provided in trans, i.e., via a helper vector in addition to the viral vector comprising the ITRs and the gene encoding the protein of interest. The invention also encompasses viral particles in which the packaging of the genome of one serotype (via the nucleic acid constructs of the invention) into the capsids of another serotype i.e., pseudotyping. Chimeric, shuffled or capsid-modified derivatives may be selected to provide one or more desired functionalities for the viral p\article. 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 viral vector comprising a naturally occurring AAV genome, such as that of AAV2. Increased efficiency of gene delivery may be affected by improved receptor or co-receptor binding at the cell surface, improved internalization, 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 viral particle 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. 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., internalization, trafficking of the viral particle. The skilled person can identify suitable sites for insertion based on their common general knowledge. The viral particle according to the invention comprises capsids 1) identical to a wild-type serotype, isolate or clade of AAV, 2) derived from a wild-type serotype, isolate or clade of AAV or 3) that has been completely engineered. Similarly, the viral particle according to the invention comprises a nucleic acid construct or a vector comprising an AAV genome or part thereof (such as the at least one or more ITRs comprised in the nucleic acid construct or vector of the invention) 1) originating from a wild-type serotype, isolate or clade of AAV, 2) derived from a wild-type serotype, isolate or clade of AAV or 3) that has been completely engineered. The AAV genome (such as the at least one or more ITRs comprised in the nucleic acid construct or vector of the invention), and the capsid (such as AAV capsid) may come from the same serotype or different serotypes. Preferably, the viral particles (such as AAV viral particles) according to the present invention are capable of transducing cells of the CNS, for example neuronal cells, astrocytes and/or oligodendrocytes. In the context of the present invention as a whole, the viral particle comprises an AAV genome and/or a capsid identical to or derived for instance from AAV serotype 1 (AAV1), AAV serotype 2 (AAV2), AAV serotype 4 (AAV4), AAV serotype 5 (AAV5), AAV serotype 8 (AAV8), AAV serotype 9 (AAV9), or AAV serotype rh10 (AAVrh10). Preferably, the viral particle comprises a AAV genome and/or a capsid identical to or derived from AAV2, AAV9 or AAVrH10. Even preferably (but not limiting), the viral particle comprises a AAV genome and/or a capsid that is identical or derived from AAV2 or AAV9. In a non-limiting example, the AAV2 derivative is AAV-TT. AAV-TT is described in detail in Tordo et al., 2018 and WO2015/121501, which are incorporated herein by reference in their entirety. In an example, should the AAV genome (such as the at least one or more ITRs comprised in the nucleic acid construct or vector of the invention) and the capsid (such as AAV capsid) be from the same serotype, the serotype can be AAV2 or a derivative of AAV2 such as AAV-TT. In another example, should the AAV genome (such as the at least one or more ITRs comprised in the nucleic acid construct or vector of the invention) and the capsid (such as AAV capsid) be from different serotypes, the serotype of the ITRs can be AAV2 and the serotype of the capsid can be AAV-TT. The nucleic acid constructs, vectors and viral particles (such as AAV particles or rAAV particles) described herein may be prepared by standard means known in the art. Thus, well established methods of production (including transfection, packaging and purification methods) can be used to prepare a suitable vector preparation. Other non-limiting examples of nucleic acid constructs according to the invention comprise or consist of: a) SEQ ID NO: 10 (AAV-06164 construct); b) SEQ ID NO: 11 (AAV-06262 construct); c) SEQ ID NO: 12 (AAV-06263 construct); or d) functional variant or fragment thereof having at least 70 %, 75 %, 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 %, 99 %, 99.5 %, or 99.9 % identity to any one of (a) to (c). Other non-limiting examples of vectors according to the invention comprise or consist of: a) SEQ ID NO: 22 (AAV-06164 plasmid); b) SEQ ID NO: 23 (AAV-06262 plasmid); c) SEQ ID NO: 24 (AAV-06263 plasmid); or d) functional variant or fragment thereof having at least 70 %, 75 %, 80 %, 85 %, 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, 98 %, 99 %, 99.5 %, or 99.9 % identity to any one of (a) to (c). In a fifth embodiment, the present invention provides a host cell comprising a nucleic acid construct of the invention or a vector of the invention. The present invention also provides a host cell which produces a viral particle (such as an AAV particle or rAAV particle) of the invention. Any suitable host cell may comprise a nucleic acid construct of the invention or a vector of the invention. Further, any suitable host cell can be used to produce a viral particle of the invention. In the context of the present invention as a whole, the host cell is preferably an insect cell or a mammalian cell. Non- limiting examples of such cells are sf9, HEK293 (including e.g., HEK293F, HEK293S or HEK293T), BHK or CHO cells. In a non-limiting example, the host cell may comprise a nucleic acid construct or a vector of the invention, and further comprises a further nucleic acid construct or a vector providing the minimal additional genome sequences needed for packaging of the nucleic acid construct in the viral particle (such as in the form of an AAV helper plasmid providing the AAV rep and cap gene). In a further non-limiting example, the host cell may comprise a nucleic acid construct or a vector of the invention, and further comprises two further nucleic acid constructs or vectors providing the minimal additional genome sequences needed for packaging of the nucleic acid construct in the viral particle (such as one nucleic acid construct or a vector providing the AAV- based minimal additional genome sequences (such as a AAV helper plasmid), and one nucleic acid construct or a vector providing Adenoviral (AdV)-based minimal additional genome sequences (such as a AdV helper plasmid)). The nucleic acid constructs, vectors and/or viral particles (such as AAV particles or rAAV particles) herein described can be formulated into pharmaceutical compositions. Therefore, in a sixth embodiment, herein provided is a pharmaceutical composition comprising a nucleic acid construct of the invention, a vector of the invention and/or a viral particle (such as AAV particles or rAAV particles) of the invention together with a pharmaceutically acceptable carrier, excipient, and/or diluent. The pharmaceutical composition of the invention may comprise a pharmaceutically acceptable excipient, carrier, buffer, stabilizer, and/or other materials well known to those skilled 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. The pharmaceutical composition may be provided in liquid form. Liquid pharmaceutical compositions generally include a liquid carrier such as water, or physiological saline solution. For injection at the site of affliction, the active ingredient will be in the form of an aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability. Those of relevant skill in the art are well able to prepare suitable solutions using, for example, isotonic vehicles such as Sodium Chloride Injection, Ringer’s Injection, Lactated Ringer’s Injection, Hartmann’s solution. Preservatives, stabilizers, buffers, antioxidants and/or other additives may be included, as required. Dosages and dosage regimes can be determined within the normal skill of the medical practitioner responsible for administration of the composition. Nucleic acid constructs, vectors and viral particles of the invention have the ability to rescue loss of an original POI (such as PGRN) function, which may occur for example by mutations in one or both alleles of the coding gene (such as a GRN gene) of a patient. “Rescue” generally means any amelioration or slowing of progression of a phenotype associated with deficiency in a given POI (such as PGRN deficiency), for example restoring the presence of the POI (such as PGRN protein) in the brain and/or reducing neuronal pathologies. The properties of nucleic acid constructs and vectors of the present invention may be tested using techniques known by the person skilled in the art. For example, should the POI be PGRN, a nucleic acid construct of the invention can be assembled into a vector of the invention and delivered to a PGRN deficient test animal, such as a mouse or a primate, and the effects observed and compared to a control. In a seventh embodiment, the present invention also encompasses the use of the nucleic acid constructs, vectors, viral particles and/or pharmaceutical compositions described herein for the treatment or the prevention of a disease or condition in a patient. Herein provided is a nucleic acid construct of the invention, a vector of the invention, a viral particle of the invention, and/or a pharmaceutical composition of the invention for use in a method of treating or preventing a disease or a condition in a patient in need thereof. The present invention further provides a method of treating or preventing a disease or condition in a patient in need thereof, said method comprising administering to the patient a therapeutically effective amount of a nucleic acid construct, a vector, a viral particle, and/or a pharmaceutical composition of the invention. The present invention also provides the use of a nucleic acid construct, a vector, a viral particle, and/or a pharmaceutical composition of the invention for the manufacture of a medicament for the treatment or prevention of a disease or condition in a patient in need thereof. The disease or condition may be characterized by a deficiency in a specific protein of interest (POI), such as PGRN deficiency. Said deficiency (such as PGRN deficiency) may arise as a result of a loss of function mutation in one or both alleles of the corresponding gene (such as a GRN gene) of the patient to be treated. In a particular aspect, should the POI be PGRN, the present invention provides a nucleic acid construct of the invention, a vector of the invention, a viral particle of the invention, and/or a pharmaceutical composition of the invention for use in a method of treating or preventing a disease characterized by progranulin (PGRN) deficiency in a patient in need thereof. The present invention further provides a method of treating or preventing a disease characterized by progranulin (PGRN) deficiency in a patient in need thereof, said method comprising administering to the patient a therapeutically effective amount of a nucleic acid construct, a vector, a viral particle, and/or a pharmaceutical composition of the invention. The present invention also provides the use of a nucleic acid construct, a vector, a viral particle, and/or a pharmaceutical composition of the invention for the manufacture of a medicament for the treatment or prevention of a disease characterized by progranulin (PGRN) deficiency. The disease characterized by PGRN deficiency to be treated in a patient with a nucleic acid construct, a vector, a viral particle, and/or a pharmaceutical composition of the invention may be (i) a disease of the central nervous system (CNS), (ii) characterized by a deficiency of PGRN in the neurons and/or the astrocytes of the patient; (iii) characterized by a loss of function mutation in at least one allele of the patient’s GRN gene; and/or (iv) characterized by a loss of function mutation in both alleles of the patient’s GRN gene. The disease characterized by PGRN deficiency to be treated with a nucleic acid construct, a vector, a viral particle, and/or a pharmaceutical composition of the invention may be frontotemporal dementia (FTD) or neuronal ceroid lipofuscinosis type 11 (NCL11). The disease characterized by PGRN deficiency to be treated with a nucleic acid construct, a vector, a viral particle, and/or a pharmaceutical composition of the invention may be further characterized by lysosomal dysfunction, such as a dysregulation of lysosomal acidification. Said lysosomal dysfunction may be characterized by increased expression levels and/or activity of cathepsin D, preferably mature heavy and/or light chain cathepsin D. The patient in need of treatment with a nucleic acid construct, a vector, a viral plasmid, and/or a pharmaceutical composition of the invention may be male or female. Said patient may have been previously identified as being at risk of, or having, a disease characterized by PGRN deficiency. Said patient may have been previously identified as being at risk of, or having, FTD or NCL11. The dose of nucleic acid construct, vector, viral particle, and/or or pharmaceutical composition of the invention may be determined according to various parameters, especially according to the age, weight, and condition of the patient to be treated; the route of administration; and the required regimen. A physician will be able to determine the required route of administration and dosage for any particular patient. The nucleic acid constructs, vectors, viral particles, and/or or pharmaceutical compositions of the invention may be administered to the brain and/or the cerebrospinal fluid (CSF) of the patient. The delivery to the brain may be selected from intracerebral delivery, intraparenchymal delivery, intraputaminal delivery, and combinations thereof. Further target regions in the brain may include the thalamus, cerebellum, subthalamic nucleus, and combinations thereof. The delivery to the CSF may be selected from intra-cisterna magna delivery, intrathecal delivery, intracerebroventricular (ICV) delivery, and combinations thereof. The delivery to the brain and/or the cerebrospinal fluid (CSF) of the patient may be by injection. The injection to the brain may be selected from intracerebral injection, intraparenchymal injection, intraputaminal injection, and combinations thereof. The delivery to the CSF may be selected from intra-cisterna magna injection, intrathecal injection, intracerebroventricular (ICV) injection, and combinations thereof. The injection to the brain and/or the cerebrospinal fluid may comprise convection enhanced delivery (CED). The CED procedure involves a minimally invasive surgical exposure of the brain, followed by placement of small diameter catheters directly into the target area of the brain. CED is described, for example by Debinski et al. (2009). The dose of the nucleic acid constructs, vectors, viral particles and/or pharmaceutical compositions of the invention may be provided as a single dose, but may be repeated in cases where vector may not have targeted the correct region. The treatment is preferably a single injection, but repeat injections, for example in future years and/or with different AAV serotypes may be considered. The present invention further provides kits comprising the nucleic acid constructs, the vectors, the viral vectors, and/or pharmaceutical compositions of the present invention. The present invention is further illustrated by the following examples that, however, are not to be construed as limiting the scope of protection. The features disclosed in the foregoing description and in the following examples may, both separately and in any combination thereof, be material for realizing the invention in diverse forms thereof. EXAMPLES Example 1 – Materials and methods Lentivirus production: All lentiviral vectors used in this study are second generation, produced using standard viral production methods. Briefly, 5.7 million HEK293T cells were plated per 10 cm dish. The following day, cells were transfected with lipofectamine2000 with 10 μg of transfer vector, 3 μg of pMD2G and 8 μg psPAX2. The media was changed 12–14 hours (hrs) post-transfection. The viral supernatant was collected 24 and 48 hrs after this media change for a total of 20 mL of virus and passed through a 0.45 um filter. The viral supernatant was concentrated to 20x in PBS using Lenti-XTM concentrator (CloneTech) prior to being snap frozen. Lentivirus Titration: All lentiviruses were tittered using Lenti-X qRT-PCR Titration Kit (Takara). AAV production: HEK293T cells (obtained from the American Tissue Collection Center, ATCC) are cultured in DMEM containing 10% FBS and 1% S/P antibiotics at 37°C in 150mm tissue culture dishes. When the cells reached 80% confluence, they were transfected (via triple co-transfection, i.e., one plasmid comprising the nucleic acid/vector of the invention, one rep/cap plasmid, and one helper plasmid). Cells were harvested and lysated according to standard protocols. AAV particles were then purified by Iodixanol Gradient Ultracentrifugation according to standard protocols. Neuron-astrocyte co-culture and Lentiviral or AAV9 transduction: Primary neuron-astrocyte co- cultures were prepared from embryonic day 17, C57BL/6J mice (Janvier Labs). Freshly dissected cortical tissue was first dissociated using papain solution. Cells were diluted in neuronal attachment medium and plated (10000 cells/well) on 96-well plates pre-coated with poly-D-Lysine (Corning). The neuronal attachment media consists of Neurobasal plus medium supplemented with 2.5% heat inactivated FBS, 1 mM sodium pyruvate, 2 mM Glutamax-100X, B27 Plus Supplement, and 50 units/ml penicillin/streptomycin (all excipients ThermoFisher Scientific). Cells were maintained by supplementing with fresh serum-free neurobasal medium every week. Lentiviral mediated transduction was performed on day 3. Lentivirus or AAV9 stocks were diluted in culture medium and applied on top of cells at given Multiplicity of Infection (MOI) as indicated in Figure legends. 10-days post transduction, cells were fixed, and immunocytochemistry performed. For Lentiviruses, MOI of 20 was used and for AAV9, MOI of 10,000 was used. Immunolabeling and Imaging: Immunocytochemistry was performed following transduction in primary neurons and astrocytes. Cells were washed three times (1X PBS) followed by fixation using 4% PFA (ThermoFischer Scientific) for 10min at room temperature. Cells were then permeabilized using 0.25%-Triton-X/3%-BSA/1X-PBS solution for 10min. Following permeabilization, cells were blocked using 3%-BSA/1X-PBS solution for 30min. Cells were then labeled with primary antibodies (60min) followed by fluorescent conjugated secondary antibodies (45min) (see Table B for the list of antibodies). Imaging was performed on Zeiss LSM 880 (SH-SY5Y cells) and Perkin Elmer Opera Phenix (Neurons/Astrocytes) instruments. Thresholding and Quantification was performed on Image J or Perkin Elmer Harmony software. Table B PRIMARY ANTIBODIES Name Host Species Catalog No. Supplier Dilution NeuN Mouse MAB377 Millipore 1:2500 GFAP Rabbit Z0334 DAKO 1:2500 Human Progranulin Goat AF2420 R&D Systems 1:1000 SECONDARY ANTIBODIES Name Host Species Catalog No. Supplier Dilution Anti-Goat 550 Donkey A32816 ThermoFisher 1:800 Anti-Mouse 488 Donkey A32766 ThermoFisher 1:800 Anti-Rabbit 647 Donkey A32795 ThermoFisher 1:800 ELISA: The human and mouse Progranulin ELISA kits (both Adipogen) were used to quantify the level of secreted PGRN following transduction of mice neuron-astrocyte co-culture. Same reagents were used for in vivo CSF hPGRN measurement. The cell culture media were collected 10-days post transduction. Samples were diluted to 1:100-1:1000 and ELISA measurement performed as per suppliers’ instruction. For CSF, samples were diluted 1:100. The colorimetric reaction was measured using a standard plate reader (Flex Station3, Molecular Devices). Quantitative real-time polymerase chain reaction (qRT-PCR): Total neuronal RNA was isolated using the RNeasy 96 kit (Qiagen) according to the manufacturer's protocol. Briefly, cDNA was synthetized from 1 µg of RNA using high-capacity cDNA reverse transcription kit (40 µl). The quantitative real-time PCR experiments were performed using specific Taqman gene expression probes for Hexb (Mm00599880_m1), Ctsd (Mm00515586_m1), Gpnmb Mm01328586_g1), Lgals3 (Mm00802901_m1), β-actin (Mm02619580_g1) and Pgk1 (Mm00435617_m1). The reactions were performed in ViiA 7 RT-PCR system (Applied Biosystems) using 5 ng of cDNA sample and the recommended concentration of the specific probe and qPCR master mix Luminaris. PCR reactions were run in duplicate and the fold changes in mRNA levels were calculated using 2−ΔΔCt method (Schmittgen and Livak, 2008) and normalized to β-actin and Pgk1 mRNA levels. Western Blot Analysis: Cells were transfected with constructs of interest using X-treme GENE™ 360 Transfection Reagent (Sigma) flowing the manufacturer’s instructions. After 48 hours post transfection cell pellets were lysed in cell lysis buffer (Cell Signaling) supplemented with PMSF (Sigma-Aldrich), Protein concentration was measured using BCA protein assay reagent (ThermoFisher). Medium were collected simultaneously followed by centrifugation at 12000g at 4 degrees for 10 minutes. Lysates and medium were mixed with 4X loading buffer (Li-Cor) and equal amounts of protein were run on Mini-PROTEAN TGX 4-15% precast polyacrylamide gels (Bio-Rad) and transferred to nitrocellulose membranes using the Trans-Blot Turbo System (Bio-Rad). Nonspecific antibody binding was blocked with Intercept TBS blocking buffer (Li-Cor) for 1 h at room temperature. The membranes were incubated with the following primary antibodies: anti- PGRN (1:1000 dilution, Abcam) in Intercept T20 TBS (Li-Cor) overnight at 4 °C; anti-GAPDH (1:5000 dilution, Sigma-Aldrich) in Intercept T20 TBS (Li-Cor) overnight at 4 °C. The membranes were washed with TBST 3 times for 5 minutes each and incubated for 1 hour with Donkey anti- mouse 680 RD (Li-Cor, 1:5000) and Donkey anti-rabbit 800 CW (Li-Cor, 1:5000) antibodies in Intercept T20 TBS and subsequently washed with TBST 3 times for 5 min each. Membranes were visualized using the Odyssey CLx (Li-Cor). For medium samples, the blot was stained with Revert™ Total Protein Stains to obtain BSA signal. Cell line culture: Ad293 cells were obtained from Agilent and Neuro-2A cells were obtained from Sigma. Both cell lines were maintained in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% FBS and 1% penicillin/streptomycin. Brain sectioning, immunohistochemistry and acquisitions: Brain sectioning was performed at Neuroscience Associates. First, brains were treated overnight with 20% glycerol and 2% dimethyl sulfoxide to prevent freeze-artifacts and embedded in a gelatin matrix using MultiBrain® Technology. After curing, the blocks were rapidly frozen by immersion in isopentane chilled to −70°C with crushed dry ice and mounted on the freezing stage of an AO860 sliding microtome. The MultiBrain® blocks were sectioned in the coronal plane at 40 μm. All sections were collected sequentially into 24 containers per block that were filled with Antigen Preserve solution (49% PBS pH 7.0, 50% Ethylene glycol, 1% Polyvinyl Pyrrolidone). Sections not stained immediately were stored at −20°C. Free-floating sections were stained by immunochemistry with an antibody to human progranulin (R&D), diluted at 1:15.000. All incubation solutions from the blocking serum onward used Tris buffered saline (TBS) with Triton X-100 as the vehicle; all rinses were with TBS. Endogenous peroxidase activity was blocked by 0.9% hydrogen peroxide treatment and non-specific binding was blocked with 1.26% whole normal serum. Following rinses, the sections were stained with a primary antibody overnight at room temperature. Vehicle solution contained 0.3% Triton X-100 for permeabilization. Following rinses, sections were incubated with an avidin-biotin-HRP complex (Vectastain Elite ABC kit, Vector Laboratories, Burlingame, CA) for one hour at room temperature. Following rinses, the sections were treated with diaminobenzidine tetrahydrochloride (DAB) and 0.0015% hydrogen peroxide to create a visible reaction product, mounted on gelatinized (subbed) glass slides, air-dried, lightly stained with thionine, dehydrated in alcohols, cleared in xylene, and mounted on covers- with Permount mounting media. Digital images of stained sections were obtained using an AxioScan Z1 slide scanner with a 20x objective (Zeiss). AAV vectors/AAV particles The corresponding plasmid sequences are provided in SEQ ID NO: 22 (AAV-06164 plasmid; comprising AAV-06164 construct of SEQ ID NO:10), SEQ ID NO: 23 (AAV- 06262 plasmid; comprising AAV-06262 construct of SEQ ID NO:11) and SEQ ID NO: 24 (AAV- 06263 plasmid; comprising AAV-06263 construct of SEQ ID NO:12). Viral (AAV) particles were produced using a triple plasmid transfection method as described previously in Grieger et al (2016) using HEK 293T or HEK293 cells respectively, including a helper plasmid, a Rep/Cap encoding plasmid, and the plasmid reported above. Figure 2 provides a schematic showing the component parts of the nucleotide sequence of SEQ ID NO: 10, 11 and 12. Example 2 – Generation of GRN promoter constructs Lentiviral vector constructs pPG41 were generated as described above. Construct pPG41 (SEQ ID NO: 6) comprises a mouse GRN promoter region (SEQ ID NO: 1). The mouse GRN promoter sequence is 2508 residues in length. Construct 06164 (SEQ ID NO: 7) comprises a truncated human GRN1 promoter region (SEQ ID NO: 3). The truncated GRN1 promoter sequence is 1801 residues in length. The corresponding AAV-06164 construct corresponds to SEQ ID NO:10. Construct 06262 (SEQ ID NO: 8) comprises a truncated human GRN2 promoter region (SEQ ID NO: 4). The truncated GRN2 promoter sequence is 632 residues in length. The corresponding AAV-06262 construct corresponds to SEQ ID NO:11. Construct 06263 (SEQ ID NO: 9) comprises a truncated human GRN3 promoter region (SEQ ID NO: 5). The truncated GRN3 promoter sequence is 489 residues in length. The corresponding AAV-06263 construct corresponds to SEQ ID NO:12. Example 3 – Evaluation of transgene expression by mouse GRN promoter in primary neurons and astrocytes ELISA and Immunocytochemistry experiments demonstrating the functionality of mouse GRN promoter in WT and KO mouse primary neurons. Mouse primary neurons were transduced to express hPGRN (human progranulin) protein under the control of mouse GRN promoter (pPG41) as depicted in Figure 1. 10-days post transduction, culture media was collected, and ELISA performed to specifically detect mouse (A) and human (B) PGRN protein. mPGRN (mouse progranulin) protein is detected only in WT (both transduced and untransduced) and not in KO neuronal cultures (A). Similarly, hPGRN protein is detected only in transduced neuronal cultures (both WT and KO). Immunocytochemistry and confocal imaging were performed on cells to quantify the percentage of transduced neurons (C), the percentage of transduced astrocytes (D) and the expression level of hPGRN (E) in pPG41 transduced WT and KO neurons. Both in WT and KO neurons, nearly 60% neurons were transduced using lentiviral construct at a MOI of 20. hPGRN expression in astrocytes was negligible. Example 4 – Evaluation of PGRN expression by truncated GRN promoters To assess the strengths of various granulin truncated promoters, three constructs respectively containing PGRN promoters with different sizes (see example 2) were examined for expression of human progranulin in Ad293 and Neuro2A cells. Western blot was employed to analyze progranulin expression under three different promoters. As shown in Figure 3, all the three promoters drove progranulin expression successfully. Among them GRN3 promoter was found to give the highest level of transgene expression in both cell lines. Since progranulin is a secreted glycoprotein, the culture medium was collected simultaneously to investigate progranulin secretion and the result indicated secreted progranulin level was more than 3-fold higher induced by GRN3 promoter than by GRN1 promoter, which was in agreement with the previous result in cell lysate. The expression of hPGRN using the three truncated promoters was also investigated in GRN-/- mice primary neurons (Figure 4). Mouse primary neurons were transduced using an AAV9 viral vector to express hPGRN protein under the control of various truncated human GRN promoters (AAV-06164, AAV-06162, and AAV-06163). 10-days post transduction, culture media were collected, and an ELISA was performed to quantify secreted hPGRN, or cells harvested for mRNA and protein extraction. Compared to GRN1 promoter, smaller promoters GRN2 and GRN3 exhibited enhanced levels of mRNA (A) and protein (B). In addition, higher levels of secreted hPGRN were detected in the culture media for the smaller promoters, compared to GRN1 (C). Example 5 - CNS expression of human PGRN (hPGRN) in WT rats following striatal injection of AAVTT-06164 Striatum of adult (2-3 months old) Sprague-Dawley Rats were bilaterally injected with an AAV-TT viral vector containing the construct of GRN1 promoter (1801 residues long) + human PGRN transgene (SEQ ID NO: 22) or vehicle (PBS) at a total dose of 2¹⁰ vector genomes (vg). Animals were sacrificed after 4 weeks and CSF, plasma and brain tissue were collected and analyzed (Figure 6). Trans-cardial perfusion was performed with 1x PBS prior to dissection. Half of the brain was fixed for immunohistochemistry (IHC) analysis, while other half was used for biochemical analysis (Western Blotting). IHC using hPGRN specific antibody revealed expression of hPGRN protein in the striatum (site of injection), but also in the brain regions away from the injection site, namely thalamus, mid-brain, substantia nigra, cortex and hippocampus (Figure 6A). No hPGRN staining was seen in the PBS injected rats (control). The hPGRN staining arise from both cellularly expressed (close to injection site with strong expression in the cell body - striatum, part of cortex, part of hippocampus, thalamus, mid-brain) and secreted/uptaken forms (distal to the site of injections, with diffused staining). The diffused staining in the distal regions suggests that secreted hPGRN is widespread distributed by ISF/CSF flow in the CNS of the rats. The hPGRN concentration in the rat CSF was also quantified using human-specific ELISA assay (Figure 6B). The CSF samples for AAVTT-06164 and PBS injected animals were collected longitudinally 2-week and 4-weeks post-surgery. Expression of hPGRN was detected only in the CSF of AAVTT-06164 injected rats, but not PBS injected rats. Notably, a slight increase in hPGRN concentration was detected between 2- and 4-weeks post-surgery. AAVTT-06164, under the control of endogenous human GRN promoter, is therefore capable of translating hPGRN in the rat CNS via a GT delivery. Example 6 -Impact of human PGRN (hPGRN) expression on lysosomal gene expression Quantitative PCR analysis of the lysosome genes, Cathepsin D (CTSD), Glycoprotein NMB (GPNMB), Hexosaminidase B (HEXB) and Galectin 3 (LGALS3) was performed using primary neuronal cultures of WT and Grn-/- (KO) mice. As may be seen from Figure 7, increased expression of these genes was observed in KO neurons compared to WT neurons, indicating lysosomal stress. Expression of hPGRN in KO neurons transduced withAAV9-06164, AAV9-06262 or AAV9-06263 reduced the level of these lysosomal markers compared to control KO neurons. LIST AND DESCRIPTION OF THE SEQUENCES SEQ I_{D NO} ^{Description Sequence} 1 Mouse TATGTGGGTTATATAGTGAGTTCAAGGCTAGCCTGGAAAACTTAGGGAGACTCCATCTCAAA GRN ATAAAAAGTAAAAAAAAAAATAAAAATAAAAATGAAGAGGCTGATCTTCTATGGCAAGATGG GAGGCAGAGTCAAGAAAATCATTTGGAGGCTTAAGGGCCAGGTATCATGAAGCACACAGCGC (mGRN) GCAGAGGCAAAAACAGAGACCTTGCCTTAAAAACAAGGTAAACGCCGGGCGTGGTGGCGCAT promoter GCCTTTAGTCCCAGCACTGGGGAGGCAGAGGCAGGCGGATTTCTGAGTTCGAGGCCAGCCTG GTCTACAAAGTGAGTTCCAGGACAGCCAGGGCTATACAGAGAAACCCTGTCTCGAAAAAAAC CAAAACCAAAACCAAAACAAACAAACAAACAAACAAGATAAACAAGGTAGGGTGGTGGTGGT GGTATGTGGCTTTGAACCCCAGCACTGAGGAGGCAGAGGCAGGTGGATCTCTCTGTGTTTGA GTCCAGCCTGGTCTATAGAGTGAGTTCCAGGCTAGCCAGAACTCCACAGAGAAACCCTTTCT TGATAAACAAAACCAGGTGGACAGATCGACTGTCCAAATGTTGTTCTGTGAAATATGCGCTC CCTCCTTCAGACGGAAACCAGAACCTCTCGTGTTAGATTAGAGCAATGCCATTAAGCTGTAG CCCCAGAAGTTTGTTCTACCTTTTTATTATTTATTTCAAGCGATTGCGTATGTAAGTCTGGG GGTGCGCTAATGCTATGGTGTGTGTGCAGAAGTCAGAAGTCGTGGTTTCTGGGAGTCATTTC TGTCTTGTGAAACAAAGGAAGCAGGTTTGTTAAGCTTTTACCTGCTCCCCATTTTATTTCCC CTTGAGGCAGTGCTGCGTCTAGGATGTAGCTCAGTTGGTAGCACTTGTAGCTCAGCATGCTC AAGGCCCTAGGTCTAATCCCAGCAGCACAGAAACTAAACACGGCAATCTGCACTTGCAATCG TGGCGCTTGGGAGATGGGGGCAGAAAACTGAGAAGTTCTGTGTCAGCTATCTATCAAGCTGA AGCTCGTCTGGAACACAGGAAACCCTGACTCAGAGGGTGAGCTGCAATGTTGCTGAGTCTGG TTTCCAACTCCTGGGGTTCAGCAGCACCCCTTCCTCAGCCTCCGCAGATGGCTGTGTCTCAC TAGAAGCATAAGCAATGGTCTGTTCTGGGGACACCTGTATGAATGTCATGGAACACCTATGC TAACACCATCAGGATGCAGAATGATGCACCAGTCTTACACACTTTCTGGGACTCCAGTGTAA GAAGCCCTCACGGAATTCCACAACCCTGCATGCACTCCTCTCTATGTAAGACTCCCACTGTC CTGAACTGTATGGCTGACCCCCATGGTCTCTATTCACCCACCATAACAATTCCTCGAAGGTG GGGACAGCTGAAACAAGGAAACCCCTTCCATCTCGACAGCCACCAGCCTACTCCACAGGCAG TGCCACACACTTGGCTAATGCCCTTATCTTGAACGTGGCTTTCAACCCTTGCTAGAGGCTGT CTGTAAAGAACAAGATATAAACTACCCAAGGAAAGGATTCACTGTCTTTCCCAATCTAGTTT CAAGTTCCTCTGTCCCACCTTATCAGCCTCTTAAAATTCTTTCAGCTTCAATTTAATGCAGT GCTATCAATATGGATTTAAATCTCTTCTTCCCCCCAGTTTGAGCCAATCTCCTGCCTCCTCC CTACACACATCTACAGTGCCCGGTACTCGCCCTTGAACCTTTATTAGATTTAGTCTAAGCCA CTCTCCCCATTCAAACCTGGGGACTATTTATCTTCACCCTCACAACCATCTTCCAACTGGTT TCGAGTCCTTGTCTGCCAGGCGTGAAGAGACAGGAATGTACAAAAGTCCCGATCCAGAAGCA GACACCCTCCAGTAAACGACCTTGAACGCGTGCCCTCAGGGCAGCTCTCCTAACTGTGGGTG CCCTTAGGCATGAGGTGTCTCATCTCTGCAACACTCTGCCGCCAGAACCCAAACCAGCAAGC TCTGCCCTGGGGGAGGCGGGCTATGTTGTCATATGATTCTCTAATCACATGATCCCTAGAAA TGGGGTGTGGGGAGAAAGAGGAAAGGGAGGAGGAATGTGAACTGAGTAGAAAAGAAACACAG CATTCCAGGAGAGTCCCGCCTCTACGTAGACAAGTAACCAATGGAAGCCCTGGATCTCCGAG CAATGGCTAATGGAAATTGAGGTGGGCGGGCCATCGTGCGGCCAAGCCCTAGTCCTGGAGCT GACCGCCAGATGCCTCCCAGGGAGCCCGGACCCCGACGCAGGTAGGAGGACCCTCTGCAGAC AATCTCCCCGGCTACTGTCCAGAGGTCCAGAGGCCTGACCAGGCTGCCTGTGCAATTGAGGG TCCTCTGGAGTCTCAGCTCAGAGACAAGAGAAGACCTGCCTCTTGAAACTCCCCTAGGGGTT TCTGATGCACTAACGAGGTTGTTTTTTT Human full GGTCTTAAACTGATTGTAATGATGCTGCATAACTCTCTTAAGACACTAAAAACCATTGAGTT length GRN GTACACTTTAATTTTTTTGTGTTGGCGGGGGTGGATGGAGTCTCGCTCTGTTGTCCAGGCTG GAATGCAGTGGCACGATCTCGGTTTACTGCAACCTCTGCATCCCGGGTTCAAGCGATTCTCC promoter TGCCTCGGCCTCCTGAGTAGGGAATTACAGACCTCGTTATCGTGGCACCTTACCCTTCTGAT GTTAAAAAAAAAAAAAAAAAGAGCGAGAGAGAGAGAGAGAAACATTTGTGAAGTAGGTTGTT GAGTCTCAGCACTATTGACCTTTTGGGCAGGATACTTCTTTGTTGTGGGGGATTGTTCTGTG TGTCGTGTGATGTTTAGTGGGATTGCTGGCCCTTACCTACCAGATGCCAGTGTCCCTCCACC CTGAGTTGTGACAACCCAGATTGTCTCCAGACACTCCTAAATGTCCCTGGCCGGCAAAATTG CCGCTGCTCAAGAATCACGGCTTTGACGATTAGACTTTGTGATATTTGTTTCAGTCTGTTTA GGTTTTTTTTCTTCTACCTGTATTTTTTTCTGGTTCTGGGTGGTTGTAATTAGTAGGTTATT GATCGATTCACCTAACATTTCATGAAAGTTTCATGTGTGTGTGTGTTTCAATAGAAGCATAA ACTATACTCCCTAGTCTCAAGATACACAGGAAGGAAAATAAGCACAAATGTGTCACCAGGGC ACAGACTAGTACTAGGTCCTCAGCAGGCCAGGTGTCTTATCCGCTGTCTGGGTCTGCTCTAG CTCCAGGCTTAGAACCCCTGCCACACGACTCCACAGCTCGGTTGGCACCCTTTCCCTCCTCC GACTTCTGCTGCCTCGAGCTTGGTTAGCCATCCCCCTGCCCCTGCCTCATCCTCAGCTCCAG TTCCTTGCTCAGGCTGCAGCAGTCTCCATCCCCTGTGCAGACACTGCCGTTCCTCCACGGCC CAGTATCAGGCTTTCCCTGGGCCTCTCCTCTCTCCTGGCCCATCTCCCATCATCCATCTCTG CCTGGCCCAGGCCCTTTGGCACCAAGCAGGCTGACTCTTGTCACTGGCTAATCTGTTCTGTG GTACATTTTCTCTCCTCACCCTCCCATATCAATTCCTCGAAGGCAGGGCCGATCTGGAGACT AGGAAGCCACTTCTCTTTCGACAGCCCCCACCACAGCCCAGCCCGTGCCAGGCACCCAGCAG CTCCTGAAGCCCACTGGCATTGAACATGGCATTCAATCCCTGCCAAGCCTGCCCTTCCCATC TGGTTTCCCAGGGCTCTTCCCAACACCTCCTCCTCCACCTGCCAGTTAAAATCTTCCCAGAC TCAGCTCAAGGAGATGCTCCTAAGGTGGAATGAAATCTCTTCTTCCCCACCTGGAGACAATC TACTTCCTCTCCCTACACCTGGCAACTGGCGCACAACCTTGTATCTTAAATTAGATTCAGCC TGAGACTGTCTCCCACCAATCCCTGCTCCCTGTCCTGCTGAGCACCTTGAGGAAAGGGCTTT GGGGCTGTTTATCTTTGTCCTGGAAACCATCCTTCAACTCACTCTGGGGCCTGCCTAGCATG TCAACCGAGTTTGGAGAATAGGGCAGAATAGGGCAGGACAGGACAGGACAAGACAGGGCAGG ATAGGATAGGAGCGAGCCAGCTCAGTAGCTCACATTTGTAATCCCAGCGCCTTGGGGGGCTG CGGTAGGAGAATCGCTTTGGGAGCAGGAGTTGCAGGCCGCAGTGAGCTATGATCAGCTTGGG CGACTGAGCGAGACCCTGTCTCTAAAACAAACACACAAGTCCGGGCGCGGTGGCTCATGCCT GTAATCTTAGCACTTTGGGAGGCCGAGGTGGGCGGATCACGAGGTCAAGAAATCGAGACCAT CCTGGCCAACATGGTGAAACCCCGTCTCTACTAAAAATACAAAAATTAGCTGGGCGTGGTGG TGCGCGCCTGTAGTCCCAGCTACTCGGGAGGCTGAGGCAGGAGAATCGCTTGAACCCGGGAG GCAGAGGTTGCAGTGAGCCGAGATCGTGCCACTGCACTCCAGCCTGGCGACAGAGTGAGACT CCGTCTCAGAACAAACAAACAAAAGGATAGAAAGGCGAGCACAAATATTCCCAATTCATAAC ACTCCCTCGCACTGTCAATGCCCCAGACACGCGCTATCATCTCTAGCAAACTCCCCCAGGCG CCTGCAGGATGGGTTAAGGAAGGCGACGAGCACCAGCTGCCCTGCTGAGGCTGTCCCGACGT CACATGATTCTCCAATCACATGATCCCTAGAAATGGGGTGTGGGGCGAGAGGAAGCAGGGAG GAGAGTGATTTGAGTAGAAAAGAAACACAGCATTCCAGGCTGGCCCCACCTCTATATTGATA AGTAGCCAATGGGAGCGGGTAGCCCTGATCCCTGGCCAATGGAAACTGAGGTAGGCGGGTCA TCGCGCTGGGGTCTGTAGTCTGAGCGCTACCCGGTTGCTGCTGCCCAAGGACCGCGGAGTCG GACGCAGG Human CTAGTACTAGGTCCTCAGCAGGCCAGGTGTCTTATCCGCTGTCTGGGTCTGCTCTAGCTCCA GRN1 GGCTTAGAACCCCTGCCACACGACTCCACAGCTCGGTTGGCACCCTTTCCCTCCTCCGACTT CTGCTGCCTCGAGCTTGGTTAGCCATCCCCCTGCCCCTGCCTCATCCTCAGCTCCAGTTCCT promoter TGCTCAGGCTGCAGCAGTCTCCATCCCCTGTGCAGACACTGCCGTTCCTCCACGGCCCAGTA TCAGGCTTTCCCTGGGCCTCTCCTCTCTCCTGGCCCATCTCCCATCATCCATCTCTGCCTGG CCCAGGCCCTTTGGCACCAAGCAGGCTGACTCTTGTCACTGGCTAATCTGTTCTGTGGTACA TTTTCTCTCCTCACCCTCCCATATCAATTCCTCGAAGGCAGGGCCGATCTGGAGACTAGGAA GCCACTTCTCTTTCGACAGCCCCCACCACAGCCCAGCCCGTGCCAGGCACCCAGCAGCTCCT GAAGCCCACTGGCATTGAACATGGCATTCAATCCCTGCCAAGCCTGCCCTTCCCATCTGGTT TCCCAGGGCTCTTCCCAACACCTCCTCCTCCACCTGCCAGTTAAAATCTTCCCAGACTCAGC TCAAGGAGATGCTCCTAAGGTGGAATGAAATCTCTTCTTCCCCACCTGGAGACAATCTACTT CCTCTCCCTACACCTGGCAACTGGCGCACAACCTTGTATCTTAAATTAGATTCAGCCTGAGA CTGTCTCCCACCAATCCCTGCTCCCTGTCCTGCTGAGCACCTTGAGGAAAGGGCTTTGGGGC TGTTTATCTTTGTCCTGGAAACCATCCTTCAACTCACTCTGGGGCCTGCCTAGCATGTCAAC CGAGTTTGGAGAATAGGGCAGAATAGGGCAGGACAGGACAGGACAAGACAGGGCAGGATAGG ATAGGAGCGAGCCAGCTCAGTAGCTCACATTTGTAATCCCAGCGCCTTGGGGGGCTGCGGTA GGAGAATCGCTTTGGGAGCAGGAGTTGCAGGCCGCAGTGAGCTATGATCAGCTTGGGCGACT GAGCGAGACCCTGTCTCTAAAACAAACACACAAGTCCGGGCGCGGTGGCTCATGCCTGTAAT CTTAGCACTTTGGGAGGCCGAGGTGGGCGGATCACGAGGTCAAGAAATCGAGACCATCCTGG CCAACATGGTGAAACCCCGTCTCTACTAAAAATACAAAAATTAGCTGGGCGTGGTGGTGCGC GCCTGTAGTCCCAGCTACTCGGGAGGCTGAGGCAGGAGAATCGCTTGAACCCGGGAGGCAGA GGTTGCAGTGAGCCGAGATCGTGCCACTGCACTCCAGCCTGGCGACAGAGTGAGACTCCGTC TCAGAACAAACAAACAAAAGGATAGAAAGGCGAGCACAAATATTCCCAATTCATAACACTCC CTCGCACTGTCAATGCCCCAGACACGCGCTATCATCTCTAGCAAACTCCCCCAGGCGCCTGC AGGATGGGTTAAGGAAGGCGACGAGCACCAGCTGCCCTGCTGAGGCTGTCCCGACGTCACAT GATTCTCCAATCACATGATCCCTAGAAATGGGGTGTGGGGCGAGAGGAAGCAGGGAGGAGAG TGATTTGAGTAGAAAAGAAACACAGCATTCCAGGCTGGCCCCACCTCTATATTGATAAGTAG CCAATGGGAGCGGGTAGCCCTGATCCCTGGCCAATGGAAACTGAGGTAGGCGGGTCATCGCG CTGGGGTCTGTAGTCTGAGCGCTACCCGGTTGCTGCTGCCCAAGGACCGCGGAGTCGGACGC AGG Human CCATCCTGGCCAACATGGTGAAACCCCGTCTCTACTAAAAATACAAAAATTAGCTGGGCGTG GRN2 GTGGTGCGCGCCTGTAGTCCCAGCTACTCGGGAGGCTGAGGCAGGAGAATCGCTTGAACCCG GGAGGCAGAGGTTGCAGTGAGCCGAGATCGTGCCACTGCACTCCAGCCTGGCGACAGAGTGA promoter GACTCCGTCTCAGAACAAACAAACAAAAGGATAGAAAGGCGAGCACAAATATTCCCAATTCA TAACACTCCCTCGCACTGTCAATGCCCCAGACACGCGCTATCATCTCTAGCAAACTCCCCCA GGCGCCTGCAGGATGGGTTAAGGAAGGCGACGAGCACCAGCTGCCCTGCTGAGGCTGTCCCG ACGTCACATGATTCTCCAATCACATGATCCCTAGAAATGGGGTGTGGGGCGAGAGGAAGCAG GGAGGAGAGTGATTTGAGTAGAAAAGAAACACAGCATTCCAGGCTGGCCCCACCTCTATATT GATAAGTAGCCAATGGGAGCGGGTAGCCCTGATCCCTGGCCAATGGAAACTGAGGTAGGCGG GTCATCGCGCTGGGGTCTGTAGTCTGAGCGCTACCCGGTTGCTGCTGCCCAAGGACCGCGGA GTCGGACGCAGG Human AGCCGAGATCGTGCCACTGCACTCCAGCCTGGCGACAGAGTGAGACTCCGTCTCAGAACAAA GRN3 CAAACAAAAGGATAGAAAGGCGAGCACAAATATTCCCAATTCATAACACTCCCTCGCACTGT CAATGCCCCAGACACGCGCTATCATCTCTAGCAAACTCCCCCAGGCGCCTGCAGGATGGGTT promoter AAGGAAGGCGACGAGCACCAGCTGCCCTGCTGAGGCTGTCCCGACGTCACATGATTCTCCAA TCACATGATCCCTAGAAATGGGGTGTGGGGCGAGAGGAAGCAGGGAGGAGAGTGATTTGAGT AGAAAAGAAACACAGCATTCCAGGCTGGCCCCACCTCTATATTGATAAGTAGCCAATGGGAG CGGGTAGCCCTGATCCCTGGCCAATGGAAACTGAGGTAGGCGGGTCATCGCGCTGGGGTCTG TAGTCTGAGCGCTACCCGGTTGCTGCTGCCCAAGGACCGCGGAGTCGGACGCAGG pPG41 TATGTGGGTTATATAGTGAGTTCAAGGCTAGCCTGGAAAACTTAGGGAGACTCCATCTCAAA construct ATAAAAAGTAAAAAAAAAAATAAAAATAAAAATGAAGAGGCTGATCTTCTATGGCAAGATGG GAGGCAGAGTCAAGAAAATCATTTGGAGGCTTAAGGGCCAGGTATCATGAAGCACACAGCGC GCAGAGGCAAAAACAGAGACCTTGCCTTAAAAACAAGGTAAACGCCGGGCGTGGTGGCGCAT GCCTTTAGTCCCAGCACTGGGGAGGCAGAGGCAGGCGGATTTCTGAGTTCGAGGCCAGCCTG GTCTACAAAGTGAGTTCCAGGACAGCCAGGGCTATACAGAGAAACCCTGTCTCGAAAAAAAC CAAAACCAAAACCAAAACAAACAAACAAACAAACAAGATAAACAAGGTAGGGTGGTGGTGGT GGTATGTGGCTTTGAACCCCAGCACTGAGGAGGCAGAGGCAGGTGGATCTCTCTGTGTTTGA GTCCAGCCTGGTCTATAGAGTGAGTTCCAGGCTAGCCAGAACTCCACAGAGAAACCCTTTCT TGATAAACAAAACCAGGTGGACAGATCGACTGTCCAAATGTTGTTCTGTGAAATATGCGCTC CCTCCTTCAGACGGAAACCAGAACCTCTCGTGTTAGATTAGAGCAATGCCATTAAGCTGTAG CCCCAGAAGTTTGTTCTACCTTTTTATTATTTATTTCAAGCGATTGCGTATGTAAGTCTGGG GGTGCGCTAATGCTATGGTGTGTGTGCAGAAGTCAGAAGTCGTGGTTTCTGGGAGTCATTTC TGTCTTGTGAAACAAAGGAAGCAGGTTTGTTAAGCTTTTACCTGCTCCCCATTTTATTTCCC CTTGAGGCAGTGCTGCGTCTAGGATGTAGCTCAGTTGGTAGCACTTGTAGCTCAGCATGCTC AAGGCCCTAGGTCTAATCCCAGCAGCACAGAAACTAAACACGGCAATCTGCACTTGCAATCG TGGCGCTTGGGAGATGGGGGCAGAAAACTGAGAAGTTCTGTGTCAGCTATCTATCAAGCTGA AGCTCGTCTGGAACACAGGAAACCCTGACTCAGAGGGTGAGCTGCAATGTTGCTGAGTCTGG TTTCCAACTCCTGGGGTTCAGCAGCACCCCTTCCTCAGCCTCCGCAGATGGCTGTGTCTCAC TAGAAGCATAAGCAATGGTCTGTTCTGGGGACACCTGTATGAATGTCATGGAACACCTATGC TAACACCATCAGGATGCAGAATGATGCACCAGTCTTACACACTTTCTGGGACTCCAGTGTAA GAAGCCCTCACGGAATTCCACAACCCTGCATGCACTCCTCTCTATGTAAGACTCCCACTGTC CTGAACTGTATGGCTGACCCCCATGGTCTCTATTCACCCACCATAACAATTCCTCGAAGGTG GGGACAGCTGAAACAAGGAAACCCCTTCCATCTCGACAGCCACCAGCCTACTCCACAGGCAG TGCCACACACTTGGCTAATGCCCTTATCTTGAACGTGGCTTTCAACCCTTGCTAGAGGCTGT CTGTAAAGAACAAGATATAAACTACCCAAGGAAAGGATTCACTGTCTTTCCCAATCTAGTTT CAAGTTCCTCTGTCCCACCTTATCAGCCTCTTAAAATTCTTTCAGCTTCAATTTAATGCAGT GCTATCAATATGGATTTAAATCTCTTCTTCCCCCCAGTTTGAGCCAATCTCCTGCCTCCTCC CTACACACATCTACAGTGCCCGGTACTCGCCCTTGAACCTTTATTAGATTTAGTCTAAGCCA CTCTCCCCATTCAAACCTGGGGACTATTTATCTTCACCCTCACAACCATCTTCCAACTGGTT TCGAGTCCTTGTCTGCCAGGCGTGAAGAGACAGGAATGTACAAAAGTCCCGATCCAGAAGCA GACACCCTCCAGTAAACGACCTTGAACGCGTGCCCTCAGGGCAGCTCTCCTAACTGTGGGTG CCCTTAGGCATGAGGTGTCTCATCTCTGCAACACTCTGCCGCCAGAACCCAAACCAGCAAGC TCTGCCCTGGGGGAGGCGGGCTATGTTGTCATATGATTCTCTAATCACATGATCCCTAGAAA TGGGGTGTGGGGAGAAAGAGGAAAGGGAGGAGGAATGTGAACTGAGTAGAAAAGAAACACAG CATTCCAGGAGAGTCCCGCCTCTACGTAGACAAGTAACCAATGGAAGCCCTGGATCTCCGAG CAATGGCTAATGGAAATTGAGGTGGGCGGGCCATCGTGCGGCCAAGCCCTAGTCCTGGAGCT GACCGCCAGATGCCTCCCAGGGAGCCCGGACCCCGACGCAGGTAGGAGGACCCTCTGCAGAC AATCTCCCCGGCTACTGTCCAGAGGTCCAGAGGCCTGACCAGGCTGCCTGTGCAATTGAGGG TCCTCTGGAGTCTCAGCTCAGAGACAAGAGAAGACCTGCCTCTTGAAACTCCCCTAGGGGTT TCTGATGCACTAACGAGGTTGTTTTTTTGGATCCCCGGGTACCGGTGCCACCATGTGGACCC TGGTGAGCTGGGTGGCCTTAACAGCAGGGCTGGTGGCTGGAACGCGGTGCCCAGATGGTCAG TTCTGCCCTGTGGCCTGCTGCCTGGACCCCGGAGGAGCCAGCTACAGCTGCTGCCGTCCCCT TCTGGACAAATGGCCCACAACACTGAGCAGGCATCTGGGTGGCCCCTGCCAGGTTGATGCCC ACTGCTCTGCCGGCCACTCCTGCATCTTTACCGTCTCAGGGACTTCCAGTTGCTGCCCCTTC CCAGAGGCCGTGGCATGCGGGGATGGCCATCACTGCTGCCCACGGGGCTTCCACTGCAGTGC AGACGGGCGATCCTGCTTCCAAAGATCAGGTAACAACTCCGTGGGTGCCATCCAGTGCCCTG ATAGTCAGTTCGAATGCCCGGACTTCTCCACGTGCTGTGTTATGGTCGATGGCTCCTGGGGG TGCTGCCCCATGCCCCAGGCTTCCTGCTGTGAAGACAGGGTGCACTGCTGTCCGCACGGTGC CTTCTGCGACCTGGTTCACACCCGCTGCATCACACCCACGGGCACCCACCCCCTGGCAAAGA AGCTCCCTGCCCAGAGGACTAACAGGGCAGTGGCCTTGTCCAGCTCGGTCATGTGTCCGGAC GCACGGTCCCGGTGCCCTGATGGTTCTACCTGCTGTGAGCTGCCCAGTGGGAAGTATGGCTG CTGCCCAATGCCCAACGCCACCTGCTGCTCCGATCACCTGCACTGCTGCCCCCAAGACACTG TGTGTGACCTGATCCAGAGTAAGTGCCTCTCCAAGGAGAACGCTACCACGGACCTCCTCACT AAGCTGCCTGCGCACACAGTGGGGGATGTGAAATGTGACATGGAGGTGAGCTGCCCAGATGG CTATACCTGCTGCCGTCTACAGTCGGGGGCCTGGGGCTGCTGCCCTTTTACCCAGGCTGTGT GCTGTGAGGACCACATACACTGCTGTCCCGCGGGGTTTACGTGTGACACGCAGAAGGGTACC TGTGAACAGGGGCCCCACCAGGTGCCCTGGATGGAGAAGGCCCCAGCTCACCTCAGCCTGCC AGACCCACAAGCCTTGAAGAGAGATGTCCCCTGTGATAATGTCAGCAGCTGTCCCTCCTCCG ATACCTGCTGCCAACTCACGTCTGGGGAGTGGGGCTGCTGTCCAATCCCAGAGGCTGTCTGC TGCTCGGACCACCAGCACTGCTGCCCCCAGGGCTACACGTGTGTAGCTGAGGGGCAGTGTCA GCGAGGAAGCGAGATCGTGGCTGGACTGGAGAAGATGCCTGCCCGCCGGGCTTCCTTATCCC ACCCCAGAGACATCGGCTGTGACCAGCACACCAGCTGCCCGGTGGGGCAGACCTGCTGCCCG AGCCTGGGTGGGAGCTGGGCCTGCTGCCAGTTGCCCCATGCTGTGTGCTGCGAGGATCGCCA GCACTGCTGCCCGGCTGGCTACACCTGCAACGTGAAGGCTCGATCCTGCGAGAAGGAAGTGG TCTCTGCCCAGCCTGCCACCTTCCTGGCCCGTAGCCCTCACGTGGGTGTGAAGGACGTGGAG TGTGGGGAAGGACACTTCTGCCATGATAACCAGACCTGCTGCCGAGACAACCGACAGGGCTG GGCCTGCTGTCCCTACCGCCAGGGCGTCTGTTGTGCTGATCGGCGCCACTGCTGTCCTGCTG GCTTCCGCTGCGCAGCCAGGGGTACCAAGTGTTTGCGCAGGGAGGCCCCGCGCTGGGACGCC CCTTTGAGGGACCCAGCCTTGAGACAGCTGCTGTGATCTAGAATTCGATATCAAGCTTATCG ATAATCAACCTCTGGATTACAAAATTTGTGAAAGATTGACTGGTATTCTTAACTATGTTGCT CCTTTTACGCTATGTGGATACGCTGCTTTAATGCCTTTGTATCATGCTATTGCTTCCCGTAT GGCTTTCATTTTCTCCTCCTTGTATAAATCCTGGTTGCTGTCTCTTTATGAGGAGTTGTGGC CCGTTGTCAGGCAACGTGGCGTGGTGTGCACTGTGTTTGCTGACGCAACCCCCACTGGTTGG GGCATTGCCACCACCTGTCAGCTCCTTTCCGGGACTTTCGCTTTCCCCCTCCCTATTGCCAC GGCGGAACTCATCGCCGCCTGCCTTGCCCGCTGCTGGACAGGGGCTCGGCTGTTGGGCACTG ACAATTCCGTGGTGTTGTCGGGGAAATCATCGTCCTTTCCTTGGCTGCTCGCCTGTGTTGCC ACCTGGATTCTGCGCGGGACGTCCTTCTGCTACGTCCCTTCGGCCCTCAATCCAGCGGACCT TCCTTCCCGCGGCCTGCTGCCGGCTCTGCGGCCTCTTCCGCGTCTTCGCCTTCGCCCTCAGA CGAGTCGGATCTCCCTTTGGGCCGCCTCCCCGCA 06164 CTAGTACTAGGTCCTCAGCAGGCCAGGTGTCTTATCCGCTGTCTGGGTCTGCTCTAGCTCCA construct GGCTTAGAACCCCTGCCACACGACTCCACAGCTCGGTTGGCACCCTTTCCCTCCTCCGACTT CTGCTGCCTCGAGCTTGGTTAGCCATCCCCCTGCCCCTGCCTCATCCTCAGCTCCAGTTCCT TGCTCAGGCTGCAGCAGTCTCCATCCCCTGTGCAGACACTGCCGTTCCTCCACGGCCCAGTA TCAGGCTTTCCCTGGGCCTCTCCTCTCTCCTGGCCCATCTCCCATCATCCATCTCTGCCTGG CCCAGGCCCTTTGGCACCAAGCAGGCTGACTCTTGTCACTGGCTAATCTGTTCTGTGGTACA TTTTCTCTCCTCACCCTCCCATATCAATTCCTCGAAGGCAGGGCCGATCTGGAGACTAGGAA GCCACTTCTCTTTCGACAGCCCCCACCACAGCCCAGCCCGTGCCAGGCACCCAGCAGCTCCT GAAGCCCACTGGCATTGAACATGGCATTCAATCCCTGCCAAGCCTGCCCTTCCCATCTGGTT TCCCAGGGCTCTTCCCAACACCTCCTCCTCCACCTGCCAGTTAAAATCTTCCCAGACTCAGC TCAAGGAGATGCTCCTAAGGTGGAATGAAATCTCTTCTTCCCCACCTGGAGACAATCTACTT CCTCTCCCTACACCTGGCAACTGGCGCACAACCTTGTATCTTAAATTAGATTCAGCCTGAGA CTGTCTCCCACCAATCCCTGCTCCCTGTCCTGCTGAGCACCTTGAGGAAAGGGCTTTGGGGC TGTTTATCTTTGTCCTGGAAACCATCCTTCAACTCACTCTGGGGCCTGCCTAGCATGTCAAC CGAGTTTGGAGAATAGGGCAGAATAGGGCAGGACAGGACAGGACAAGACAGGGCAGGATAGG ATAGGAGCGAGCCAGCTCAGTAGCTCACATTTGTAATCCCAGCGCCTTGGGGGGCTGCGGTA GGAGAATCGCTTTGGGAGCAGGAGTTGCAGGCCGCAGTGAGCTATGATCAGCTTGGGCGACT GAGCGAGACCCTGTCTCTAAAACAAACACACAAGTCCGGGCGCGGTGGCTCATGCCTGTAAT CTTAGCACTTTGGGAGGCCGAGGTGGGCGGATCACGAGGTCAAGAAATCGAGACCATCCTGG CCAACATGGTGAAACCCCGTCTCTACTAAAAATACAAAAATTAGCTGGGCGTGGTGGTGCGC GCCTGTAGTCCCAGCTACTCGGGAGGCTGAGGCAGGAGAATCGCTTGAACCCGGGAGGCAGA GGTTGCAGTGAGCCGAGATCGTGCCACTGCACTCCAGCCTGGCGACAGAGTGAGACTCCGTC TCAGAACAAACAAACAAAAGGATAGAAAGGCGAGCACAAATATTCCCAATTCATAACACTCC CTCGCACTGTCAATGCCCCAGACACGCGCTATCATCTCTAGCAAACTCCCCCAGGCGCCTGC AGGATGGGTTAAGGAAGGCGACGAGCACCAGCTGCCCTGCTGAGGCTGTCCCGACGTCACAT GATTCTCCAATCACATGATCCCTAGAAATGGGGTGTGGGGCGAGAGGAAGCAGGGAGGAGAG TGATTTGAGTAGAAAAGAAACACAGCATTCCAGGCTGGCCCCACCTCTATATTGATAAGTAG CCAATGGGAGCGGGTAGCCCTGATCCCTGGCCAATGGAAACTGAGGTAGGCGGGTCATCGCG CTGGGGTCTGTAGTCTGAGCGCTACCCGGTTGCTGCTGCCCAAGGACCGCGGAGTCGGACGC AGGCAGACCATGTGGACCCTGGTGAGCTGGGTGGCCTTAACAGCAGGGCTGGTGGCTGGAAC GCGGTGCCCAGATGGTCAGTTCTGCCCTGTGGCCTGCTGCCTGGACCCCGGAGGAGCCAGCT ACAGCTGCTGCCGTCCCCTTCTGGACAAATGGCCCACAACACTGAGCAGGCATCTGGGTGGC CCCTGCCAGGTTGATGCCCACTGCTCTGCCGGCCACTCCTGCATCTTTACCGTCTCAGGGAC TTCCAGTTGCTGCCCCTTCCCAGAGGCCGTGGCATGCGGGGATGGCCATCACTGCTGCCCAC GGGGCTTCCACTGCAGTGCAGACGGGCGATCCTGCTTCCAAAGATCAGGTAACAACTCCGTG GGTGCCATCCAGTGCCCTGATAGTCAGTTCGAATGCCCGGACTTCTCCACGTGCTGTGTTAT GGTCGATGGCTCCTGGGGGTGCTGCCCCATGCCCCAGGCTTCCTGCTGTGAAGACAGGGTGC ACTGCTGTCCGCACGGTGCCTTCTGCGACCTGGTTCACACCCGCTGCATCACACCCACGGGC ACCCACCCCCTGGCAAAGAAGCTCCCTGCCCAGAGGACTAACAGGGCAGTGGCCTTGTCCAG CTCGGTCATGTGTCCGGACGCACGGTCCCGGTGCCCTGATGGTTCTACCTGCTGTGAGCTGC CCAGTGGGAAGTATGGCTGCTGCCCAATGCCCAACGCCACCTGCTGCTCCGATCACCTGCAC TGCTGCCCCCAAGACACTGTGTGTGACCTGATCCAGAGTAAGTGCCTCTCCAAGGAGAACGC TACCACGGACCTCCTCACTAAGCTGCCTGCGCACACAGTGGGGGATGTGAAATGTGACATGG AGGTGAGCTGCCCAGATGGCTATACCTGCTGCCGTCTACAGTCGGGGGCCTGGGGCTGCTGC CCTTTTACCCAGGCTGTGTGCTGTGAGGACCACATACACTGCTGTCCCGCGGGGTTTACGTG TGACACGCAGAAGGGTACCTGTGAACAGGGGCCCCACCAGGTGCCCTGGATGGAGAAGGCCC CAGCTCACCTCAGCCTGCCAGACCCACAAGCCTTGAAGAGAGATGTCCCCTGTGATAATGTC AGCAGCTGTCCCTCCTCCGATACCTGCTGCCAACTCACGTCTGGGGAGTGGGGCTGCTGTCC AATCCCAGAGGCTGTCTGCTGCTCGGACCACCAGCACTGCTGCCCCCAGGGCTACACGTGTG TAGCTGAGGGGCAGTGTCAGCGAGGAAGCGAGATCGTGGCTGGACTGGAGAAGATGCCTGCC CGCCGGGCTTCCTTATCCCACCCCAGAGACATCGGCTGTGACCAGCACACCAGCTGCCCGGT GGGGCAGACCTGCTGCCCGAGCCTGGGTGGGAGCTGGGCCTGCTGCCAGTTGCCCCATGCTG TGTGCTGCGAGGATCGCCAGCACTGCTGCCCGGCTGGCTACACCTGCAACGTGAAGGCTCGA TCCTGCGAGAAGGAAGTGGTCTCTGCCCAGCCTGCCACCTTCCTGGCCCGTAGCCCTCACGT GGGTGTGAAGGACGTGGAGTGTGGGGAAGGACACTTCTGCCATGATAACCAGACCTGCTGCC GAGACAACCGACAGGGCTGGGCCTGCTGTCCCTACCGCCAGGGCGTCTGTTGTGCTGATCGG CGCCACTGCTGTCCTGCTGGCTTCCGCTGCGCAGCCAGGGGTACCAAGTGTTTGCGCAGGGA GGCCCCGCGCTGGGACGCCCCTTTGAGGGACCCAGCCTTGAGACAGCTGCTGTGA 06262 CCATCCTGGCCAACATGGTGAAACCCCGTCTCTACTAAAAATACAAAAATTAGCTGGGCGTG construct GTGGTGCGCGCCTGTAGTCCCAGCTACTCGGGAGGCTGAGGCAGGAGAATCGCTTGAACCCG GGAGGCAGAGGTTGCAGTGAGCCGAGATCGTGCCACTGCACTCCAGCCTGGCGACAGAGTGA GACTCCGTCTCAGAACAAACAAACAAAAGGATAGAAAGGCGAGCACAAATATTCCCAATTCA TAACACTCCCTCGCACTGTCAATGCCCCAGACACGCGCTATCATCTCTAGCAAACTCCCCCA GGCGCCTGCAGGATGGGTTAAGGAAGGCGACGAGCACCAGCTGCCCTGCTGAGGCTGTCCCG ACGTCACATGATTCTCCAATCACATGATCCCTAGAAATGGGGTGTGGGGCGAGAGGAAGCAG GGAGGAGAGTGATTTGAGTAGAAAAGAAACACAGCATTCCAGGCTGGCCCCACCTCTATATT GATAAGTAGCCAATGGGAGCGGGTAGCCCTGATCCCTGGCCAATGGAAACTGAGGTAGGCGG GTCATCGCGCTGGGGTCTGTAGTCTGAGCGCTACCCGGTTGCTGCTGCCCAAGGACCGCGGA GTCGGACGCAGGCAGACCATGTGGACCCTGGTGAGCTGGGTGGCCTTAACAGCAGGGCTGGT GGCTGGAACGCGGTGCCCAGATGGTCAGTTCTGCCCTGTGGCCTGCTGCCTGGACCCCGGAG GAGCCAGCTACAGCTGCTGCCGTCCCCTTCTGGACAAATGGCCCACAACACTGAGCAGGCAT CTGGGTGGCCCCTGCCAGGTTGATGCCCACTGCTCTGCCGGCCACTCCTGCATCTTTACCGT CTCAGGGACTTCCAGTTGCTGCCCCTTCCCAGAGGCCGTGGCATGCGGGGATGGCCATCACT GCTGCCCACGGGGCTTCCACTGCAGTGCAGACGGGCGATCCTGCTTCCAAAGATCAGGTAAC AACTCCGTGGGTGCCATCCAGTGCCCTGATAGTCAGTTCGAATGCCCGGACTTCTCCACGTG CTGTGTTATGGTCGATGGCTCCTGGGGGTGCTGCCCCATGCCCCAGGCTTCCTGCTGTGAAG ACAGGGTGCACTGCTGTCCGCACGGTGCCTTCTGCGACCTGGTTCACACCCGCTGCATCACA CCCACGGGCACCCACCCCCTGGCAAAGAAGCTCCCTGCCCAGAGGACTAACAGGGCAGTGGC CTTGTCCAGCTCGGTCATGTGTCCGGACGCACGGTCCCGGTGCCCTGATGGTTCTACCTGCT GTGAGCTGCCCAGTGGGAAGTATGGCTGCTGCCCAATGCCCAACGCCACCTGCTGCTCCGAT CACCTGCACTGCTGCCCCCAAGACACTGTGTGTGACCTGATCCAGAGTAAGTGCCTCTCCAA GGAGAACGCTACCACGGACCTCCTCACTAAGCTGCCTGCGCACACAGTGGGGGATGTGAAAT GTGACATGGAGGTGAGCTGCCCAGATGGCTATACCTGCTGCCGTCTACAGTCGGGGGCCTGG GGCTGCTGCCCTTTTACCCAGGCTGTGTGCTGTGAGGACCACATACACTGCTGTCCCGCGGG GTTTACGTGTGACACGCAGAAGGGTACCTGTGAACAGGGGCCCCACCAGGTGCCCTGGATGG AGAAGGCCCCAGCTCACCTCAGCCTGCCAGACCCACAAGCCTTGAAGAGAGATGTCCCCTGT GATAATGTCAGCAGCTGTCCCTCCTCCGATACCTGCTGCCAACTCACGTCTGGGGAGTGGGG CTGCTGTCCAATCCCAGAGGCTGTCTGCTGCTCGGACCACCAGCACTGCTGCCCCCAGGGCT ACACGTGTGTAGCTGAGGGGCAGTGTCAGCGAGGAAGCGAGATCGTGGCTGGACTGGAGAAG ATGCCTGCCCGCCGGGCTTCCTTATCCCACCCCAGAGACATCGGCTGTGACCAGCACACCAG CTGCCCGGTGGGGCAGACCTGCTGCCCGAGCCTGGGTGGGAGCTGGGCCTGCTGCCAGTTGC CCCATGCTGTGTGCTGCGAGGATCGCCAGCACTGCTGCCCGGCTGGCTACACCTGCAACGTG AAGGCTCGATCCTGCGAGAAGGAAGTGGTCTCTGCCCAGCCTGCCACCTTCCTGGCCCGTAG CCCTCACGTGGGTGTGAAGGACGTGGAGTGTGGGGAAGGACACTTCTGCCATGATAACCAGA CCTGCTGCCGAGACAACCGACAGGGCTGGGCCTGCTGTCCCTACCGCCAGGGCGTCTGTTGT GCTGATCGGCGCCACTGCTGTCCTGCTGGCTTCCGCTGCGCAGCCAGGGGTACCAAGTGTTT GCGCAGGGAGGCCCCGCGCTGGGACGCCCCTTTGAGGGACCCAGCCTTGAGACAGCTGCTGT GA 06263 AGCCGAGATCGTGCCACTGCACTCCAGCCTGGCGACAGAGTGAGACTCCGTCTCAGAACAAA construct CAAACAAAAGGATAGAAAGGCGAGCACAAATATTCCCAATTCATAACACTCCCTCGCACTGT CAATGCCCCAGACACGCGCTATCATCTCTAGCAAACTCCCCCAGGCGCCTGCAGGATGGGTT AAGGAAGGCGACGAGCACCAGCTGCCCTGCTGAGGCTGTCCCGACGTCACATGATTCTCCAA TCACATGATCCCTAGAAATGGGGTGTGGGGCGAGAGGAAGCAGGGAGGAGAGTGATTTGAGT AGAAAAGAAACACAGCATTCCAGGCTGGCCCCACCTCTATATTGATAAGTAGCCAATGGGAG CGGGTAGCCCTGATCCCTGGCCAATGGAAACTGAGGTAGGCGGGTCATCGCGCTGGGGTCTG TAGTCTGAGCGCTACCCGGTTGCTGCTGCCCAAGGACCGCGGAGTCGGACGCAGGCAGACCA TGTGGACCCTGGTGAGCTGGGTGGCCTTAACAGCAGGGCTGGTGGCTGGAACGCGGTGCCCA GATGGTCAGTTCTGCCCTGTGGCCTGCTGCCTGGACCCCGGAGGAGCCAGCTACAGCTGCTG CCGTCCCCTTCTGGACAAATGGCCCACAACACTGAGCAGGCATCTGGGTGGCCCCTGCCAGG TTGATGCCCACTGCTCTGCCGGCCACTCCTGCATCTTTACCGTCTCAGGGACTTCCAGTTGC TGCCCCTTCCCAGAGGCCGTGGCATGCGGGGATGGCCATCACTGCTGCCCACGGGGCTTCCA CTGCAGTGCAGACGGGCGATCCTGCTTCCAAAGATCAGGTAACAACTCCGTGGGTGCCATCC AGTGCCCTGATAGTCAGTTCGAATGCCCGGACTTCTCCACGTGCTGTGTTATGGTCGATGGC TCCTGGGGGTGCTGCCCCATGCCCCAGGCTTCCTGCTGTGAAGACAGGGTGCACTGCTGTCC GCACGGTGCCTTCTGCGACCTGGTTCACACCCGCTGCATCACACCCACGGGCACCCACCCCC TGGCAAAGAAGCTCCCTGCCCAGAGGACTAACAGGGCAGTGGCCTTGTCCAGCTCGGTCATG TGTCCGGACGCACGGTCCCGGTGCCCTGATGGTTCTACCTGCTGTGAGCTGCCCAGTGGGAA GTATGGCTGCTGCCCAATGCCCAACGCCACCTGCTGCTCCGATCACCTGCACTGCTGCCCCC AAGACACTGTGTGTGACCTGATCCAGAGTAAGTGCCTCTCCAAGGAGAACGCTACCACGGAC CTCCTCACTAAGCTGCCTGCGCACACAGTGGGGGATGTGAAATGTGACATGGAGGTGAGCTG CCCAGATGGCTATACCTGCTGCCGTCTACAGTCGGGGGCCTGGGGCTGCTGCCCTTTTACCC AGGCTGTGTGCTGTGAGGACCACATACACTGCTGTCCCGCGGGGTTTACGTGTGACACGCAG AAGGGTACCTGTGAACAGGGGCCCCACCAGGTGCCCTGGATGGAGAAGGCCCCAGCTCACCT CAGCCTGCCAGACCCACAAGCCTTGAAGAGAGATGTCCCCTGTGATAATGTCAGCAGCTGTC CCTCCTCCGATACCTGCTGCCAACTCACGTCTGGGGAGTGGGGCTGCTGTCCAATCCCAGAG GCTGTCTGCTGCTCGGACCACCAGCACTGCTGCCCCCAGGGCTACACGTGTGTAGCTGAGGG GCAGTGTCAGCGAGGAAGCGAGATCGTGGCTGGACTGGAGAAGATGCCTGCCCGCCGGGCTT CCTTATCCCACCCCAGAGACATCGGCTGTGACCAGCACACCAGCTGCCCGGTGGGGCAGACC TGCTGCCCGAGCCTGGGTGGGAGCTGGGCCTGCTGCCAGTTGCCCCATGCTGTGTGCTGCGA GGATCGCCAGCACTGCTGCCCGGCTGGCTACACCTGCAACGTGAAGGCTCGATCCTGCGAGA AGGAAGTGGTCTCTGCCCAGCCTGCCACCTTCCTGGCCCGTAGCCCTCACGTGGGTGTGAAG GACGTGGAGTGTGGGGAAGGACACTTCTGCCATGATAACCAGACCTGCTGCCGAGACAACCG ACAGGGCTGGGCCTGCTGTCCCTACCGCCAGGGCGTCTGTTGTGCTGATCGGCGCCACTGCT GTCCTGCTGGCTTCCGCTGCGCAGCCAGGGGTACCAAGTGTTTGCGCAGGGAGGCCCCGCGC TGGGACGCCCCTTTGAGGGACCCAGCCTTGAGACAGCTGCTGTGA AAV-06164 CTAGTACTAGGTCCTCAGCAGGCCAGGTGTCTTATCCGCTGTCTGGGTCTGCTCTAGCTCCA construct GGCTTAGAACCCCTGCCACACGACTCCACAGCTCGGTTGGCACCCTTTCCCTCCTCCGACTT CTGCTGCCTCGAGCTTGGTTAGCCATCCCCCTGCCCCTGCCTCATCCTCAGCTCCAGTTCCT TGCTCAGGCTGCAGCAGTCTCCATCCCCTGTGCAGACACTGCCGTTCCTCCACGGCCCAGTA TCAGGCTTTCCCTGGGCCTCTCCTCTCTCCTGGCCCATCTCCCATCATCCATCTCTGCCTGG CCCAGGCCCTTTGGCACCAAGCAGGCTGACTCTTGTCACTGGCTAATCTGTTCTGTGGTACA TTTTCTCTCCTCACCCTCCCATATCAATTCCTCGAAGGCAGGGCCGATCTGGAGACTAGGAA GCCACTTCTCTTTCGACAGCCCCCACCACAGCCCAGCCCGTGCCAGGCACCCAGCAGCTCCT GAAGCCCACTGGCATTGAACATGGCATTCAATCCCTGCCAAGCCTGCCCTTCCCATCTGGTT TCCCAGGGCTCTTCCCAACACCTCCTCCTCCACCTGCCAGTTAAAATCTTCCCAGACTCAGC TCAAGGAGATGCTCCTAAGGTGGAATGAAATCTCTTCTTCCCCACCTGGAGACAATCTACTT CCTCTCCCTACACCTGGCAACTGGCGCACAACCTTGTATCTTAAATTAGATTCAGCCTGAGA CTGTCTCCCACCAATCCCTGCTCCCTGTCCTGCTGAGCACCTTGAGGAAAGGGCTTTGGGGC TGTTTATCTTTGTCCTGGAAACCATCCTTCAACTCACTCTGGGGCCTGCCTAGCATGTCAAC CGAGTTTGGAGAATAGGGCAGAATAGGGCAGGACAGGACAGGACAAGACAGGGCAGGATAGG ATAGGAGCGAGCCAGCTCAGTAGCTCACATTTGTAATCCCAGCGCCTTGGGGGGCTGCGGTA GGAGAATCGCTTTGGGAGCAGGAGTTGCAGGCCGCAGTGAGCTATGATCAGCTTGGGCGACT GAGCGAGACCCTGTCTCTAAAACAAACACACAAGTCCGGGCGCGGTGGCTCATGCCTGTAAT CTTAGCACTTTGGGAGGCCGAGGTGGGCGGATCACGAGGTCAAGAAATCGAGACCATCCTGG CCAACATGGTGAAACCCCGTCTCTACTAAAAATACAAAAATTAGCTGGGCGTGGTGGTGCGC GCCTGTAGTCCCAGCTACTCGGGAGGCTGAGGCAGGAGAATCGCTTGAACCCGGGAGGCAGA GGTTGCAGTGAGCCGAGATCGTGCCACTGCACTCCAGCCTGGCGACAGAGTGAGACTCCGTC TCAGAACAAACAAACAAAAGGATAGAAAGGCGAGCACAAATATTCCCAATTCATAACACTCC CTCGCACTGTCAATGCCCCAGACACGCGCTATCATCTCTAGCAAACTCCCCCAGGCGCCTGC AGGATGGGTTAAGGAAGGCGACGAGCACCAGCTGCCCTGCTGAGGCTGTCCCGACGTCACAT GATTCTCCAATCACATGATCCCTAGAAATGGGGTGTGGGGCGAGAGGAAGCAGGGAGGAGAG TGATTTGAGTAGAAAAGAAACACAGCATTCCAGGCTGGCCCCACCTCTATATTGATAAGTAG CCAATGGGAGCGGGTAGCCCTGATCCCTGGCCAATGGAAACTGAGGTAGGCGGGTCATCGCG CTGGGGTCTGTAGTCTGAGCGCTACCCGGTTGCTGCTGCCCAAGGACCGCGGAGTCGGACGC AGGCAGACCATGTGGACCCTGGTGAGCTGGGTGGCCTTAACAGCAGGGCTGGTGGCTGGAAC GCGGTGCCCAGATGGTCAGTTCTGCCCTGTGGCCTGCTGCCTGGACCCCGGAGGAGCCAGCT ACAGCTGCTGCCGTCCCCTTCTGGACAAATGGCCCACAACACTGAGCAGGCATCTGGGTGGC CCCTGCCAGGTTGATGCCCACTGCTCTGCCGGCCACTCCTGCATCTTTACCGTCTCAGGGAC TTCCAGTTGCTGCCCCTTCCCAGAGGCCGTGGCATGCGGGGATGGCCATCACTGCTGCCCAC GGGGCTTCCACTGCAGTGCAGACGGGCGATCCTGCTTCCAAAGATCAGGTAACAACTCCGTG GGTGCCATCCAGTGCCCTGATAGTCAGTTCGAATGCCCGGACTTCTCCACGTGCTGTGTTAT GGTCGATGGCTCCTGGGGGTGCTGCCCCATGCCCCAGGCTTCCTGCTGTGAAGACAGGGTGC ACTGCTGTCCGCACGGTGCCTTCTGCGACCTGGTTCACACCCGCTGCATCACACCCACGGGC ACCCACCCCCTGGCAAAGAAGCTCCCTGCCCAGAGGACTAACAGGGCAGTGGCCTTGTCCAG CTCGGTCATGTGTCCGGACGCACGGTCCCGGTGCCCTGATGGTTCTACCTGCTGTGAGCTGC CCAGTGGGAAGTATGGCTGCTGCCCAATGCCCAACGCCACCTGCTGCTCCGATCACCTGCAC TGCTGCCCCCAAGACACTGTGTGTGACCTGATCCAGAGTAAGTGCCTCTCCAAGGAGAACGC TACCACGGACCTCCTCACTAAGCTGCCTGCGCACACAGTGGGGGATGTGAAATGTGACATGG AGGTGAGCTGCCCAGATGGCTATACCTGCTGCCGTCTACAGTCGGGGGCCTGGGGCTGCTGC CCTTTTACCCAGGCTGTGTGCTGTGAGGACCACATACACTGCTGTCCCGCGGGGTTTACGTG TGACACGCAGAAGGGTACCTGTGAACAGGGGCCCCACCAGGTGCCCTGGATGGAGAAGGCCC CAGCTCACCTCAGCCTGCCAGACCCACAAGCCTTGAAGAGAGATGTCCCCTGTGATAATGTC AGCAGCTGTCCCTCCTCCGATACCTGCTGCCAACTCACGTCTGGGGAGTGGGGCTGCTGTCC AATCCCAGAGGCTGTCTGCTGCTCGGACCACCAGCACTGCTGCCCCCAGGGCTACACGTGTG TAGCTGAGGGGCAGTGTCAGCGAGGAAGCGAGATCGTGGCTGGACTGGAGAAGATGCCTGCC CGCCGGGCTTCCTTATCCCACCCCAGAGACATCGGCTGTGACCAGCACACCAGCTGCCCGGT GGGGCAGACCTGCTGCCCGAGCCTGGGTGGGAGCTGGGCCTGCTGCCAGTTGCCCCATGCTG TGTGCTGCGAGGATCGCCAGCACTGCTGCCCGGCTGGCTACACCTGCAACGTGAAGGCTCGA TCCTGCGAGAAGGAAGTGGTCTCTGCCCAGCCTGCCACCTTCCTGGCCCGTAGCCCTCACGT GGGTGTGAAGGACGTGGAGTGTGGGGAAGGACACTTCTGCCATGATAACCAGACCTGCTGCC GAGACAACCGACAGGGCTGGGCCTGCTGTCCCTACCGCCAGGGCGTCTGTTGTGCTGATCGG CGCCACTGCTGTCCTGCTGGCTTCCGCTGCGCAGCCAGGGGTACCAAGTGTTTGCGCAGGGA GGCCCCGCGCTGGGACGCCCCTTTGAGGGACCCAGCCTTGAGACAGCTGCTGTGAGAATTCT CTAGAGAATTCGATCCAGACATGATAAGATACATTGATGAGTTTGGACAAACCACAACTAGA ATGCAGTGAAAAAAATGCTTTATTTGTGAAATTTGTGATGCTATTGCTTTATTTGTAACCAT TATAAGCTGCAATAAACAAGTTAACAACAACAATTGCATTCATTTTATGTTTCAGGTTCAGG GGGAGGTGTGGGAGGTTTTTTAG AAV-06262 CCATCCTGGCCAACATGGTGAAACCCCGTCTCTACTAAAAATACAAAAATTAGCTGGGCGTG construct GTGGTGCGCGCCTGTAGTCCCAGCTACTCGGGAGGCTGAGGCAGGAGAATCGCTTGAACCCG GGAGGCAGAGGTTGCAGTGAGCCGAGATCGTGCCACTGCACTCCAGCCTGGCGACAGAGTGA GACTCCGTCTCAGAACAAACAAACAAAAGGATAGAAAGGCGAGCACAAATATTCCCAATTCA TAACACTCCCTCGCACTGTCAATGCCCCAGACACGCGCTATCATCTCTAGCAAACTCCCCCA GGCGCCTGCAGGATGGGTTAAGGAAGGCGACGAGCACCAGCTGCCCTGCTGAGGCTGTCCCG ACGTCACATGATTCTCCAATCACATGATCCCTAGAAATGGGGTGTGGGGCGAGAGGAAGCAG GGAGGAGAGTGATTTGAGTAGAAAAGAAACACAGCATTCCAGGCTGGCCCCACCTCTATATT GATAAGTAGCCAATGGGAGCGGGTAGCCCTGATCCCTGGCCAATGGAAACTGAGGTAGGCGG GTCATCGCGCTGGGGTCTGTAGTCTGAGCGCTACCCGGTTGCTGCTGCCCAAGGACCGCGGA GTCGGACGCAGGCAGACCATGTGGACCCTGGTGAGCTGGGTGGCCTTAACAGCAGGGCTGGT GGCTGGAACGCGGTGCCCAGATGGTCAGTTCTGCCCTGTGGCCTGCTGCCTGGACCCCGGAG GAGCCAGCTACAGCTGCTGCCGTCCCCTTCTGGACAAATGGCCCACAACACTGAGCAGGCAT CTGGGTGGCCCCTGCCAGGTTGATGCCCACTGCTCTGCCGGCCACTCCTGCATCTTTACCGT CTCAGGGACTTCCAGTTGCTGCCCCTTCCCAGAGGCCGTGGCATGCGGGGATGGCCATCACT GCTGCCCACGGGGCTTCCACTGCAGTGCAGACGGGCGATCCTGCTTCCAAAGATCAGGTAAC AACTCCGTGGGTGCCATCCAGTGCCCTGATAGTCAGTTCGAATGCCCGGACTTCTCCACGTG CTGTGTTATGGTCGATGGCTCCTGGGGGTGCTGCCCCATGCCCCAGGCTTCCTGCTGTGAAG ACAGGGTGCACTGCTGTCCGCACGGTGCCTTCTGCGACCTGGTTCACACCCGCTGCATCACA CCCACGGGCACCCACCCCCTGGCAAAGAAGCTCCCTGCCCAGAGGACTAACAGGGCAGTGGC CTTGTCCAGCTCGGTCATGTGTCCGGACGCACGGTCCCGGTGCCCTGATGGTTCTACCTGCT GTGAGCTGCCCAGTGGGAAGTATGGCTGCTGCCCAATGCCCAACGCCACCTGCTGCTCCGAT CACCTGCACTGCTGCCCCCAAGACACTGTGTGTGACCTGATCCAGAGTAAGTGCCTCTCCAA GGAGAACGCTACCACGGACCTCCTCACTAAGCTGCCTGCGCACACAGTGGGGGATGTGAAAT GTGACATGGAGGTGAGCTGCCCAGATGGCTATACCTGCTGCCGTCTACAGTCGGGGGCCTGG GGCTGCTGCCCTTTTACCCAGGCTGTGTGCTGTGAGGACCACATACACTGCTGTCCCGCGGG GTTTACGTGTGACACGCAGAAGGGTACCTGTGAACAGGGGCCCCACCAGGTGCCCTGGATGG AGAAGGCCCCAGCTCACCTCAGCCTGCCAGACCCACAAGCCTTGAAGAGAGATGTCCCCTGT GATAATGTCAGCAGCTGTCCCTCCTCCGATACCTGCTGCCAACTCACGTCTGGGGAGTGGGG CTGCTGTCCAATCCCAGAGGCTGTCTGCTGCTCGGACCACCAGCACTGCTGCCCCCAGGGCT ACACGTGTGTAGCTGAGGGGCAGTGTCAGCGAGGAAGCGAGATCGTGGCTGGACTGGAGAAG ATGCCTGCCCGCCGGGCTTCCTTATCCCACCCCAGAGACATCGGCTGTGACCAGCACACCAG CTGCCCGGTGGGGCAGACCTGCTGCCCGAGCCTGGGTGGGAGCTGGGCCTGCTGCCAGTTGC CCCATGCTGTGTGCTGCGAGGATCGCCAGCACTGCTGCCCGGCTGGCTACACCTGCAACGTG AAGGCTCGATCCTGCGAGAAGGAAGTGGTCTCTGCCCAGCCTGCCACCTTCCTGGCCCGTAG CCCTCACGTGGGTGTGAAGGACGTGGAGTGTGGGGAAGGACACTTCTGCCATGATAACCAGA CCTGCTGCCGAGACAACCGACAGGGCTGGGCCTGCTGTCCCTACCGCCAGGGCGTCTGTTGT GCTGATCGGCGCCACTGCTGTCCTGCTGGCTTCCGCTGCGCAGCCAGGGGTACCAAGTGTTT GCGCAGGGAGGCCCCGCGCTGGGACGCCCCTTTGAGGGACCCAGCCTTGAGACAGCTGCTGT GATCTAGAGAATTCGATCCAGACATGATAAGATACATTGATGAGTTTGGACAAACCACAACT AGAATGCAGTGAAAAAAATGCTTTATTTGTGAAATTTGTGATGCTATTGCTTTATTTGTAAC CATTATAAGCTGCAATAAACAAGTTAACAACAACAATTGCATTCATTTTATGTTTCAGGTTC AGGGGGAGGTGTGGGAGGTTTTTTAG AAV-06263 AGCCGAGATCGTGCCACTGCACTCCAGCCTGGCGACAGAGTGAGACTCCGTCTCAGAACAAA construct CAAACAAAAGGATAGAAAGGCGAGCACAAATATTCCCAATTCATAACACTCCCTCGCACTGT CAATGCCCCAGACACGCGCTATCATCTCTAGCAAACTCCCCCAGGCGCCTGCAGGATGGGTT AAGGAAGGCGACGAGCACCAGCTGCCCTGCTGAGGCTGTCCCGACGTCACATGATTCTCCAA TCACATGATCCCTAGAAATGGGGTGTGGGGCGAGAGGAAGCAGGGAGGAGAGTGATTTGAGT AGAAAAGAAACACAGCATTCCAGGCTGGCCCCACCTCTATATTGATAAGTAGCCAATGGGAG CGGGTAGCCCTGATCCCTGGCCAATGGAAACTGAGGTAGGCGGGTCATCGCGCTGGGGTCTG TAGTCTGAGCGCTACCCGGTTGCTGCTGCCCAAGGACCGCGGAGTCGGACGCAGGCAGACCA TGTGGACCCTGGTGAGCTGGGTGGCCTTAACAGCAGGGCTGGTGGCTGGAACGCGGTGCCCA GATGGTCAGTTCTGCCCTGTGGCCTGCTGCCTGGACCCCGGAGGAGCCAGCTACAGCTGCTG CCGTCCCCTTCTGGACAAATGGCCCACAACACTGAGCAGGCATCTGGGTGGCCCCTGCCAGG TTGATGCCCACTGCTCTGCCGGCCACTCCTGCATCTTTACCGTCTCAGGGACTTCCAGTTGC TGCCCCTTCCCAGAGGCCGTGGCATGCGGGGATGGCCATCACTGCTGCCCACGGGGCTTCCA CTGCAGTGCAGACGGGCGATCCTGCTTCCAAAGATCAGGTAACAACTCCGTGGGTGCCATCC AGTGCCCTGATAGTCAGTTCGAATGCCCGGACTTCTCCACGTGCTGTGTTATGGTCGATGGC TCCTGGGGGTGCTGCCCCATGCCCCAGGCTTCCTGCTGTGAAGACAGGGTGCACTGCTGTCC GCACGGTGCCTTCTGCGACCTGGTTCACACCCGCTGCATCACACCCACGGGCACCCACCCCC TGGCAAAGAAGCTCCCTGCCCAGAGGACTAACAGGGCAGTGGCCTTGTCCAGCTCGGTCATG TGTCCGGACGCACGGTCCCGGTGCCCTGATGGTTCTACCTGCTGTGAGCTGCCCAGTGGGAA GTATGGCTGCTGCCCAATGCCCAACGCCACCTGCTGCTCCGATCACCTGCACTGCTGCCCCC AAGACACTGTGTGTGACCTGATCCAGAGTAAGTGCCTCTCCAAGGAGAACGCTACCACGGAC CTCCTCACTAAGCTGCCTGCGCACACAGTGGGGGATGTGAAATGTGACATGGAGGTGAGCTG CCCAGATGGCTATACCTGCTGCCGTCTACAGTCGGGGGCCTGGGGCTGCTGCCCTTTTACCC AGGCTGTGTGCTGTGAGGACCACATACACTGCTGTCCCGCGGGGTTTACGTGTGACACGCAG AAGGGTACCTGTGAACAGGGGCCCCACCAGGTGCCCTGGATGGAGAAGGCCCCAGCTCACCT CAGCCTGCCAGACCCACAAGCCTTGAAGAGAGATGTCCCCTGTGATAATGTCAGCAGCTGTC CCTCCTCCGATACCTGCTGCCAACTCACGTCTGGGGAGTGGGGCTGCTGTCCAATCCCAGAG GCTGTCTGCTGCTCGGACCACCAGCACTGCTGCCCCCAGGGCTACACGTGTGTAGCTGAGGG GCAGTGTCAGCGAGGAAGCGAGATCGTGGCTGGACTGGAGAAGATGCCTGCCCGCCGGGCTT CCTTATCCCACCCCAGAGACATCGGCTGTGACCAGCACACCAGCTGCCCGGTGGGGCAGACC TGCTGCCCGAGCCTGGGTGGGAGCTGGGCCTGCTGCCAGTTGCCCCATGCTGTGTGCTGCGA GGATCGCCAGCACTGCTGCCCGGCTGGCTACACCTGCAACGTGAAGGCTCGATCCTGCGAGA AGGAAGTGGTCTCTGCCCAGCCTGCCACCTTCCTGGCCCGTAGCCCTCACGTGGGTGTGAAG GACGTGGAGTGTGGGGAAGGACACTTCTGCCATGATAACCAGACCTGCTGCCGAGACAACCG ACAGGGCTGGGCCTGCTGTCCCTACCGCCAGGGCGTCTGTTGTGCTGATCGGCGCCACTGCT GTCCTGCTGGCTTCCGCTGCGCAGCCAGGGGTACCAAGTGTTTGCGCAGGGAGGCCCCGCGC TGGGACGCCCCTTTGAGGGACCCAGCCTTGAGACAGCTGCTGTGATCTAGAGAATTCGATCC AGACATGATAAGATACATTGATGAGTTTGGACAAACCACAACTAGAATGCAGTGAAAAAAAT GCTTTATTTGTGAAATTTGTGATGCTATTGCTTTATTTGTAACCATTATAAGCTGCAATAAA CAAGTTAACAACAACAATTGCATTCATTTTATGTTTCAGGTTCAGGGGGAGGTGTGGGAGGT TTTTTAG Human ATGTGGACCCTGGTGAGCTGGGTGGCCTTAACAGCAGGGCTGGTGGCTGGAACGCGGTGCCC PGRN AGATGGTCAGTTCTGCCCTGTGGCCTGCTGCCTGGACCCCGGAGGAGCCAGCTACAGCTGCT GCCGTCCCCTTCTGGACAAATGGCCCACAACACTGAGCAGGCATCTGGGTGGCCCCTGCCAG coding GTTGATGCCCACTGCTCTGCCGGCCACTCCTGCATCTTTACCGTCTCAGGGACTTCCAGTTG sequence CTGCCCCTTCCCAGAGGCCGTGGCATGCGGGGATGGCCATCACTGCTGCCCACGGGGCTTCC ACTGCAGTGCAGACGGGCGATCCTGCTTCCAAAGATCAGGTAACAACTCCGTGGGTGCCATC CAGTGCCCTGATAGTCAGTTCGAATGCCCGGACTTCTCCACGTGCTGTGTTATGGTCGATGG CTCCTGGGGGTGCTGCCCCATGCCCCAGGCTTCCTGCTGTGAAGACAGGGTGCACTGCTGTC CGCACGGTGCCTTCTGCGACCTGGTTCACACCCGCTGCATCACACCCACGGGCACCCACCCC CTGGCAAAGAAGCTCCCTGCCCAGAGGACTAACAGGGCAGTGGCCTTGTCCAGCTCGGTCAT GTGTCCGGACGCACGGTCCCGGTGCCCTGATGGTTCTACCTGCTGTGAGCTGCCCAGTGGGA AGTATGGCTGCTGCCCAATGCCCAACGCCACCTGCTGCTCCGATCACCTGCACTGCTGCCCC CAAGACACTGTGTGTGACCTGATCCAGAGTAAGTGCCTCTCCAAGGAGAACGCTACCACGGA CCTCCTCACTAAGCTGCCTGCGCACACAGTGGGGGATGTGAAATGTGACATGGAGGTGAGCT GCCCAGATGGCTATACCTGCTGCCGTCTACAGTCGGGGGCCTGGGGCTGCTGCCCTTTTACC CAGGCTGTGTGCTGTGAGGACCACATACACTGCTGTCCCGCGGGGTTTACGTGTGACACGCA GAAGGGTACCTGTGAACAGGGGCCCCACCAGGTGCCCTGGATGGAGAAGGCCCCAGCTCACC TCAGCCTGCCAGACCCACAAGCCTTGAAGAGAGATGTCCCCTGTGATAATGTCAGCAGCTGT CCCTCCTCCGATACCTGCTGCCAACTCACGTCTGGGGAGTGGGGCTGCTGTCCAATCCCAGA GGCTGTCTGCTGCTCGGACCACCAGCACTGCTGCCCCCAGGGCTACACGTGTGTAGCTGAGG GGCAGTGTCAGCGAGGAAGCGAGATCGTGGCTGGACTGGAGAAGATGCCTGCCCGCCGGGCT TCCTTATCCCACCCCAGAGACATCGGCTGTGACCAGCACACCAGCTGCCCGGTGGGGCAGAC CTGCTGCCCGAGCCTGGGTGGGAGCTGGGCCTGCTGCCAGTTGCCCCATGCTGTGTGCTGCG AGGATCGCCAGCACTGCTGCCCGGCTGGCTACACCTGCAACGTGAAGGCTCGATCCTGCGAG AAGGAAGTGGTCTCTGCCCAGCCTGCCACCTTCCTGGCCCGTAGCCCTCACGTGGGTGTGAA GGACGTGGAGTGTGGGGAAGGACACTTCTGCCATGATAACCAGACCTGCTGCCGAGACAACC GACAGGGCTGGGCCTGCTGTCCCTACCGCCAGGGCGTCTGTTGTGCTGATCGGCGCCACTGC TGTCCTGCTGGCTTCCGCTGCGCAGCCAGGGGTACCAAGTGTTTGCGCAGGGAGGCCCCGCG CTGGGACGCCCCTTTGAGGGACCCAGCCTTGAGACAGCTGCTGTGA Human MWTLVSWVALTAGLVAGTRCPDGQFCPVACCLDPGGASYSCCRPLLDKWPTTLSRHLGGPCQ PGRN VDAHCSAGHSCIFTVSGTSSCCPFPEAVACGDGHHCCPRGFHCSADGRSCFQRSGNNSVGAI QCPDSQFECPDFSTCCVMVDGSWGCCPMPQASCCEDRVHCCPHGAFCDLVHTRCITPTGTHP amino acid LAKKLPAQRTNRAVALSSSVMCPDARSRCPDGSTCCELPSGKYGCCPMPNATCCSDHLHCCP sequence QDTVCDLIQSKCLSKENATTDLLTKLPAHTVGDVKCDMEVSCPDGYTCCRLQSGAWGCCPFT QAVCCEDHIHCCPAGFTCDTQKGTCEQGPHQVPWMEKAPAHLSLPDPQALKRDVPCDNVSSC PSSDTCCQLTSGEWGCCPIPEAVCCSDHQHCCPQGYTCVAEGQCQRGSEIVAGLEKMPARRA SLSHPRDIGCDQHTSCPVGQTCCPSLGGSWACCQLPHAVCCEDRQHCCPAGYTCNVKARSCE KEVVSAQPATFLARSPHVGVKDVECGEGHFCHDNQTCCRDNRQGWACCPYRQGVCCADRRHC CPAGFRCAARGTKCLRREAPRWDAPLRDPALRQLL BamH1 GGATCC restriction site (5’ to 3’) Xba1 TCTAGA restriction site (5’ to 3’) EcoR1 GAATTC restriction site (5’ to 3’) Linker CCGGGTACCGGT sequence 1 (pPG41) Linker TCTAGAATTCGATATCAAGCTTATCGATAA sequence 2 (pPG41) W_PRE ^{TCAACCTCTGGATTACAAAATTTGTGAAAGATTGACTGGTATTCTTAACTATGTTGCTCCTT} TTACGCTATGTGGATACGCTGCTTTAATGCCTTTGTATCATGCTATTGCTTCCCGTATGGCT TTCATTTTCTCCTCCTTGTATAAATCCTGGTTGCTGTCTCTTTATGAGGAGTTGTGGCCCGT TGTCAGGCAACGTGGCGTGGTGTGCACTGTGTTTGCTGACGCAACCCCCACTGGTTGGGGCA TTGCCACCACCTGTCAGCTCCTTTCCGGGACTTTCGCTTTCCCCCTCCCTATTGCCACGGCG GAACTCATCGCCGCCTGCCTTGCCCGCTGCTGGACAGGGGCTCGGCTGTTGGGCACTGACAA TTCCGTGGTGTTGTCGGGGAAATCATCGTCCTTTCCTTGGCTGCTCGCCTGTGTTGCCACCT GGATTCTGCGCGGGACGTCCTTCTGCTACGTCCCTTCGGCCCTCAATCCAGCGGACCTTCCT TCCCGCGGCCTGCTGCCGGCTCTGCGGCCTCTTCCGCGTCTTCGCCTTCGCCCTCAGACGAG TCGGATCTCCCTTTGGGCCGCCTCCCCGCA PolyA signal GATCCAGACATGATAAGATACATTGATGAGTTTGGACAAACCACAACTAGAATGCAGTGAAA sequence AAAATGCTTTATTTGTGAAATTTGTGATGCTATTGCTTTATTTGTAACCATTATAAGCTGCA ATAAACAAGTTAACAACAACAATTGCATTCATTTTATGTTTCAGGTTCAGGGGGAGGTGTGG (SV40) GAGGTTTTTTAG AAV-06164 AATAAATTGCAGTTTCATTTGATGCTCGATGAGTTTTTCTAACTCATGACCAAAATCCCTTA plasmid ACGTGAGTTACGCGCGCGTCGTTCCACTGAGCGTCAGACCCCGTAGAAAAGATCAAAGGATC TTCTTGAGATCCTTTTTTTCTGCGCGTAATCTGCTGCTTGCAAACAAAAAAACCACCGCTAC CAGCGGTGGTTTGTTTGCCGGATCAAGAGCTACCAACTCTTTTTCCGAAGGTAACTGGCTTC AGCAGAGCGCAGATACCAAATACTGTTCTTCTAGTGTAGCCGTAGTTAGCCCACCACTTCAA GAACTCTGTAGCACCGCCTACATACCTCGCTCTGCTAATCCTGTTACCAGTGGCTGCTGCCA GTGGCGATAAGTCGTGTCTTACCGGGTTGGACTCAAGACGATAGTTACCGGATAAGGCGCAG CGGTCGGGCTGAACGGGGGGTTCGTGCACACAGCCCAGCTTGGAGCGAACGACCTACACCGA ACTGAGATACCTACAGCGTGAGCTATGAGAAAGCGCCACGCTTCCCGAAGGGAGAAAGGCGG ACAGGTATCCGGTAAGCGGCAGGGTCGGAACAGGAGAGCGCACGAGGGAGCTTCCAGGGGGA AACGCCTGGTATCTTTATAGTCCTGTCGGGTTTCGCCACCTCTGACTTGAGCGTCGATTTTT GTGATGCTCGTCAGGGGGGCGGAGCCTATGGAAAAACGCCAGCAACGCGGCCTTTTTACGGT TCCTGGCCTTTTGCTGGCCTTTTGCTCACATGTTCTTTCCTGCGTTATCCCCTGATTCTGTG GATAACCGTATTACCGCCTTTGAGTGAGCTGATACCGCTCAAGGCTGACTGCAGGGCGAGAA GATTGCGAGCTGTGCGGCTGAGTTGACGTATCTGTGCTGGATGATTACTCATAACGGCACCG CTATCAAACGTGCCACGTTCATGTCCTACAGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGG CAAAGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGA GAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTTCTGCTAGTACTAGGTCCTCAGCAGGCC AGGTGTCTTATCCGCTGTCTGGGTCTGCTCTAGCTCCAGGCTTAGAACCCCTGCCACACGAC TCCACAGCTCGGTTGGCACCCTTTCCCTCCTCCGACTTCTGCTGCCTCGAGCTTGGTTAGCC ATCCCCCTGCCCCTGCCTCATCCTCAGCTCCAGTTCCTTGCTCAGGCTGCAGCAGTCTCCAT CCCCTGTGCAGACACTGCCGTTCCTCCACGGCCCAGTATCAGGCTTTCCCTGGGCCTCTCCT CTCTCCTGGCCCATCTCCCATCATCCATCTCTGCCTGGCCCAGGCCCTTTGGCACCAAGCAG GCTGACTCTTGTCACTGGCTAATCTGTTCTGTGGTACATTTTCTCTCCTCACCCTCCCATAT CAATTCCTCGAAGGCAGGGCCGATCTGGAGACTAGGAAGCCACTTCTCTTTCGACAGCCCCC ACCACAGCCCAGCCCGTGCCAGGCACCCAGCAGCTCCTGAAGCCCACTGGCATTGAACATGG CATTCAATCCCTGCCAAGCCTGCCCTTCCCATCTGGTTTCCCAGGGCTCTTCCCAACACCTC CTCCTCCACCTGCCAGTTAAAATCTTCCCAGACTCAGCTCAAGGAGATGCTCCTAAGGTGGA ATGAAATCTCTTCTTCCCCACCTGGAGACAATCTACTTCCTCTCCCTACACCTGGCAACTGG CGCACAACCTTGTATCTTAAATTAGATTCAGCCTGAGACTGTCTCCCACCAATCCCTGCTCC CTGTCCTGCTGAGCACCTTGAGGAAAGGGCTTTGGGGCTGTTTATCTTTGTCCTGGAAACCA TCCTTCAACTCACTCTGGGGCCTGCCTAGCATGTCAACCGAGTTTGGAGAATAGGGCAGAAT AGGGCAGGACAGGACAGGACAAGACAGGGCAGGATAGGATAGGAGCGAGCCAGCTCAGTAGC TCACATTTGTAATCCCAGCGCCTTGGGGGGCTGCGGTAGGAGAATCGCTTTGGGAGCAGGAG TTGCAGGCCGCAGTGAGCTATGATCAGCTTGGGCGACTGAGCGAGACCCTGTCTCTAAAACA AACACACAAGTCCGGGCGCGGTGGCTCATGCCTGTAATCTTAGCACTTTGGGAGGCCGAGGT GGGCGGATCACGAGGTCAAGAAATCGAGACCATCCTGGCCAACATGGTGAAACCCCGTCTCT ACTAAAAATACAAAAATTAGCTGGGCGTGGTGGTGCGCGCCTGTAGTCCCAGCTACTCGGGA GGCTGAGGCAGGAGAATCGCTTGAACCCGGGAGGCAGAGGTTGCAGTGAGCCGAGATCGTGC CACTGCACTCCAGCCTGGCGACAGAGTGAGACTCCGTCTCAGAACAAACAAACAAAAGGATA GAAAGGCGAGCACAAATATTCCCAATTCATAACACTCCCTCGCACTGTCAATGCCCCAGACA CGCGCTATCATCTCTAGCAAACTCCCCCAGGCGCCTGCAGGATGGGTTAAGGAAGGCGACGA GCACCAGCTGCCCTGCTGAGGCTGTCCCGACGTCACATGATTCTCCAATCACATGATCCCTA GAAATGGGGTGTGGGGCGAGAGGAAGCAGGGAGGAGAGTGATTTGAGTAGAAAAGAAACACA GCATTCCAGGCTGGCCCCACCTCTATATTGATAAGTAGCCAATGGGAGCGGGTAGCCCTGAT CCCTGGCCAATGGAAACTGAGGTAGGCGGGTCATCGCGCTGGGGTCTGTAGTCTGAGCGCTA CCCGGTTGCTGCTGCCCAAGGACCGCGGAGTCGGACGCAGGCAGACCATGTGGACCCTGGTG AGCTGGGTGGCCTTAACAGCAGGGCTGGTGGCTGGAACGCGGTGCCCAGATGGTCAGTTCTG CCCTGTGGCCTGCTGCCTGGACCCCGGAGGAGCCAGCTACAGCTGCTGCCGTCCCCTTCTGG ACAAATGGCCCACAACACTGAGCAGGCATCTGGGTGGCCCCTGCCAGGTTGATGCCCACTGC TCTGCCGGCCACTCCTGCATCTTTACCGTCTCAGGGACTTCCAGTTGCTGCCCCTTCCCAGA GGCCGTGGCATGCGGGGATGGCCATCACTGCTGCCCACGGGGCTTCCACTGCAGTGCAGACG GGCGATCCTGCTTCCAAAGATCAGGTAACAACTCCGTGGGTGCCATCCAGTGCCCTGATAGT CAGTTCGAATGCCCGGACTTCTCCACGTGCTGTGTTATGGTCGATGGCTCCTGGGGGTGCTG CCCCATGCCCCAGGCTTCCTGCTGTGAAGACAGGGTGCACTGCTGTCCGCACGGTGCCTTCT GCGACCTGGTTCACACCCGCTGCATCACACCCACGGGCACCCACCCCCTGGCAAAGAAGCTC CCTGCCCAGAGGACTAACAGGGCAGTGGCCTTGTCCAGCTCGGTCATGTGTCCGGACGCACG GTCCCGGTGCCCTGATGGTTCTACCTGCTGTGAGCTGCCCAGTGGGAAGTATGGCTGCTGCC CAATGCCCAACGCCACCTGCTGCTCCGATCACCTGCACTGCTGCCCCCAAGACACTGTGTGT GACCTGATCCAGAGTAAGTGCCTCTCCAAGGAGAACGCTACCACGGACCTCCTCACTAAGCT GCCTGCGCACACAGTGGGGGATGTGAAATGTGACATGGAGGTGAGCTGCCCAGATGGCTATA CCTGCTGCCGTCTACAGTCGGGGGCCTGGGGCTGCTGCCCTTTTACCCAGGCTGTGTGCTGT GAGGACCACATACACTGCTGTCCCGCGGGGTTTACGTGTGACACGCAGAAGGGTACCTGTGA ACAGGGGCCCCACCAGGTGCCCTGGATGGAGAAGGCCCCAGCTCACCTCAGCCTGCCAGACC CACAAGCCTTGAAGAGAGATGTCCCCTGTGATAATGTCAGCAGCTGTCCCTCCTCCGATACC TGCTGCCAACTCACGTCTGGGGAGTGGGGCTGCTGTCCAATCCCAGAGGCTGTCTGCTGCTC GGACCACCAGCACTGCTGCCCCCAGGGCTACACGTGTGTAGCTGAGGGGCAGTGTCAGCGAG GAAGCGAGATCGTGGCTGGACTGGAGAAGATGCCTGCCCGCCGGGCTTCCTTATCCCACCCC AGAGACATCGGCTGTGACCAGCACACCAGCTGCCCGGTGGGGCAGACCTGCTGCCCGAGCCT GGGTGGGAGCTGGGCCTGCTGCCAGTTGCCCCATGCTGTGTGCTGCGAGGATCGCCAGCACT GCTGCCCGGCTGGCTACACCTGCAACGTGAAGGCTCGATCCTGCGAGAAGGAAGTGGTCTCT GCCCAGCCTGCCACCTTCCTGGCCCGTAGCCCTCACGTGGGTGTGAAGGACGTGGAGTGTGG GGAAGGACACTTCTGCCATGATAACCAGACCTGCTGCCGAGACAACCGACAGGGCTGGGCCT GCTGTCCCTACCGCCAGGGCGTCTGTTGTGCTGATCGGCGCCACTGCTGTCCTGCTGGCTTC CGCTGCGCAGCCAGGGGTACCAAGTGTTTGCGCAGGGAGGCCCCGCGCTGGGACGCCCCTTT GAGGGACCCAGCCTTGAGACAGCTGCTGTGAGAATTCTCTAGAGAATTCGATCCAGACATGA TAAGATACATTGATGAGTTTGGACAAACCACAACTAGAATGCAGTGAAAAAAATGCTTTATT TGTGAAATTTGTGATGCTATTGCTTTATTTGTAACCATTATAAGCTGCAATAAACAAGTTAA CAACAACAATTGCATTCATTTTATGTTTCAGGTTCAGGGGGAGGTGTGGGAGGTTTTTTAGG GATCCTCAGAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTC ACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAG CGAGCGAGCGCGCACTGTCATTAGCAACTCCTTGTCCTTCGATCTCGTCAACAACAGCTTGC AGTTCAAATACAAGACCCAGAAGGCGACTATTCTGGAAGCGAGCTTGAAGAGTTAACCTGCA GAGAGCCCCCGCAGTGTCGACAATTAATCATCGGCATAGTATATCGGCATAGTATAATACGA CAAGGTGAGGAAGTAAAAAATGAGCCATATCCAACGGGAAACGTCGAGGCCGCGATTAAATT CCAACATGGATGCTGATTTATATGGGTATAAATGGGCTCGCGATAATGTCGGGCAATCAGGT GCGACAATCTATCGCTTGTATGGGAAGCCCGATGCGCCAGAGTTGTTTCTGAAACATGGCAA AGGTAGCGTTGCCAATGATGTTACAGATGAGATGGTCAGACTAAACTGGCTGACGGAATTTA TGCCACTTCCGACCATCAAGCATTTTATCCGTACTCCTGATGATGCATGGTTACTCACCACT GCGATCCCCGGAAAAACAGCGTTCCAGGTATTAGAAGAATATCCTGATTCAGGTGAAAATAT TGTTGATGCGCTGGCAGTGTTCCTGCGCCGGTTGCACTCGATTCCTGTTTGTAATTGTCCTT TTAACAGCGATCGCGTATTTCGCCTCGCTCAGGCGCAATCACGAATGAATAACGGTTTGGTT GATGCGAGTGATTTTGATGACGAGCGTAATGGCTGGCCTGTTGAACAAGTCTGGAAAGAAAT GCATAAACTTTTGCCATTCTCACCGGATTCAGTCGTCACTCATGGTGATTTCTCACTTGATA ACCTTATTTTTGACGAGGGGAAATTAATAGGTTGTATTGATGTTGGACGAGTCGGAATCGCA GACCGATACCAGGATCTTGCCATCCTATGGAACTGCCTCGGTGAGTTTTCTCCTTCATTACA GAAACGGCTTTTTCAAAAATATGGTATTGATAATCCTGATATG AAV-06262 AATAAATTGCAGTTTCATTTGATGCTCGATGAGTTTTTCTAACTCATGACCAAAATCCCTTA plasmid ACGTGAGTTACGCGCGCGTCGTTCCACTGAGCGTCAGACCCCGTAGAAAAGATCAAAGGATC TTCTTGAGATCCTTTTTTTCTGCGCGTAATCTGCTGCTTGCAAACAAAAAAACCACCGCTAC CAGCGGTGGTTTGTTTGCCGGATCAAGAGCTACCAACTCTTTTTCCGAAGGTAACTGGCTTC AGCAGAGCGCAGATACCAAATACTGTTCTTCTAGTGTAGCCGTAGTTAGCCCACCACTTCAA GAACTCTGTAGCACCGCCTACATACCTCGCTCTGCTAATCCTGTTACCAGTGGCTGCTGCCA GTGGCGATAAGTCGTGTCTTACCGGGTTGGACTCAAGACGATAGTTACCGGATAAGGCGCAG CGGTCGGGCTGAACGGGGGGTTCGTGCACACAGCCCAGCTTGGAGCGAACGACCTACACCGA ACTGAGATACCTACAGCGTGAGCTATGAGAAAGCGCCACGCTTCCCGAAGGGAGAAAGGCGG ACAGGTATCCGGTAAGCGGCAGGGTCGGAACAGGAGAGCGCACGAGGGAGCTTCCAGGGGGA AACGCCTGGTATCTTTATAGTCCTGTCGGGTTTCGCCACCTCTGACTTGAGCGTCGATTTTT GTGATGCTCGTCAGGGGGGCGGAGCCTATGGAAAAACGCCAGCAACGCGGCCTTTTTACGGT TCCTGGCCTTTTGCTGGCCTTTTGCTCACATGTTCTTTCCTGCGTTATCCCCTGATTCTGTG GATAACCGTATTACCGCCTTTGAGTGAGCTGATACCGCTCAAGGCTGACTGCAGGGCGAGAA GATTGCGAGCTGTGCGGCTGAGTTGACGTATCTGTGCTGGATGATTACTCATAACGGCACCG CTATCAAACGTGCCACGTTCATGTCCTACAGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGG CAAAGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGA GAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTTCTGCCATCCTGGCCAACATGGTGAAAC CCCGTCTCTACTAAAAATACAAAAATTAGCTGGGCGTGGTGGTGCGCGCCTGTAGTCCCAGC TACTCGGGAGGCTGAGGCAGGAGAATCGCTTGAACCCGGGAGGCAGAGGTTGCAGTGAGCCG AGATCGTGCCACTGCACTCCAGCCTGGCGACAGAGTGAGACTCCGTCTCAGAACAAACAAAC AAAAGGATAGAAAGGCGAGCACAAATATTCCCAATTCATAACACTCCCTCGCACTGTCAATG CCCCAGACACGCGCTATCATCTCTAGCAAACTCCCCCAGGCGCCTGCAGGATGGGTTAAGGA AGGCGACGAGCACCAGCTGCCCTGCTGAGGCTGTCCCGACGTCACATGATTCTCCAATCACA TGATCCCTAGAAATGGGGTGTGGGGCGAGAGGAAGCAGGGAGGAGAGTGATTTGAGTAGAAA AGAAACACAGCATTCCAGGCTGGCCCCACCTCTATATTGATAAGTAGCCAATGGGAGCGGGT AGCCCTGATCCCTGGCCAATGGAAACTGAGGTAGGCGGGTCATCGCGCTGGGGTCTGTAGTC TGAGCGCTACCCGGTTGCTGCTGCCCAAGGACCGCGGAGTCGGACGCAGGCAGACCATGTGG ACCCTGGTGAGCTGGGTGGCCTTAACAGCAGGGCTGGTGGCTGGAACGCGGTGCCCAGATGG TCAGTTCTGCCCTGTGGCCTGCTGCCTGGACCCCGGAGGAGCCAGCTACAGCTGCTGCCGTC CCCTTCTGGACAAATGGCCCACAACACTGAGCAGGCATCTGGGTGGCCCCTGCCAGGTTGAT GCCCACTGCTCTGCCGGCCACTCCTGCATCTTTACCGTCTCAGGGACTTCCAGTTGCTGCCC CTTCCCAGAGGCCGTGGCATGCGGGGATGGCCATCACTGCTGCCCACGGGGCTTCCACTGCA GTGCAGACGGGCGATCCTGCTTCCAAAGATCAGGTAACAACTCCGTGGGTGCCATCCAGTGC CCTGATAGTCAGTTCGAATGCCCGGACTTCTCCACGTGCTGTGTTATGGTCGATGGCTCCTG GGGGTGCTGCCCCATGCCCCAGGCTTCCTGCTGTGAAGACAGGGTGCACTGCTGTCCGCACG GTGCCTTCTGCGACCTGGTTCACACCCGCTGCATCACACCCACGGGCACCCACCCCCTGGCA AAGAAGCTCCCTGCCCAGAGGACTAACAGGGCAGTGGCCTTGTCCAGCTCGGTCATGTGTCC GGACGCACGGTCCCGGTGCCCTGATGGTTCTACCTGCTGTGAGCTGCCCAGTGGGAAGTATG GCTGCTGCCCAATGCCCAACGCCACCTGCTGCTCCGATCACCTGCACTGCTGCCCCCAAGAC ACTGTGTGTGACCTGATCCAGAGTAAGTGCCTCTCCAAGGAGAACGCTACCACGGACCTCCT CACTAAGCTGCCTGCGCACACAGTGGGGGATGTGAAATGTGACATGGAGGTGAGCTGCCCAG ATGGCTATACCTGCTGCCGTCTACAGTCGGGGGCCTGGGGCTGCTGCCCTTTTACCCAGGCT GTGTGCTGTGAGGACCACATACACTGCTGTCCCGCGGGGTTTACGTGTGACACGCAGAAGGG TACCTGTGAACAGGGGCCCCACCAGGTGCCCTGGATGGAGAAGGCCCCAGCTCACCTCAGCC TGCCAGACCCACAAGCCTTGAAGAGAGATGTCCCCTGTGATAATGTCAGCAGCTGTCCCTCC TCCGATACCTGCTGCCAACTCACGTCTGGGGAGTGGGGCTGCTGTCCAATCCCAGAGGCTGT CTGCTGCTCGGACCACCAGCACTGCTGCCCCCAGGGCTACACGTGTGTAGCTGAGGGGCAGT GTCAGCGAGGAAGCGAGATCGTGGCTGGACTGGAGAAGATGCCTGCCCGCCGGGCTTCCTTA TCCCACCCCAGAGACATCGGCTGTGACCAGCACACCAGCTGCCCGGTGGGGCAGACCTGCTG CCCGAGCCTGGGTGGGAGCTGGGCCTGCTGCCAGTTGCCCCATGCTGTGTGCTGCGAGGATC GCCAGCACTGCTGCCCGGCTGGCTACACCTGCAACGTGAAGGCTCGATCCTGCGAGAAGGAA GTGGTCTCTGCCCAGCCTGCCACCTTCCTGGCCCGTAGCCCTCACGTGGGTGTGAAGGACGT GGAGTGTGGGGAAGGACACTTCTGCCATGATAACCAGACCTGCTGCCGAGACAACCGACAGG GCTGGGCCTGCTGTCCCTACCGCCAGGGCGTCTGTTGTGCTGATCGGCGCCACTGCTGTCCT GCTGGCTTCCGCTGCGCAGCCAGGGGTACCAAGTGTTTGCGCAGGGAGGCCCCGCGCTGGGA CGCCCCTTTGAGGGACCCAGCCTTGAGACAGCTGCTGTGATCTAGAGAATTCGATCCAGACA TGATAAGATACATTGATGAGTTTGGACAAACCACAACTAGAATGCAGTGAAAAAAATGCTTT ATTTGTGAAATTTGTGATGCTATTGCTTTATTTGTAACCATTATAAGCTGCAATAAACAAGT TAACAACAACAATTGCATTCATTTTATGTTTCAGGTTCAGGGGGAGGTGTGGGAGGTTTTTT AGGGATCCTCAGAGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCG CTCACTGAGGCCGGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGT GAGCGAGCGAGCGCGCACTGTCATTAGCAACTCCTTGTCCTTCGATCTCGTCAACAACAGCT TGCAGTTCAAATACAAGACCCAGAAGGCGACTATTCTGGAAGCGAGCTTGAAGAGTTAACCT GCAGAGAGCCCCCGCAGTGTCGACAATTAATCATCGGCATAGTATATCGGCATAGTATAATA CGACAAGGTGAGGAAGTAAAAAATGAGCCATATCCAACGGGAAACGTCGAGGCCGCGATTAA ATTCCAACATGGATGCTGATTTATATGGGTATAAATGGGCTCGCGATAATGTCGGGCAATCA GGTGCGACAATCTATCGCTTGTATGGGAAGCCCGATGCGCCAGAGTTGTTTCTGAAACATGG CAAAGGTAGCGTTGCCAATGATGTTACAGATGAGATGGTCAGACTAAACTGGCTGACGGAAT TTATGCCACTTCCGACCATCAAGCATTTTATCCGTACTCCTGATGATGCATGGTTACTCACC ACTGCGATCCCCGGAAAAACAGCGTTCCAGGTATTAGAAGAATATCCTGATTCAGGTGAAAA TATTGTTGATGCGCTGGCAGTGTTCCTGCGCCGGTTGCACTCGATTCCTGTTTGTAATTGTC CTTTTAACAGCGATCGCGTATTTCGCCTCGCTCAGGCGCAATCACGAATGAATAACGGTTTG GTTGATGCGAGTGATTTTGATGACGAGCGTAATGGCTGGCCTGTTGAACAAGTCTGGAAAGA AATGCATAAACTTTTGCCATTCTCACCGGATTCAGTCGTCACTCATGGTGATTTCTCACTTG ATAACCTTATTTTTGACGAGGGGAAATTAATAGGTTGTATTGATGTTGGACGAGTCGGAATC GCAGACCGATACCAGGATCTTGCCATCCTATGGAACTGCCTCGGTGAGTTTTCTCCTTCATT ACAGAAACGGCTTTTTCAAAAATATGGTATTGATAATCCTGATATG AAV-06263 AATAAATTGCAGTTTCATTTGATGCTCGATGAGTTTTTCTAACTCATGACCAAAATCCCTTA plasmid ACGTGAGTTACGCGCGCGTCGTTCCACTGAGCGTCAGACCCCGTAGAAAAGATCAAAGGATC TTCTTGAGATCCTTTTTTTCTGCGCGTAATCTGCTGCTTGCAAACAAAAAAACCACCGCTAC CAGCGGTGGTTTGTTTGCCGGATCAAGAGCTACCAACTCTTTTTCCGAAGGTAACTGGCTTC AGCAGAGCGCAGATACCAAATACTGTTCTTCTAGTGTAGCCGTAGTTAGCCCACCACTTCAA GAACTCTGTAGCACCGCCTACATACCTCGCTCTGCTAATCCTGTTACCAGTGGCTGCTGCCA GTGGCGATAAGTCGTGTCTTACCGGGTTGGACTCAAGACGATAGTTACCGGATAAGGCGCAG CGGTCGGGCTGAACGGGGGGTTCGTGCACACAGCCCAGCTTGGAGCGAACGACCTACACCGA ACTGAGATACCTACAGCGTGAGCTATGAGAAAGCGCCACGCTTCCCGAAGGGAGAAAGGCGG ACAGGTATCCGGTAAGCGGCAGGGTCGGAACAGGAGAGCGCACGAGGGAGCTTCCAGGGGGA AACGCCTGGTATCTTTATAGTCCTGTCGGGTTTCGCCACCTCTGACTTGAGCGTCGATTTTT GTGATGCTCGTCAGGGGGGCGGAGCCTATGGAAAAACGCCAGCAACGCGGCCTTTTTACGGT TCCTGGCCTTTTGCTGGCCTTTTGCTCACATGTTCTTTCCTGCGTTATCCCCTGATTCTGTG GATAACCGTATTACCGCCTTTGAGTGAGCTGATACCGCTCAAGGCTGACTGCAGGGCGAGAA GATTGCGAGCTGTGCGGCTGAGTTGACGTATCTGTGCTGGATGATTACTCATAACGGCACCG CTATCAAACGTGCCACGTTCATGTCCTACAGCGCGCTCGCTCGCTCACTGAGGCCGCCCGGG CAAAGCCCGGGCGTCGGGCGACCTTTGGTCGCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGA GAGGGAGTGGCCAACTCCATCACTAGGGGTTCCTTCTGAGCCGAGATCGTGCCACTGCACTC CAGCCTGGCGACAGAGTGAGACTCCGTCTCAGAACAAACAAACAAAAGGATAGAAAGGCGAG CACAAATATTCCCAATTCATAACACTCCCTCGCACTGTCAATGCCCCAGACACGCGCTATCA TCTCTAGCAAACTCCCCCAGGCGCCTGCAGGATGGGTTAAGGAAGGCGACGAGCACCAGCTG CCCTGCTGAGGCTGTCCCGACGTCACATGATTCTCCAATCACATGATCCCTAGAAATGGGGT GTGGGGCGAGAGGAAGCAGGGAGGAGAGTGATTTGAGTAGAAAAGAAACACAGCATTCCAGG CTGGCCCCACCTCTATATTGATAAGTAGCCAATGGGAGCGGGTAGCCCTGATCCCTGGCCAA TGGAAACTGAGGTAGGCGGGTCATCGCGCTGGGGTCTGTAGTCTGAGCGCTACCCGGTTGCT GCTGCCCAAGGACCGCGGAGTCGGACGCAGGCAGACCATGTGGACCCTGGTGAGCTGGGTGG CCTTAACAGCAGGGCTGGTGGCTGGAACGCGGTGCCCAGATGGTCAGTTCTGCCCTGTGGCC TGCTGCCTGGACCCCGGAGGAGCCAGCTACAGCTGCTGCCGTCCCCTTCTGGACAAATGGCC CACAACACTGAGCAGGCATCTGGGTGGCCCCTGCCAGGTTGATGCCCACTGCTCTGCCGGCC ACTCCTGCATCTTTACCGTCTCAGGGACTTCCAGTTGCTGCCCCTTCCCAGAGGCCGTGGCA TGCGGGGATGGCCATCACTGCTGCCCACGGGGCTTCCACTGCAGTGCAGACGGGCGATCCTG CTTCCAAAGATCAGGTAACAACTCCGTGGGTGCCATCCAGTGCCCTGATAGTCAGTTCGAAT GCCCGGACTTCTCCACGTGCTGTGTTATGGTCGATGGCTCCTGGGGGTGCTGCCCCATGCCC CAGGCTTCCTGCTGTGAAGACAGGGTGCACTGCTGTCCGCACGGTGCCTTCTGCGACCTGGT TCACACCCGCTGCATCACACCCACGGGCACCCACCCCCTGGCAAAGAAGCTCCCTGCCCAGA GGACTAACAGGGCAGTGGCCTTGTCCAGCTCGGTCATGTGTCCGGACGCACGGTCCCGGTGC CCTGATGGTTCTACCTGCTGTGAGCTGCCCAGTGGGAAGTATGGCTGCTGCCCAATGCCCAA CGCCACCTGCTGCTCCGATCACCTGCACTGCTGCCCCCAAGACACTGTGTGTGACCTGATCC AGAGTAAGTGCCTCTCCAAGGAGAACGCTACCACGGACCTCCTCACTAAGCTGCCTGCGCAC ACAGTGGGGGATGTGAAATGTGACATGGAGGTGAGCTGCCCAGATGGCTATACCTGCTGCCG TCTACAGTCGGGGGCCTGGGGCTGCTGCCCTTTTACCCAGGCTGTGTGCTGTGAGGACCACA TACACTGCTGTCCCGCGGGGTTTACGTGTGACACGCAGAAGGGTACCTGTGAACAGGGGCCC CACCAGGTGCCCTGGATGGAGAAGGCCCCAGCTCACCTCAGCCTGCCAGACCCACAAGCCTT GAAGAGAGATGTCCCCTGTGATAATGTCAGCAGCTGTCCCTCCTCCGATACCTGCTGCCAAC TCACGTCTGGGGAGTGGGGCTGCTGTCCAATCCCAGAGGCTGTCTGCTGCTCGGACCACCAG CACTGCTGCCCCCAGGGCTACACGTGTGTAGCTGAGGGGCAGTGTCAGCGAGGAAGCGAGAT CGTGGCTGGACTGGAGAAGATGCCTGCCCGCCGGGCTTCCTTATCCCACCCCAGAGACATCG GCTGTGACCAGCACACCAGCTGCCCGGTGGGGCAGACCTGCTGCCCGAGCCTGGGTGGGAGC TGGGCCTGCTGCCAGTTGCCCCATGCTGTGTGCTGCGAGGATCGCCAGCACTGCTGCCCGGC TGGCTACACCTGCAACGTGAAGGCTCGATCCTGCGAGAAGGAAGTGGTCTCTGCCCAGCCTG CCACCTTCCTGGCCCGTAGCCCTCACGTGGGTGTGAAGGACGTGGAGTGTGGGGAAGGACAC TTCTGCCATGATAACCAGACCTGCTGCCGAGACAACCGACAGGGCTGGGCCTGCTGTCCCTA CCGCCAGGGCGTCTGTTGTGCTGATCGGCGCCACTGCTGTCCTGCTGGCTTCCGCTGCGCAG CCAGGGGTACCAAGTGTTTGCGCAGGGAGGCCCCGCGCTGGGACGCCCCTTTGAGGGACCCA GCCTTGAGACAGCTGCTGTGATCTAGAGAATTCGATCCAGACATGATAAGATACATTGATGA GTTTGGACAAACCACAACTAGAATGCAGTGAAAAAAATGCTTTATTTGTGAAATTTGTGATG CTATTGCTTTATTTGTAACCATTATAAGCTGCAATAAACAAGTTAACAACAACAATTGCATT CATTTTATGTTTCAGGTTCAGGGGGAGGTGTGGGAGGTTTTTTAGGGATCCTCAGAGGAACC CCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCCGGGCGAC CAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGCGCGCACT GTCATTAGCAACTCCTTGTCCTTCGATCTCGTCAACAACAGCTTGCAGTTCAAATACAAGAC CCAGAAGGCGACTATTCTGGAAGCGAGCTTGAAGAGTTAACCTGCAGAGAGCCCCCGCAGTG TCGACAATTAATCATCGGCATAGTATATCGGCATAGTATAATACGACAAGGTGAGGAAGTAA AAAATGAGCCATATCCAACGGGAAACGTCGAGGCCGCGATTAAATTCCAACATGGATGCTGA TTTATATGGGTATAAATGGGCTCGCGATAATGTCGGGCAATCAGGTGCGACAATCTATCGCT TGTATGGGAAGCCCGATGCGCCAGAGTTGTTTCTGAAACATGGCAAAGGTAGCGTTGCCAAT GATGTTACAGATGAGATGGTCAGACTAAACTGGCTGACGGAATTTATGCCACTTCCGACCAT CAAGCATTTTATCCGTACTCCTGATGATGCATGGTTACTCACCACTGCGATCCCCGGAAAAA CAGCGTTCCAGGTATTAGAAGAATATCCTGATTCAGGTGAAAATATTGTTGATGCGCTGGCA GTGTTCCTGCGCCGGTTGCACTCGATTCCTGTTTGTAATTGTCCTTTTAACAGCGATCGCGT ATTTCGCCTCGCTCAGGCGCAATCACGAATGAATAACGGTTTGGTTGATGCGAGTGATTTTG ATGACGAGCGTAATGGCTGGCCTGTTGAACAAGTCTGGAAAGAAATGCATAAACTTTTGCCA TTCTCACCGGATTCAGTCGTCACTCATGGTGATTTCTCACTTGATAACCTTATTTTTGACGA GGGGAAATTAATAGGTTGTATTGATGTTGGACGAGTCGGAATCGCAGACCGATACCAGGATC TTGCCATCCTATGGAACTGCCTCGGTGAGTTTTCTCCTTCATTACAGAAACGGCTTTTTCAA AAATATGGTATTGATAATCCTGATATG 5_{’ ITR} ^{GCGCGCTCGCTCGCTCACTGAGGCCGCCCGGGCAAAGCCCGGGCGTCGGGCGACCTTTGGTC} GCCCGGCCTCAGTGAGCGAGCGAGCGCGCAGAGAGGGAGTGGCCAACTCCATCACTAGGGGT TCCT 3_{’ ITR} ^{AGGAACCCCTAGTGATGGAGTTGGCCACTCCCTCTCTGCGCGCTCGCTCGCTCACTGAGGCC} GGGCGACCAAAGGTCGCCCGACGCCCGGGCTTTGCCCGGGCGGCCTCAGTGAGCGAGCGAGC GCGC Kozak CAGACC sequence mGRN TATGTGGGTTATATAGTGAGTTCAAGGCTAGCCTGGAAAACTTAGGGAGACTCCATCTCAAA promoter ATAAAAAGTAAAAAAAAAAATAAAAATAAAAATGAAGAGGCTGATCTTCTATGGCAAGATGG GAGGCAGAGTCAAGAAAATCATTTGGAGGCTTAAGGGCCAGGTATCATGAAGCACACAGCGC construct ^{GCAGAGGCAAAAACAGAGACCTTGCCTTAAAAACAAGGTAAACGCCGGGCGTGGTGGCGCAT} GCCTTTAGTCCCAGCACTGGGGAGGCAGAGGCAGGCGGATTTCTGAGTTCGAGGCCAGCCTG GTCTACAAAGTGAGTTCCAGGACAGCCAGGGCTATACAGAGAAACCCTGTCTCGAAAAAAAC CAAAACCAAAACCAAAACAAACAAACAAACAAACAAGATAAACAAGGTAGGGTGGTGGTGGT GGTATGTGGCTTTGAACCCCAGCACTGAGGAGGCAGAGGCAGGTGGATCTCTCTGTGTTTGA GTCCAGCCTGGTCTATAGAGTGAGTTCCAGGCTAGCCAGAACTCCACAGAGAAACCCTTTCT TGATAAACAAAACCAGGTGGACAGATCGACTGTCCAAATGTTGTTCTGTGAAATATGCGCTC CCTCCTTCAGACGGAAACCAGAACCTCTCGTGTTAGATTAGAGCAATGCCATTAAGCTGTAG CCCCAGAAGTTTGTTCTACCTTTTTATTATTTATTTCAAGCGATTGCGTATGTAAGTCTGGG GGTGCGCTAATGCTATGGTGTGTGTGCAGAAGTCAGAAGTCGTGGTTTCTGGGAGTCATTTC TGTCTTGTGAAACAAAGGAAGCAGGTTTGTTAAGCTTTTACCTGCTCCCCATTTTATTTCCC CTTGAGGCAGTGCTGCGTCTAGGATGTAGCTCAGTTGGTAGCACTTGTAGCTCAGCATGCTC AAGGCCCTAGGTCTAATCCCAGCAGCACAGAAACTAAACACGGCAATCTGCACTTGCAATCG TGGCGCTTGGGAGATGGGGGCAGAAAACTGAGAAGTTCTGTGTCAGCTATCTATCAAGCTGA AGCTCGTCTGGAACACAGGAAACCCTGACTCAGAGGGTGAGCTGCAATGTTGCTGAGTCTGG TTTCCAACTCCTGGGGTTCAGCAGCACCCCTTCCTCAGCCTCCGCAGATGGCTGTGTCTCAC TAGAAGCATAAGCAATGGTCTGTTCTGGGGACACCTGTATGAATGTCATGGAACACCTATGC TAACACCATCAGGATGCAGAATGATGCACCAGTCTTACACACTTTCTGGGACTCCAGTGTAA GAAGCCCTCACGGAATTCCACAACCCTGCATGCACTCCTCTCTATGTAAGACTCCCACTGTC CTGAACTGTATGGCTGACCCCCATGGTCTCTATTCACCCACCATAACAATTCCTCGAAGGTG GGGACAGCTGAAACAAGGAAACCCCTTCCATCTCGACAGCCACCAGCCTACTCCACAGGCAG TGCCACACACTTGGCTAATGCCCTTATCTTGAACGTGGCTTTCAACCCTTGCTAGAGGCTGT CTGTAAAGAACAAGATATAAACTACCCAAGGAAAGGATTCACTGTCTTTCCCAATCTAGTTT CAAGTTCCTCTGTCCCACCTTATCAGCCTCTTAAAATTCTTTCAGCTTCAATTTAATGCAGT GCTATCAATATGGATTTAAATCTCTTCTTCCCCCCAGTTTGAGCCAATCTCCTGCCTCCTCC CTACACACATCTACAGTGCCCGGTACTCGCCCTTGAACCTTTATTAGATTTAGTCTAAGCCA CTCTCCCCATTCAAACCTGGGGACTATTTATCTTCACCCTCACAACCATCTTCCAACTGGTT TCGAGTCCTTGTCTGCCAGGCGTGAAGAGACAGGAATGTACAAAAGTCCCGATCCAGAAGCA GACACCCTCCAGTAAACGACCTTGAACGCGTGCCCTCAGGGCAGCTCTCCTAACTGTGGGTG CCCTTAGGCATGAGGTGTCTCATCTCTGCAACACTCTGCCGCCAGAACCCAAACCAGCAAGC TCTGCCCTGGGGGAGGCGGGCTATGTTGTCATATGATTCTCTAATCACATGATCCCTAGAAA TGGGGTGTGGGGAGAAAGAGGAAAGGGAGGAGGAATGTGAACTGAGTAGAAAAGAAACACAG CATTCCAGGAGAGTCCCGCCTCTACGTAGACAAGTAACCAATGGAAGCCCTGGATCTCCGAG CAATGGCTAATGGAAATTGAGGTGGGCGGGCCATCGTGCGGCCAAGCCCTAGTCCTGGAGCT GACCGCCAGATGCCTCCCAGGGAGCCCGGACCCCGACGCAGGTAGGAGGACCCTCTGCAGAC AATCTCCCCGGCTACTGTCCAGAGGTCCAGAGGCCTGACCAGGCTGCCTGTGCAATTGAGGG TCCTCTGGAGTCTCAGCTCAGAGACAAGAGAAGACCTGCCTCTTGAAACTCCCCTAGGGGTT TCTGATGCACTAACGAGGTTGTTTTTTTGGATCCCCGGGTACCGGTGCCACCATGTGGACCC TGGTGAGCTGGGTGGCCTTAACAGCAGGGCTGGTGGCTGGAACGCGGTGCCCAGATGGTCAG TTCTGCCCTGTGGCCTGCTGCCTGGACCCCGGAGGAGCCAGCTACAGCTGCTGCCGTCCCCT TCTGGACAAATGGCCCACAACACTGAGCAGGCATCTGGGTGGCCCCTGCCAGGTTGATGCCC ACTGCTCTGCCGGCCACTCCTGCATCTTTACCGTCTCAGGGACTTCCAGTTGCTGCCCCTTC CCAGAGGCCGTGGCATGCGGGGATGGCCATCACTGCTGCCCACGGGGCTTCCACTGCAGTGC AGACGGGCGATCCTGCTTCCAAAGATCAGGTAACAACTCCGTGGGTGCCATCCAGTGCCCTG ATAGTCAGTTCGAATGCCCGGACTTCTCCACGTGCTGTGTTATGGTCGATGGCTCCTGGGGG TGCTGCCCCATGCCCCAGGCTTCCTGCTGTGAAGACAGGGTGCACTGCTGTCCGCACGGTGC CTTCTGCGACCTGGTTCACACCCGCTGCATCACACCCACGGGCACCCACCCCCTGGCAAAGA AGCTCCCTGCCCAGAGGACTAACAGGGCAGTGGCCTTGTCCAGCTCGGTCATGTGTCCGGAC GCACGGTCCCGGTGCCCTGATGGTTCTACCTGCTGTGAGCTGCCCAGTGGGAAGTATGGCTG CTGCCCAATGCCCAACGCCACCTGCTGCTCCGATCACCTGCACTGCTGCCCCCAAGACACTG TGTGTGACCTGATCCAGAGTAAGTGCCTCTCCAAGGAGAACGCTACCACGGACCTCCTCACT AAGCTGCCTGCGCACACAGTGGGGGATGTGAAATGTGACATGGAGGTGAGCTGCCCAGATGG CTATACCTGCTGCCGTCTACAGTCGGGGGCCTGGGGCTGCTGCCCTTTTACCCAGGCTGTGT GCTGTGAGGACCACATACACTGCTGTCCCGCGGGGTTTACGTGTGACACGCAGAAGGGTACC TGTGAACAGGGGCCCCACCAGGTGCCCTGGATGGAGAAGGCCCCAGCTCACCTCAGCCTGCC AGACCCACAAGCCTTGAAGAGAGATGTCCCCTGTGATAATGTCAGCAGCTGTCCCTCCTCCG ATACCTGCTGCCAACTCACGTCTGGGGAGTGGGGCTGCTGTCCAATCCCAGAGGCTGTCTGC TGCTCGGACCACCAGCACTGCTGCCCCCAGGGCTACACGTGTGTAGCTGAGGGGCAGTGTCA GCGAGGAAGCGAGATCGTGGCTGGACTGGAGAAGATGCCTGCCCGCCGGGCTTCCTTATCCC ACCCCAGAGACATCGGCTGTGACCAGCACACCAGCTGCCCGGTGGGGCAGACCTGCTGCCCG AGCCTGGGTGGGAGCTGGGCCTGCTGCCAGTTGCCCCATGCTGTGTGCTGCGAGGATCGCCA GCACTGCTGCCCGGCTGGCTACACCTGCAACGTGAAGGCTCGATCCTGCGAGAAGGAAGTGG TCTCTGCCCAGCCTGCCACCTTCCTGGCCCGTAGCCCTCACGTGGGTGTGAAGGACGTGGAG TGTGGGGAAGGACACTTCTGCCATGATAACCAGACCTGCTGCCGAGACAACCGACAGGGCTG GGCCTGCTGTCCCTACCGCCAGGGCGTCTGTTGTGCTGATCGGCGCCACTGCTGTCCTGCTG GCTTCCGCTGCGCAGCCAGGGGTACCAAGTGTTTGCGCAGGGAGGCCCCGCGCTGGGACGCC CCTTTGAGGGACCCAGCCTTGAGACAGCTGCTGTGA REFERENCES Olney et al., Neurol. 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Claims

CLAIMS 1. A nucleic acid construct comprising a granulin (GRN) promoter operably linked to a nucleotide sequence encoding a protein of interest (POI), wherein the GRN promoter is a full-length GRN promoter or a truncated GRN promoter. 2. The nucleic acid construct according to claim 1, wherein the POI is a progranulin (PGRN) protein. 3. The nucleic acid construct according to any one of claims 1-2, wherein the GRN promoter comprises or consists of: (a) the nucleotide sequence of SEQ ID NO: 1 or 2, or a functional variant and/or fragment thereof having at least 90 % identity to the nucleotide sequence of SEQ ID NO: 1 or 2; (b) the nucleotide sequence of SEQ ID NO: 3, or a functional variant and/or fragment thereof having at least 90 % identity to the nucleotide sequence of SEQ ID NO: 3; (c) the nucleotide sequence of SEQ ID NO: 4 or a functional variant and/or fragment thereof having at least 90 % identity to the nucleotide sequence of SEQ ID NO: 4; (d) the nucleotide sequence of SEQ ID NO: 5 or a functional variant and/or fragment thereof having at least 90 % identity to the nucleotide sequence of SEQ ID NO: 5. 4. The nucleic acid construct according to any one of claims 1-3, wherein the nucleic acid construct comprises or consists of in the 5ʹ to 3ʹ direction: (a) a GRN promoter sequence such as a truncated GRN promoter; (b) optionally a Kozak sequence; (c) a polynucleotide sequence encoding the POI, such as PGRN protein; and (d) optionally a posttranscriptional regulatory element such as WPRE and/or a poly(A) sequence such as an SV40 poly(A) sequence. 5. A vector comprising a nucleic acid construct according to any one of claims 1-4, wherein the vector further comprises at least one inverted terminal repeat (ITR) flanking said nucleic acid construct at 5’ and/or 3’, preferably a 5’ITR and a 3’ITR. 6. A viral particle comprising 1) a capsid and a nucleic acid construct according to any one of claims 1-4 packaged therein or 2) a capsid and a vector according to claim 5. 7. The viral particle according to claim 6, which is selected from: (a) an adeno-associated virus (AAV) particle or a viral particle which comprises an AAV genome, or a derivative thereof, optionally wherein said derivative is a chimeric, shuffled, or capsid modified derivative; or (b) a lentiviral particle or a viral particle which comprises a lentivirus genome or a derivative thereof. 8. The viral particle of claim 7, which is an AAV particle comprising a capsid identical to or derived from AAV serotype 1 (AAV1), AAV serotype 2 (AAV2), AAV serotype 4 (AAV4), AAV serotype 5 (AAV5), AAV serotype 8 (AAV8), AAV serotype 9 (AAV9), or AAV serotype rh10 (AAVrh10), preferably wherein the AAV particle comprises a capsid identical to or derived from AAV2, AAV9 or AAVrH10. 9. The viral particle according to claim 8, wherein the particle comprises a capsid derived from AAV2, preferably wherein the AAV2 derivative is AAV-TT. 10. A host cell which comprises a nucleic acid construct according to any one of claims 1-4 and/or a vector according to claim 5, and/or which produces a viral particle according to any one of claims 6-9, optionally wherein the host cell is a HEK293 cell or a HEK293T cell. 11. A pharmaceutical composition comprising a nucleic acid construct according to any one of claims 1-4, a vector according to claim 5, and/or a viral particle according to any one of claims 6-9 together with a pharmaceutically acceptable carrier, excipient, and/or diluent. 12. A nucleic acid construct according to any one of claims 1-4, a vector according to claim 5, a viral particle according to any one of claims 6-9, and/or a pharmaceutical composition according to claim 11 for use in a method of treating or preventing a disease characterized by a deficiency in a Protein of interest (POI), such as progranulin (PGRN) deficiency, in a patient in need thereof. 13. A method of treating or preventing a disease characterized by a deficiency in a Protein of interest (POI), such as progranulin (PGRN) deficiency, in a patient in need thereof, said method comprising administering to the patient a therapeutically effective amount of a nucleic acid construct according to any one of claims 1-4, a vector according to claim 5, a viral particle according to any one of claims 6-9, and/or a pharmaceutical composition according to claim 11. 14. Use of a nucleic acid construct according to any one of claims 1-4, a vector according to claim 5, a viral particle according to any one of claims 6-9, and/or a pharmaceutical composition according to claim 11 for the manufacture of a medicament for the treatment or prevention of a disease characterized by a deficiency in a Protein of interest (POI), such as progranulin (PGRN) deficiency, in a patient in need thereof. 15. The nucleic acid construct, vector, viral particle, or pharmaceutical composition for use according to claim 12, the method of claim 13, or the use of claim 14, wherein the POI is progranulin and wherein : (i) the disease characterized by PGRN deficiency is a disease of the central nervous system; (ii) the disease characterized by PGRN deficiency is characterized by a deficiency of PGRN in the neurons and/or the astrocytes of the patient; (iii) the patient has a loss of function mutation in at least one allele of their GRN gene; and/or (iv) the patient has a loss of function mutation in both alleles of their GRN gene. 16. The nucleic acid construct, vector, viral particle, or pharmaceutical composition for use according to claim 15, the method according to claim 15, or the use according to claim 15, wherein the disease characterized by PGRN deficiency is frontotemporal dementia (FTD) or neuronal ceroid lipofuscinosis type 11 (NCL11). 17. The nucleic acid construct according to any one of claims 1 to 4, wherein the nucleic acid construct comprises the nucleotide sequence of: (a) (b) SEQ ID NO: 7 or a functional variant or fragment thereof having at least 70 % identity to the nucleotide sequence of SEQ ID NO: 7; (b) SEQ ID NO: 8 or a functional variant or fragment thereof having at least 70 % identity to the nucleotide sequence of SEQ ID NO: 8; (c) SEQ ID NO: 9 or a functional variant or fragment thereof having at least 70 % identity to the nucleotide sequence of SEQ ID NO: 9; (d) SEQ ID NO: 10 or a functional variant or fragment thereof having at least 70 % identity to the nucleotide sequence of SEQ ID NO: 10; (e) SEQ ID NO: 11 or a functional variant or fragment thereof having at least 70 % identity to the nucleotide sequence of SEQ ID NO: 11; or (f) SEQ ID NO: 12 or a functional variant or fragment thereof having at least 70 % identity to the nucleotide sequence of SEQ ID NO: 12. 18. The vector according to claim 5, wherein the vector comprises the nucleotide sequence of: (a) SEQ ID NO: 22 or a functional variant or fragment thereof having at least 70 % identity to the nucleotide sequence of SEQ ID NO: 22; (b) SEQ ID NO: 23 or a functional variant or fragment thereof having at least 70 % identity to the nucleotide sequence of SEQ ID NO: 23; or (c) SEQ ID NO: 24or a functional variant or fragment thereof having at least 70 % identity to the nucleotide sequence of SEQ ID NO: 24.