Abstract: The present invention provides a recombinant adeno-associated virus (rAAV) vector for treating a blood coagulation-related disease to provide a novel gene therapy means for hemophilia. The virus vector comprises a virus genome comprising a liver-specific promoter sequence and a polynucleotide sequence encoding a genome editing means operably linked to the promoter sequence, wherein the genome editing means is (a) a means comprising CRISPR/Cas9 composed of a Cas9 protein and a guide RNA (gRNA) and a repair gene, or (b) a means comprising CRISPR/Cas9 composed of a Cas9 protein and a gRNA, and the gRNA comprises a nucleotide region complementary to a part of a region related to expression of a disease-related protein on the genome of a patient and a region that interacts with the Cas9 protein.

Abstract: The present invention relates to the production of adeno-associated viral vectors in insect cells. The insect cells therefore comprise a first nucleotide sequence encoding the adeno-associated virus (AAV) capsid proteins, whereby the initiation codon for translation of the AAV VP1 capsid protein is a non-ATG, suboptimal initiation codon. The insect cell further comprises a second nucleotide sequence comprising at least one AAV inverted terminal repeat (ITR) nucleotide sequence; a third nucleotide sequence comprising a Rep52 or a Rep40 coding sequence operably linked to expression control sequences for expression in an insect cell; and, a fourth nucleotide sequence comprising a Rep78 or a Rep68 coding sequence operably linked to expression control sequences for expression in an insect cell. The invention further relates to adeno-associated viral vectors with an altered ratio of the viral capsid proteins that provides improved infectivity of the viral particles.

Abstract: The present invention relates to the production of adeno-associated viral vectors in insect cells. The insect cells therefore comprise a first nucleotide sequence encoding the adeno-associated virus (AAV) capsid proteins, whereby the initiation codon for translation of the AAV VP1 capsid protein is a non-ATG, suboptimal initiation codon. The insect cell further comprises a second nucleotide sequence comprising at least one AAV inverted terminal repeat (ITR) nucleotide sequence; a third nucleotide sequence comprising a Rep52 or a Rep40 coding sequence operably linked to expression control sequences for expression in an insect cell; and, a fourth nucleotide sequence comprising a Rep78 or a Rep68 coding sequence operably linked to expression control sequences for expression in an insect cell. The invention further relates to adeno-associated viral vectors with an altered ratio of the viral capsid proteins that provides improved infectivity of the viral particles.

Abstract: A gene transfer efficiency enhancer of the present invention which contains a histone deacetylase inhibitor (especially compound (A)) as an active ingredient is capable of enhancing gene transfer efficiency in a gene transfer mediated by an adeno-associated virus vector while retaining the advantages of the adeno-associated virus vector.

Abstract: Methods for treating Parkinson's disease (PD) are provided. Recombinant adeno-associated virus (rAAV) virions are used to deliver genes encoding dopamine-synthesizing enzymes to the central nervous system of a primate. Once delivered, the genes are expressed, which then results in dopamine synthesis and amelioration in the clinical signs and symptoms of PD. The methods of the present invention can be used to deliver the three central dopamine synthesizing enzymes: tyrosine hydroxylase, aromatic L-amino acid decarboxylase, and guanosine triphosphate cyclohydrolase I thereby enhancing dopamine biosynthesis and providing for enhanced therapeutic efficacy.

Abstract: A gene transfer efficiency enhancer of the present invention which contains a histone deacetylase inhibitor (especially compound (A)) as an active ingredient is capable of enhancing gene transfer efficiency in a gene transfer mediated by an adeno-associated virus vector while retaining the advantages of the adeno-associated virus vector.

Abstract: The object of the present invention is to provide an agent for specific adsorption of type 5 adenoviral vector to undifferentiated blood cells which enables infection with a viral concentration that does not impart toxicity to undifferentiated blood cells, without requiring the construction of a new viral genome, or special modification of viral particles such as biotination, etc. The above objective has been achieved by providing a polypeptide which has affinity for both adenovirus and undifferentiated blood cells. Use of the polypeptide of the present invention enables improved efficiency of adenoviral vector-mediated gene transfer of any gene to undifferentiated blood cells, and there is provided a method of introducing any gene for which transient expression in these cells is desired. In particular, the method is useful for intracellular DNA recombination by transiently expressing site-specific recombinase, and for induction into any cells of different lines by transient expression of master genes.

Abstract: The use of recombinant adeno-associated virus (rAAV) virions for delivery of genes encoding angiogenic factors to muscle tissue is disclosed. The invention describes such methods of delivery and also describes methods for treating an ischemic condition such as myocardial ischemia. The methods include direct delivery of rAAV virions to a muscle via intramuscular injection and indirect delivery to a muscle via an injection into a blood vessel supplying blood to the muscle. The invention provides for sustained expression of the rAAV virion-delivered angiogenic factor gene or genes, which subsequently leads to a quantifiable therapeutic effect, namely an increase in new blood vessel formation resulting in an increase in blood flow to the ischemic muscle tissue.

Abstract: Compositions and methods for delivering GDNF to skeletal muscles to result in a therapeutic effect are disclosed. The compositions and methods use adeno-associated virus (AAV)-based gene delivery systems. The methods are useful for treating motoneuron diseases, such as amyotrophic lateral sclerosis (ALS).

Abstract: The present invention provides a method for transplanting lymphohematopoietic cells into a mammal, which comprises the step of injecting cells into a bone marrow cavity, and wherein the cells have an exogenous gene encoding a receptor that induces cell proliferation in response to ligand binding. By combining intra-bone marrow transplantation (iBMT) and selective amplifier gene (SAG), marrow conditioning before the injection of the cells can be omitted. The present invention further provides a bone marrow transplant and a kit for transplanting lymphohematopoietic cells into mammals. Furthermore, the invention provides an SAG particularly suitable for such transplantation.

Abstract: Compositions and methods for delivering GDNF to skeletal muscles to result in a therapeutic effect are disclosed. The compositions and methods use adeno-associated virus (AAV)-based gene delivery systems. The methods are useful for treating motoneuron diseases, such as amyotrophic lateral sclerosis (ALS).

Abstract: Methods for treating and/or preventing vascular disease are disclosed. The methods use gene delivery techniques to deliver nucleic acid molecules encoding anti-inflammatory cytokines to a subject.

Abstract: Disclosed is an expression control system with which any gene of interest can be transferred into mammalian cells to thereby change the nature thereof and the gene can be excised at any time by administering a low molecular weight compound to the cells. Specifically disclosed is a vector satisfying specific requirements when inserted into the genome of a mammalian cell.

Abstract: Methods for delivering a heterologous gene to a mammalian subject using recombinant adeno-associated virus (rAAV) virions are described. Recombinant AAV virions containing a heterologous gene encoding a metabolic protein are delivered to a mammalian subject having a metabolic disorder. The rAAV virion-delivered heterologous gene is expressed at a therapeutic level thereby ameliorating a sign or symptom of the metabolic disease. Exemplary examples of metabolic diseases are those caused by defects in aromatic amino acid metabolism. Exemplary examples of heterologous genes include those encoding an aromatic amino acid hydroxylase, aromatic amino acid decarboxylase, and enzymes involved in tetrahydrobiopterin synthesis. Methods for treating phenylketonuria are also described.

Abstract: Methods for delivering a heterologous gene to the periosteum or periosteal cells of a mammal by recombinant adeno-associated virus (rAAV) virions are described. The methods of the present invention are useful in the treatment of various skeletal disorders including degenerative diseases such as osteoarthritis and osteoporosis. The methods of the present invention are also useful in the treatment of inflammatory joint diseases such as rheumatoid arthritis. The heterologous gene can code for growth factors known to stimulate osteogenesis or chondrogenesis. Such growth factors include transforming growth factor-beta, insulin-like growth factor, fibroblast growth factor, and bone morphogenetic proteins. Alternatively, the heterologous gene can code for anti-inflammatory molecules such as tumor necrosis factor soluble receptor, interleukin-4, interleukin-10, and interleukin-13.

Abstract: Methods for treating and/or preventing vascular disease are disclosed. The methods use gene delivery techniques to deliver nucleic acid molecules encoding anti-inflammatory cytokines to a subject.

Abstract: Methods for delivering a heterologous gene to a mammalian subject using recombinant adeno-associated virus (rAAV) virions are described. Recombinant AAV virions containing a heterologous gene encoding a metabolic protein are delivered to a mammalian subject having a metabolic disorder. The rAAV virion-delivered heterologous gene is expressed at a therapeutic level thereby ameliorating a sign or symptom of the metabolic disease. Exemplary examples of metabolic diseases are those caused by defects in aromatic amino acid metabolism. Exemplary examples of heterologous genes include those encoding an aromatic amino acid hydroxylase, aromatic amino acid decarboxylase, and enzymes involved in tetrahydrobiopterin synthesis. Methods for treating phenylketonuria are also described.

Abstract: Selective amplification of cells is enabled by introducing into cells a gene encoding a fusion protein comprising (a) a ligand-binding domain, (b) a domain that associates when the ligand binds to the domain of (a), and (c) a domain that imparts proliferation activity to the cells upon the association and stimulating the cells with the ligand.

Abstract: Compositions and methods for delivering GDNF to skeletal muscles to result in a therapeutic effect are disclosed. The compositions and methods use adeno-associated virus (AAV)-based gene delivery systems. The methods are useful for treating motoneuron diseases, such as amyotrophic lateral sclerosis (ALS).

Abstract: The object of the present invention is to provide an agent for specific adsorption of type 5 adenoviral vector to undifferentiated blood cells which enables infection with a viral concentration that does not impart toxicity to undifferentiated blood cells, without requiring the construction of a new viral genome, or special modification of viral particles such as biotination, etc. The above objective has been achieved by providing a polypeptide which has affinity for both adenovirus and undifferentiated blood cells. Use of the polypeptide of the present invention enables improved efficiency of adenoviral vector-mediated gene transfer of any gene to undifferentiated blood cells, and there is provided a method of introducing any gene for which transient expression in these cells is desired. In particular, the method is useful for intracellular DNA recombination by transiently expressing site-specific recombinase, and for induction into any cells of different lines by transient expression of master genes.