The present disclosure relates to methods and compositions for elevating and stabilizing retromer for treating and/or preventing Alzheimer's disease and other neurodegenerative disorders. Additionally, the disclosure relates to adenoviral based therapy for treating Alzheimer's disease (AD), and other neurodegenerative conditions such as Parkinson's Disease (PD), neuronal ceroid lipofuscinosis (NCL), and transmissible spongiform encephalopathies (TSEs or prion disease), multiple system atrophy (MSA), Down's syndrome, and hereditary spastic paraplegia, as well as tauopathies such as progressive supranuclear palsy (PSP), frontotemporal lobar dementia linked to chromosome 17q21-22 and its subtypes (FTLD-17/FTLD-Tau), Lewy Body Disease (LBD), amyotrophic lateral sclerosis (ALS), frontal-temporal degeneration (FTD), ALS-FTD, and chronic traumatic encephalopathy (CTE).

A method for treating a subject having a medical condition associated with inflammation and/or an unwanted immune response without an alpha1-antitrypsin (AAT) deficiency, wherein the method comprises administering genetically modified mesenchymal stem cells to the subject, wherein said genetically modified mesenchymal stem cells comprise an exogenous nucleic acid comprising (i) an Alpha-1 antitrypsin (AAT) encoding region operably linked to (ii) a promoter or promoter/enhancer combination.

Nucleic acid regulatory elements that are able to enhance muscle-specific expression of genes, in particular expression in muscle cells and/or tissues such as in diaphragm, smooth muscle, heart and/or skeletal muscle, including at least two diaphragm-specific regulatory elements and a heart- and skeletal muscle-specific regulatory element. Expression cassettes and vectors containing these nucleic acid regulatory elements, as well as uses thereof such as applications using gene therapy of muscle-related disorders, more particularly diaphragm, heart and/or skeletal muscle-directed gene therapy, and for vaccination purposes.

Compositions and methods for the treatment of muscular dystrophies are provided.

Provided are improved compositions and methods for achieving gene therapy in hematopoietic cells and hematopoietic precursor cells, including erythrocytes, erythroid progenitors, and embryonic stem cells. Also provided are improved gene therapy methods for treating hematopoietic-related disorders. Retroviral gene therapy vectors that are optimized for erythroid specific expression and treatment of hemoglobinopathic conditions are disclosed.

The present invention relates to a gene therapy vector which is useful in the treatment or prevention of hypertrophic cardiomyopathy in a subject in need thereof. The gene therapy vector of the invention comprises a nucleic acid sequence encoding a cardiac sarcomeric protein and a cardiomyocyte-specific promoter which is operably linked to said nucleic acid sequence. The invention furthermore relates to a cell which comprises the gene therapy vector. Pharmaceutical compositions which comprise the gene therapy vector and/or a cell comprising said vector are also provided. In another aspect, the invention relates to a method for treating or preventing hypertrophic cardiomyopathy in a subject by introducing the gene therapy vector of the invention into a subject in need of treatment.

A recombinant vector having an expression cassette is provided which comprises a modified human low density lipoprotein receptor (hLDLR) gene is provided, wherein said hLDLR gene encodes a modified hLDLR comprising (a) one or more of the following amino acid substitutions: L318H, N295D, H306D, V307D, N309A, D310N, L318H, and/or L318D; or (b) an amino acid substitution of any of (a) in combination with one or more of the following amino acid substitutions: K796, K809R and/or C818A. Also provided are pharmaceutical compositions containing this vector and uses therefor in lowering cholesterol and/or treating familial hypercholesterolemia.

Regimens useful in reducing the frequency of apheresis in a human patient having familial hypercholesterolemia are described. The method involves administering to the human subject via a peripheral vein by infusion of a suspension of replication deficient recombinant adeno-associated virus (rAAV).

Oncolytic adenoviruses capable of selectively replicating in tumor cells deficient in p53 transcriptional activity are described. Recombinant adenovirus genomes that encode the p53-selective adenoviruses are also described. The recombinant adenoviruses and adenovirus genomes, or compositions thereof, can be used, for example, to reduce or inhibit tumor progression, or reduce tumor volume in a subject with a tumor having dysregulated p53 activity.

Recombinant adenovirus genomes that include a synthetic transcriptional circuit are described. Synthetic adenoviruses positively regulated using two-step transcriptional amplification (TSTA) are further described. Selection of the heterologous promoter is based on the desired replication characteristics of the synthetic virus. For example, the heterologous promoter can be a constitutive promoter, a tumor-specific promoter or a tissue-specific promoter.