The disclosure provides compositions and methods useful for the depletion of a specific population of endogenous hematopoietic stem cells and/or immune cells from a subject prior to transplantation with genetically modified stem cells to improve the engraftment of the transplanted stem cells and provide gene therapy. The disclosure provides compositions and methods for the treatment of various hematopoietic diseases, metabolic disorders, cancers, and autoimmune diseases, among others. Described herein are antibodies, antigen-binding fragments, and conjugates thereof that can be applied to effect the treatment of these conditions, for instance, by depleting a population of CD117+ or CD45+ cells in a patient, such as a human.

Provided are nucleic acid constructs, Toxoplasma comprising same, pharmaceutical compositions comprising same and methods using same for delivering a protein-of-interest to a tissue-of-interest of a subject, such as the CNS and further treating a pathology which is treatable by administration of a therapeutic polypeptide in a central nervous system of the subject.

Provided herein are methods for the treatment of lysosomal storage disease comprising administration of genes encoding for a lysosomal enzyme and a pharmaceutical agent. Combining gene therapy with pharmaceutical compositions by co-administration not only further enhances the effects of each individual therapy, but also provides a multi-faceted approach to treatment because of the varying mechanism of action of each individual composition.

The present invention provides, among other things, compositions and methods for CNS delivery of lysosomal enzymes for effective treatment of lysosomal storage diseases. In some embodiments, the present invention includes a stable formulation for direct CNS intrathecal administration comprising a heparan N-sulfatase (HNS) protein, salt, and a polysorbate surfactant for the treatment of Sanfilippo Syndrome Type A.

Among other things, the present invention provides methods and compositions of treating Sanfilippo syndrome type B (Sanfilippo B) by, e.g., intrathecal (IT) administration of a Naglu protein. A suitable Naglu protein can be a recombinant, gene-activated or natural protein. In some embodiments, a suitable Naglu protein is a recombinant Naglu protein. In some embodiments, a recombinant Naglu protein is a fusion protein containing a Naglu domain and a lysosomal targeting moiety. In some embodiments, the lysosomal targeting domain is an IGF-II moiety.

A composition formulated for intrathecal delivery of a recombinant adeno-associated virus (rAAV) vector comprising an AAVhu68 capsid carrying a human galactosylceramidase (GALC) gene for administration to Krabbe patients is provided. Also provided are novel gene sequences and uses thereof.

The invention provides compositions and methods for the treatment of lysosomal storage diseases such as metachromatic leukodystrophy and related disorders. A significant unmet clinical need still exists with the current clinical lentiviral vectors due to the high integration requirement and currently insufficient levels of ARSA expression to correct onset of early symptomatic disease. Methods and compositions for producing a protein such as sulfatase and for treating a disease or disorder such as metachromatic leukodystrophy and related disorders are disclosed.

The invention relates to virus like particles (VLP) associated with an enzyme abnormally expressed in particular leukodystrophies or an expression vector encoding the enzyme or an mRNA encoding the enzyme or a combination thereof which are used in a method for the treatment of the particular leukodystrophies in a subject in the need thereof, preferably a human. The invention also relates to a pharmaceutical composition for use in a method for the treatment of the particular leukodystrophies, to an expression vector encoding the abnormally expressed enzyme and to a method of associating a VLP with the enzyme, an expression vector encoding the enzyme or an mRNA encoding the enzyme or a combination thereof.

The present invention provides, among other things, compositions and methods for CNS delivery of lysosomal enzymes for effective treatment of lysosomal storage diseases. In some embodiments, the present invention includes a stable formulation for direct CNS intrathecal administration comprising an iduronate-2-sulfatase (I2S) protein, salt, and a polysorbate surfactant for the treatment of Hunters Syndrome.

The present invention provides an effective and less invasive approach for direct delivery of therapeutic agents to the central nervous system (CNS). In some embodiments, the present invention provides methods including a step of administering intrathecally to a subject suffering from or susceptible to a lysosomal storage disease associated with reduced level or activity of a lysosomal enzyme, a composition comprising a replacement enzyme for the lysosomal enzyme.