Phenylalanine ammonia-lyase (PAL) variants with a greater phenylalanine-converting activity and/or a reduced immunogenicity as compared to a wild-type PAL for therapeutic uses, including the treatment of adolescent subjects having PKU.

Provided herein are phenylalanine ammonia-lyase (PAL) variants produced by prokaryotes, wherein such prokaryotic PAL variant has a greater phenylalanine-converting activity and/or a reduced immunogenicity as compared to a wild-type PAL. Further provided are compositions of prokaryotic PAL and biologically active fragments, mutants, variants or analogs thereof, as well as methods for the production, purification, formulation, and use of such compositions for industrial and therapeutic purposes, e.g., treating hyperphenylalaninemia, including phenylketonuria, and other disorders, including cancer.

Disclosed herein are synergistically effective combinations of Amino Acid Depletion Agents (AADA) and Amino Acid Depletion Agent Sensitizers (AADAS). Also disclosed are methods of using the disclosed combinations to treat subjects with a disease treatable by amino acid depletion-induced cell death (e.g. apoptosis). For example, the disclosed combinations are useful in the treatment or the manufacture of a medicament for use in the treatment of adult and pediatric cancers, in particular, acute lymphoblastic leukemia (ALL), as well as other conditions where amino acid depletion-induced apoptosis is expected to have a therapeutically useful effect. The synergistic combinations are also effective against solid tumors and lymphomas, including gastric cancer, pancreatic cancer, NK lymphoma, DLBCL, colorectal cancer, bladder cancer, hepatic cancer and glioblastoma.

Disclosed herein are synergistically effective combinations of Amino Acid Depletion Agents (AADA) and Amino Acid Depletion Agent Sensitizers (AADAS). Also disclosed are methods of using the disclosed combinations to treat subjects with a disease treatable by amino acid depletion-induced cell death (e.g. apoptosis). For example, the disclosed combinations are useful in the treatment or the manufacture of a medicament for use in the treatment of adult and pediatric cancers, in particular, acute lymphoblastic leukemia (ALL), as well as other conditions where amino acid depletion-induced apoptosis is expected to have a therapeutically useful effect. The synergistic combinations are also effective against solid tumors and lymphomas, including gastric cancer, pancreatic cancer, NK lymphoma, DLBCL, colorectal cancer, bladder cancer, hepatic cancer and glioblastoma.

Provided herein are improved compositions and methods for enzyme replacement therapy using modified human cystathionine beta synthase (CBS) in the treatment of homocystinuria and related diseases and disorders.

Provided herein are improved compositions and methods for enzyme replacement therapy using modified human cystathionine beta synthase (CBS) in the treatment of homocystinuria and related diseases and disorders.

The present invention provides a method of PEGylating a human truncated cystathionine β-synthase protein containing a mutation of a cysteine to a serine at amino acid position 15 (htCBS C15S). The htCBS C15S was PEGylated with one of 5 kDa, 10 kDa, or 20 kDa NHS ester PEG molecules. In-process monitoring of the PEGylation process was used in the method to reduce levels of unPEGylated htCBS C15S and htCBS C15S with insufficient PEGylation. Administration of the PEGylated htCBS C15S had efficacy throughout the course of treatment for homocystinuria.

The present invention provides a method of PEGylating a human truncated cystathionine β-synthase protein containing a mutation of a cysteine to a serine at amino acid position 15 (htCBS C15S). The htCBS C15S was PEGylated with one of 5 kDa, 10 kDa, or 20 kDa NHS ester PEG molecules. In-process monitoring of the PEGylation process was used in the method to reduce levels of unPEGylated htCBS C15S and htCBS C15S with insufficient PEGylation. Administration of the PEGylated htCBS C15S had efficacy throughout the course of treatment for homocystinuria.

The invention provides a composition for use as a medicament, comprising cells of a recombinant microorganism capable of producing increased amounts of one or more of 5-hydroxytryptophan (5-HTP), 5-hydroxytryptamine (5-HT) and tryptamine (TRM) as compared to the non-recombinant microorganism from which it was derived. The composition finds use in preventing and/or treating TRM-; 5-HTP-, or 5-HT-related disorders of the central nerve system (CNS); enteric nervous system (ENS); gastro intestine (GI) and metabolism in a mammal, and may be orally administered to a mammal in need thereof. Additionally, a composition comprising cells of a recombinant microorganism capable of producing melatonin is provided for use as a medicament, such as for treatment of depression, dementia, cancer and sleep disorder.

The invention provides a composition for use as a medicament, comprising cells of a recombinant microorganism capable of producing increased amounts of one or more of 5-hydroxytryptophan (5-HTP), 5-hydroxytryptamine (5-HT) and tryptamine (TRM) as compared to the non-recombinant microorganism from which it was derived. The composition finds use in preventing and/or treating TRM-; 5-HTP-, or 5-HT-related disorders of the central nerve system (CNS); enteric nervous system (ENS); gastro intestine (GI) and metabolism in a mammal, and may be orally administered to a mammal in need thereof. Additionally, a composition comprising cells of a recombinant microorganism capable of producing melatonin is provided for use as a medicament, such as for treatment of depression, dementia, cancer and sleep disorder.