The present disclosure provides messenger RNAs (mRNAs) having chemical and/or structural modifications, including RNA elements and/or modified nucleotides, which provide desirable regulation of mRNA localization, stability, and/or translation to yield increased mRNA expression and activity of an encoded polypeptide.

Methods and compositions for producing heme and treating sideroblastic anemia are disclosed.

The present invention relates to polynucleotides comprising a Factor IX nucleotide sequence, wherein the Factor IX nucleotide sequence comprises a coding sequence that encodes a Factor IX protein or fragment thereof and wherein a portion of the coding sequence is not wild type. The present invention further relates to viral particles comprising a recombinant genome comprising the polynucleotide of the invention, compositions comprising the polynucleotides or viral particles, and methods and uses of the polynucleotides, viral particles or compositions.

The present invention provides gene editing systems comprising gene editing dimerization switches comprising a first and second gene editing switch domain that allow for the regulation of a gene editing function by the introduction, e.g., administration, of a gene editing dimerization molecule having the ability to bring together a first gene editing switch domain and a second gene editing switch domain. A regulated gene editing function provides, e.g., less off-target side effects, and increases the therapeutic window.

The present invention also provides improved FKBP/FRB-based dimerization switches wherein the FRB switch domain or the FKBP switch domain, or both the FRB and FKBP switch domains, comprise one or more mutations that optimize performance, e.g., that alter, e.g., enhance the formation of a complex between the first switch domain, the second switch domain, and the dimerization molecule, rapamycin, or a rapalog, e.g., RAD001.

In certain embodiments a lentiviral vector for the treatment of X-linked chronic granulomatous disease (X-CGD) is provided. In certain embodiments the vector comprises an expression cassette comprising a nucleic acid construct comprising a CYBB promoter or effective fragment thereof; and a nucleic acid that encodes gp91.sup.phox operably linked to the CYBB promoter or promoter fragment.

The present invention provides a synthetic MMACHC polynucleotide comprising a polynucleotide encoding MMACHC that is codon-optimized for expression in a human. Also provided is a polypeptide encoded by a synthetic MMACHC polynucleotide, an expression vector comprising a MMACHC gene sequence under the control of a chicken beta actin (CBA) promoter, and an expression vector comprising a synthetic MMACHC polynucleotide. Methods of treating cobalamin C deficiency and for detecting or tracking exogenous MMACHC are also provided.

The present invention relates to a DNA construct encoding one or more human IGF-1 isoforms that can be used for treatment of neuropathy. Further provided herein are a pharmaceutical composition including the DNA construct as an active ingredient and a method of administering the DNA construct for treatment of neuropathy. The present invention provides a safe and effective way of treating neuropathic patients.

Disclosed herein are methods and compositions for inactivating TCR and/or HLA genes, using engineered nucleases comprising at least one DNA binding domain and a cleavage domain or cleavage half-domain in conditions able to preserve cell viability. Polynucleotides encoding nucleases, vectors comprising polynucleotides encoding nucleases and cells comprising polynucleotides encoding nucleases and/or cells comprising nucleases are also provided.

Described herein are compositions and methods for treating a subject having or at risk of developing Crohn's disease. Using the compositions and methods of the disclosure, a patient, such as an adult human patient, may be provided one or more agents that elevate the expression and/or activity levels of Nucleotide-binding oligomerization domain-containing protein 2 (NOD2). Exemplary agents that may be used in conjunction with the compositions and methods of the disclosure for this purpose include cells, such as pluripotent cells, that express NOD2.

Provided herein, in some aspects, are tools (e.g., methods, compositions and nucleic acids) for building genetic circuits in Bacteroides and Parabacteroides bacteria, as well as the bacteria containing the genetic circuits.