Composition and methods for treatment of ornithine transcarbamylase deficiency
The present invention provides, among other things, methods of treating ornithine transcarbamylase deficiency, including administering to a subject in need of treatment a composition comprising an mRNA encoding an ornithine transcarbamylase protein at a low dose and at an administration interval such that at least one symptom or feature of the OTC deficiency is reduced.
1. A method of treating OTC deficiency in a human comprising:
administering a pharmaceutical composition comprising an mRNA encoding an ornithine transcarbamylase (OTC) protein at a therapeutic low dose of 0.5 mg/kg or less of mRNA and at a dosing interval of once every two weeks or a longer dosing interval, thereby to reduce an ammonia level relative to a control level prior to the treatment for the period of the dosing interval or longer, wherein the mRNA encoding the OTC protein is codon optimized and comprises a polynucleotide sequence at least 90% identical to SEQ ID NO: 3, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 9, or SEQ ID NO: 10,
wherein the mRNA is encapsulated within a liposome.
2. The method of claim 1 , wherein the therapeutic low dose is sufficient to maintain the reduced ammonia level in a tissue or a body fluid of the human for the period of the dosing interval or longer.
3. The method of claim 1 , wherein the administering the pharmaceutical composition increases a plasma citrulline level relative to the baseline level prior to the treatment.
4. The method of claim 1 , wherein the administering the pharmaceutical composition reduces a plasma glutamate level relative to the baseline level prior to the treatment.