Recombinant bacteria expressing phenylalanine ammonia lyase, phenylalanine transporter and l-amino acid deaminase for reducing hyperphenylalaninemia
AssigneeSynlogic Operating Company, Inc.
InventorsAoife Brennan, Caroline Kurtz, Marja Puurunen, Neal Sondheimer
Life of this patent
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Abstract
Methods of modulating and treating diseases associated with hyperphenylalaniemia are disclosed.
Claims61
A method of reducing phenylalanine in a subject, comprising administering to the subject a genetically engineered bacterium comprising:
- a. one or more heterologous gene(s) encoding a phenylalanine ammonia lyase (PAL),
- b. one or more heterologous gene(s) encoding a phenylalanine transporter, and
- c. one or more heterologous gene(s) encoding a L-amino acid deaminase (LAAD),
- wherein the subject achieves a reduction in a phenylalanine level after administration as compared to a baseline level of phenylalanine in the subject before administration.
A method of reducing hyperphenylalaninemia in a subject, comprising administering to the subject a genetically engineered bacterium comprising:
- a. one or more heterologous gene(s) encoding a phenylalanine ammonia lyase (PAL),
- b. one or more heterologous gene(s) encoding a phenylalanine transporter, and
- c. one or more heterologous gene(s) encoding a L-amino acid deaminase (LAAD),
- wherein the subject achieves a reduction in a phenylalanine level after administration as compared to a baseline level of phenylalanine in the subject before administration.
A method of treating phenylketonuria in a subject, comprising administering to the subject a genetically engineered bacterium comprising:
- a. one or more heterologous gene(s) encoding a phenylalanine ammonia lyase (PAL),
- b. one or more heterologous gene(s) encoding a phenylalanine transporter, and
- c. one or more heterologous gene(s) encoding a L-amino acid deaminase (LAAD),
- wherein the subject achieves a reduction in a phenylalanine level after administration as compared to a baseline level of phenylalanine in the subject before administration.
The method of any one of the preceding claims, further comprising administering to the subject an additional blood phenylalanine (Phe) level management regimen.
The method of any one of the preceding claims, wherein the subject is on a Phe-restricted diet.
The method of any one of the preceding claims, wherein the subject achieves at least a 20% reduction in the level of phenylalanine after administration of the genetically engineered bacterium, or a formulation comprising the genetically engineered bacterium, as compared to the baseline level of phenylalanine.
The method of any one of the preceding claims, wherein the subject achieves at least a 30% reduction in the phenylalanine level after administration of the genetically engineered bacterium, or a formulation comprising the genetically engineered bacterium, as compared to the baseline level of phenylalanine.
The method of any one of the preceding claims, wherein the subject achieves at least a 40% reduction in the phenylalanine level after administration of the genetically engineered bacterium, or a formulation comprising the genetically engineered bacterium, as compared to the baseline level of phenylalanine.
The method of any one of the preceding claims, wherein the baseline level of phenylalanine in the blood or plasma is ≥600 μmol/L prior to administration of the genetically engineered bacterium, or a formulation comprising the genetically engineered bacterium, and achieves a blood or plasma Phe level≤600 μmol/L after administration of the genetically engineered bacterium, or formulation comprising the genetically engineered bacterium.
The method of any one of the preceding claims, wherein the baseline level of phenylalanine in the blood or plasma is ≥600 μmol/L prior to administration of the genetically engineered bacterium, or a formulation comprising the genetically engineered bacterium, and achieves a blood or plasma Phe level≤360 μmol/L after administration of the genetically engineered bacterium, or formulation comprising the genetically engineered bacterium.
The method of any one of the preceding claims, wherein the baseline level of Phe in the blood or plasma is ≥600 μmol/L prior to administration of the genetically engineered bacterium, or a formulation comprising the genetically engineered bacterium, and achieves a blood or plasma Phe level≤240 μmol/L after administration of the genetically engineered bacterium, or formulation comprising the genetically engineered bacterium.
The method of any one of the preceding claims, wherein the baseline level of Phe in the blood or plasma is >360 μmol/L prior to administration of the genetically engineered bacterium, or a formulation comprising the genetically engineered bacterium, and achieves a blood or plasma Phe level≤360 μmol/L after administration of the genetically engineered bacterium, or formulation comprising the genetically engineered bacterium.
The method of any one of the preceding claims, wherein the baseline level of Phe in blood or plasma is >360 μmol/L prior to administration of the genetically engineered bacterium, or a formulation comprising the genetically engineered bacterium, and achieves a blood or plasma Phe level≤240 μmol/L after administration of the genetically engineered bacterium, or formulation comprising the genetically engineered bacterium.
The method of any one of the previous claims, further comprising measuring the baseline level of phenylalanine in blood or plasma of the subject, and selecting the subject for treatment when the baseline level is equal to or greater than 600 μmol/L, 360 μmol/L μmol/L or 240 μmol/L.
The method of any one of the previous claims, further comprising measuring the phenylalanine level in the blood or plasma of the subject post administration, wherein a decrease of at least 20% as compared to the baseline level indicates that the treatment is effective.
The method of any one of the previous claims, comprising:
- (i) measuring the baseline level of phenylalanine in blood or plasma of the subject, and selecting the subject for treatment when the baseline level is equal to or greater than 600 μmol/L, 360 μmol/L μmol/L or 240 μmol/L:
- (ii) administering the genetically engineered bacterium to the subject for a first dosing interval of 21 days:
- a. at a dose of about 1×1011 cells once per day for days 1-3;
- b. at a dose of about 1×1011 cells twice per day for days 4-6;
- c. at a dose of about 1×1011 cells three times per day for days 7-9;
- d. at a dose of about 3×1011 cells once per day for days 10-11;
- e. at a dose of about 3×1011 cells twice per day for days 12-14;
- and
- f. at a dose of about 3×1011 cells three times per day for days 15-21,
- as determined by live cell counting;
- (iii) measuring the phenylalanine level in the blood or plasma of the subject after day 21 of administration;
- (iv) determining whether there was at least a 20% reduction in the phenylalanine level in the blood or plasma of the subject after day 21 of administration in step (iii) with the baseline level of phenylalanine in step (i);
- (v) selecting the subject for further treatment with the genetically engineered bacterium once at least a 20% reduction in the phenylalanine level in the blood or plasma of the subject after administration as compared to the baseline level is achieved, and
- (vi) optionally further treating the patient with the genetically engineered bacterium.
Dependencies are inferred from the claim text.