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US 2025/0043310 A1Published application
Gene therapy of hemophilia a using viral vectors encoding recombinant fviii variants with increased expression
AssigneeTakeda Pharmaceutical Company Limited
InventorsHanspeter Rottensteiner, Werner Hoellriegl
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Abstract
The present disclosure provides, among other aspects, codon-altered polynucleotides encoding Factor VIII variants for expression in mammalian cells. In some embodiments, the disclosure also provides mammalian gene therapy vectors and methods for treating hemophilia A. In some embodiments, the present disclosure provides methods for dosing a hemophilia A patient with a polynucleotide, e.g., a codon-altered polynucleotide, encoding a Factor VII polypeptide.
Claims41
A method for treating hemophilia A comprising intravenously infusing, to a human subject diagnosed with hemophilia A, a dose of 2×1012 adeno-associated virus (AAV) particles per kilogram body weight of the human subject, wherein the AAV particles comprise a polynucleotide comprising a nucleic acid sequence of SEQ ID NO:
- 1 (CS04-FL-NA).
A method for treating hemophilia A comprising intravenously infusing, to a human subject diagnosed with hemophilia A, a dose of 6×1012 adeno-associated virus (AAV) particles per kilogram body weight of the human subject, wherein the AAV particles comprise a polynucleotide comprising a nucleic acid sequence of SEQ ID NO:
- 1 (CS04-FL-NA).
A method comprising:
- determining a first level of Factor VIII activity in a blood sample collected from a human subject diagnosed with Hemophilia A following administration of adeno-associated virus (AAV) particles comprising a polynucleotide encoding a Factor VIII protein to the human subject, and while the human subject is receiving an initial course of glucocorticoid steroid treatment;
- determining a second level of Factor VIII activity in a blood sample collected from the human subject after completion of the initial course of glucocorticoid steroid treatment;
- comparing the second level of Factor VIII activity to the first level of Factor VIII activity;
- and
- administering a tapering dose of the glucocorticoid steroid, wherein:
- when the second level of Factor VIII activity is not less than the first level of Factor VIII activity, a first tapering dose of the glucocorticoid steroid is administered over a time period of no more than three weeks;
- and
- when the second level of Factor VIII activity is less than the first level of Factor VIII activity, a second tapering dose of the glucocorticoid steroid is administered over a time period exceeding three weeks.
5 more elements
A method comprising:
- determining a first level of liver enzyme activity in a blood sample collected from a human subject diagnosed with Hemophilia A prior to administration of adeno-associated virus (AAV) particles comprising a polynucleotide encoding a Factor VIII protein to the human subject;
- determining a second level of liver enzyme activity in a blood sample collected from the human subject after administration of AAV particles comprising a polynucleotide encoding a Factor VIII protein to the human, and after completion of an initial course of glucocorticoid steroid treatment;
- comparing the second level of liver enzyme activity to the first level of liver enzyme activity;
- and
- administering a tapering dose of the glucocorticoid steroid, wherein:
- when the second level of liver enzyme activity is not more than the first level of liver enzyme activity, a first tapering dose of the glucocorticoid steroid is administered over a time period of no more than three weeks;
- and
- when the second level of liver enzyme activity is greater than the first level of Factor VIII activity, a second tapering dose of the glucocorticoid steroid is administered over a time period exceeding three weeks.
5 more elements
A method for monitoring the efficacy of Factor VIII gene therapy of hemophilia A using adeno-associated virus (AAV) particles comprising a polynucleotide encoding a Factor VIII polypeptide, the method comprising:
- determining whether Factor VIII inhibitor antibodies are present in a blood sample collected from the human subject after administration of the AAV particles to the human subject;
- and
- upon detecting the presence of a Factor VIII inhibitor in the blood of the human subject, administering an alternative agent for treatment of hemophilia A to the human subject.
A method comprising:
- a) administering to a hemophilia A patient a dose of 2×1012 adeno-associated virus (AAV) particles per kilogram body weight of said patient, wherein the AAV particles comprise a polynucleotide comprising a nucleic acid sequence of SEQ ID NO:
- 1 (CS04-FL-NA) at a first time point;
- and
- b) measuring the level of SEQ ID NO:
- 1 or a fragment thereof in said patient's blood stream at a later time point, wherein said later time point is 7 days or longer.
2 more elements
A method comprising:
- a) administering to a hemophilia A patient a dose of 6×1012 adeno-associated virus (AAV) particles per kilogram body weight of said patient, wherein the AAV particles comprise a polynucleotide comprising a nucleic acid sequence of SEQ ID NO:
- 1 (CS04-FL-NA) at a first time point;
- and
- b) measuring the level of SEQ ID NO:
- 1 or a fragment thereof in said patient's blood stream at a later time point, wherein said later time point is 7 days or longer.
2 more elements
A method comprising:
- a) administering to a hemophilia A patient a dose of adeno-associated virus (AAV) particles, wherein the AAV particles comprise a polynucleotide encoding a Factor VIII protein at a first time point;
- and
- b) measuring the level of polynucleotide encoding the Factor VIII protein or a fragment thereof in said patient's blood stream at a later time point, wherein said later time point is 7 days or longer.
A method comprising:
- a) administering to a hemophilia A patient a dose of 2×1012 adeno-associated virus (AAV) particles per kilogram body weight of said patient, wherein the AAV particles comprise a capsid protein and a polynucleotide comprising a nucleic acid sequence of SEQ ID NO:
- 1 (CS04-FL-NA) at a first time point;
- and
- b) measuring the level of said capsid protein in said patient's blood stream at a later time point, wherein said later time point is 7 days or longer.
1 more element
A method comprising:
- a) administering to a hemophilia A patient a dose of 6×1012 adeno-associated virus (AAV) particles per kilogram body weight of said patient, wherein the AAV particles comprise a capsid protein and a polynucleotide comprising a nucleic acid sequence of SEQ ID NO:
- 1 (CS04-FL-NA) at a first time point;
- and
- b) measuring the level of said capsid protein in said patient's blood stream at a later time point, wherein said later time point is 7 days or longer.
1 more element
A method comprising:
- a) administering to a hemophilia A patient a dose of adeno-associated virus (AAV) particles, wherein the AAV particles comprise a capsid protein and a polynucleotide encoding a Factor VIII protein at a first time point;
- and
- b) measuring the level of said capsid protein in said patient's blood stream at a later time point, wherein said later time point is 7 days or longer.
A method comprising:
- a) administering to a hemophilia A patient a dose of 2×1012 adeno-associated virus (AAV) particles per kilogram body weight of said patient, wherein the AAV particles comprise a polynucleotide comprising a nucleic acid sequence of SEQ ID NO:
- 1 (CS04-FL-NA) at a first time point;
- and
- b) measuring the level of anti-Factor VIII antibodies in said patient's blood stream at a later time point, wherein said later time point is 7 days or longer.
1 more element
A method comprising:
- a) administering to a hemophilia A patient a dose of 6×1012 adeno-associated virus (AAV) particles per kilogram body weight of said patient, wherein the AAV particles comprise a polynucleotide comprising a nucleic acid sequence of SEQ ID NO:
- 1 (CS04-FL-NA) at a first time point;
- and
- b) measuring the level of anti-Factor VIII antibodies in said patient's blood stream at a later time point, wherein said later time point is 7 days or longer.
1 more element
A method comprising:
- a) administering to a hemophilia A patient a dose of adeno-associated virus (AAV) particles, wherein the AAV particles comprise a polynucleotide encoding a Factor VIII protein at a first time point;
- and
- b) measuring the level of anti-Factor VIII antibodies in said patient's blood stream at a later time point, wherein said later time point is 7 days or longer.
32 A method according to any one of claims 29 to 31, wherein said later time point is at 7 days.
A method comprising:
- a) administering to a hemophilia A patient a dose of 2×1012 adeno-associated virus (AAV) particles per kilogram body weight of said patient, wherein the AAV particles comprise a capsid protein and a polynucleotide comprising a nucleic acid sequence of SEQ ID NO:
- 1 (CS04-FL-NA) at a first time point;
- and
- b) measuring the level of anti-capsid protein antibodies in said patient's blood stream at a later time point, wherein said later time point is 7 days or longer.
1 more element
A method comprising:
- a) administering to a hemophilia A patient a dose of 6×1012 adeno-associated virus (AAV) particles per kilogram body weight of said patient, wherein the AAV particles comprise a capsid protein and a polynucleotide comprising a nucleic acid sequence of SEQ ID NO:
- 1 (CS04-FL-NA) at a first time point;
- and
- b) measuring the level of anti-capsid protein antibodies in said patient's blood stream at a later time point, wherein said later time point is 7 days or longer.
1 more element
A method comprising:
- a) administering to a hemophilia A patient a dose of adeno-associated virus (AAV) particles, wherein the AAV particles comprise a capsid protein and a polynucleotide encoding a Factor VIII protein at a first time point;
- and
- b) measuring the level of anti-capsid protein antibodies in said patient's blood stream at a later time point, wherein said later time point is 7 days or longer.
Dependencies are inferred from the claim text.