Gene therapy for treating citrullenemia
Inventors
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Assignees
University of Pennsylvania Penn
Member
University of Pennsylvania (Penn)The University of Pennsylvania (Penn), founded in 1740 by Benjamin Franklin, is a world-renowned Ivy League institution located in Philadelphia. Penn is dedicated to advancing knowledge, fostering innovation, and making a positive impact locally and globally. With a strong commitment to interdisciplinary research, academic excellence, and community engagement, Penn offers a diverse and inclusive environment for students, faculty, and staff. The university is recognized for its leadership in research, robust financial aid programs, and a tradition of civic involvement. Penn's strategic initiatives, such as Penn Forward, focus on reshaping education, research, and service to meet the challenges of a rapidly changing world. The university is also a leader in sustainability, aiming for carbon neutrality by 2042 and net-zero endowment emissions by 2050, and is home to a vibrant ecosystem of innovation, global engagement, and community partnership.
The University of Pennsylvania (Penn), founded in 1740 by Benjamin Franklin, is a world-renowned Ivy League institution located in Philadelphia. Penn is dedicated to advancing knowledge, fostering innovation, and making a positive impact locally and globally. With a strong commitment to interdisciplinary research, academic excellence, and community engagement, Penn offers a diverse and inclusive environment for students, faculty, and staff. The university is recognized for its leadership in research, robust financial aid programs, and a tradition of civic involvement. Penn's strategic initiatives, such as Penn Forward, focus on reshaping education, research, and service to meet the challenges of a rapidly changing world. The university is also a leader in sustainability, aiming for carbon neutrality by 2042 and net-zero endowment emissions by 2050, and is home to a vibrant ecosystem of innovation, global engagement, and community partnership.
Publication Number
US-12385065-B2
Publication Date
2025-08-12
Expiration Date
Abstract
Compositions and regimens useful in treating type I citrullenemia are provided. The compositions include recombinant adeno-associated virus (rAAV) with a transthyretin enhancer and promoter driving expression of a human Argininosuccinate Synthase 1 (ASS1).
Core Innovation
Compositions and regimens useful in treating type I citrullenemia are provided. The compositions include recombinant adeno-associated virus (rAAV) with a transthyretin enhancer and promoter driving expression of a human Argininosuccinate Synthase 1 (ASS1).
Type I citrullenemia is an autosomal recessive disease caused by mutations in argininosuccinate synthase 1 (ASS1) enzyme that catalyzes the synthesis of argininosuccinate from citrulline and aspartate, resulting in citrullinemia and buildup of ammonia. The clinical spectrum of Type I citrullenemia ranges from severe neonatal onset form to milder late-onset forms, and existing treatments including dietary restriction, nitrogen scavenger therapy, carnitine, arginine supplementation, and liver transplantation have limitations; liver-directed gene therapy did not fully correct the biochemical phenotype of systemic ASS1 deficiency in a murine model.
The embodiments relate to an AAV gene therapy vector for delivering normal human Argininosuccinate Synthase 1 (ASS1) to a subject in need thereof following intravenous administration, resulting in long-term, perhaps 10 years or more, of clinically meaningful correction of Type I citrullenemia. The recombinant AAV vector should have a tropism for the liver (e.g., an rAAV bearing an AAV8 capsid), and the hASS1 transgene should be controlled by liver-specific expression control elements which may include an enhancer, a promoter, an intron, a WPRE, and a polyA signal; the hASS1 coding sequence is disclosed (SEQ ID NO: 3) and an engineered codon optimized sequence is disclosed (SEQ ID NO: 2).
Claims Coverage
The independent claims define three inventive features directed to (1) a recombinant AAV comprising an expression cassette encoding human ASS1 comprising SEQ ID NO: 2, (2) a recombinant AAV genome flanked by AAV ITR sequences encoding human ASS1 comprising SEQ ID NO: 2, and (3) a plasmid comprising an expression cassette encoding human ASS1 comprising SEQ ID NO: 2.
Recombinant AAV comprising a SEQ ID NO: 2 human ASS1 transgene
A recombinant adeno-associated virus (AAV) comprising an AAV capsid, and a vector genome packaged therein, the vector genome comprising an expression cassette comprising a promoter operably linked to a nucleotide sequence encoding a human argininosuccinate synthase 1 (ASS1); wherein the nucleotide sequence encoding the human ASS1 comprises SEQ ID NO: 2.
Recombinant AAV genome flanked by AAV ITRs encoding SEQ ID NO: 2 ASS1
A recombinant adeno-associated virus (AAV) comprising an AAV capsid, and a vector genome packaged therein, the vector genome comprising: (a) an AAV 5′ ITR sequence; (b) a nucleotide sequence encoding a human argininosuccinate synthase 1(ASS1); and (c) an AAV 3′ ITR sequence, wherein the nucleotide sequence encoding the human ASS1 comprises SEQ ID NO: 2.
Plasmid comprising an expression cassette encoding SEQ ID NO: 2 ASS1
A plasmid comprising an expression cassette, the expression cassette comprising a promoter operably linked to a nucleotide sequence encoding a human argininosuccinate synthase 1 (ASS1), wherein the nucleotide sequence encoding the human ASS1 comprises SEQ ID NO: 2.
The independent claims focus on delivery and genetic constructs encoding human ASS1 comprising SEQ ID NO: 2, encompassing recombinant AAV particles (with capsid and packaged vector genome), vector genomes flanked by AAV ITR sequences, and plasmid expression cassettes driving SEQ ID NO: 2 ASS1 expression.
Stated Advantages
Long-term, perhaps 10 years or more, of clinically meaningful correction of Type I citrullenemia.
Delivery of ASS1 which results in near normal citrulline, glutamine and ammonia plasma levels.
Any reduction in citrulline, glutamine, and/or ammonia levels is desirable as a clinical endpoint.
Other suitable clinical outcomes may include reduction in the use of scavenger, less restrictive diet or no need for liver transplant.
Documented Applications
Use of a replication deficient adeno-associated virus (AAV) to deliver a human Argininosuccinate Synthase 1 (hASS1) gene to liver cells of patients diagnosed with type I citrullenemia (CTLN1).
An aqueous suspension suitable for administration to a CTLN1 patient which includes the rAAV described herein, the suspension being suitable for intravenous injection.
A method of treating a patient having CTLN1 with an rAAV as described herein, including treatment of patients with moderate to severe Type I citrullenemia, including the acute neonatal form, a milder late-onset form, or the form in which women have onset of severe symptoms during pregnancy or post-partum.
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