Compositions comprising TALENs and methods of treating HIV
Inventors
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Assignees
Member
University of Nevada, Las VegasThe University of Nevada, Las Vegas is a public research university offering comprehensive undergraduate, graduate, and professional programs. The institution is recognized for research initiatives, interdisciplinary curriculum, community partnerships, and diverse student support. UNLV provides resources spanning financial assistance, technology, career development, outreach, and research, advancing individual achievement and community engagement in a multicultural environment.
The University of Nevada, Las Vegas is a public research university offering comprehensive undergraduate, graduate, and professional programs. The institution is recognized for research initiatives, interdisciplinary curriculum, community partnerships, and diverse student support. UNLV provides resources spanning financial assistance, technology, career development, outreach, and research, advancing individual achievement and community engagement in a multicultural environment.
Publication Number
US-11046959-B2
Publication Date
2021-06-29
Expiration Date
Abstract
Disclosed herein, are compositions and methods for the treatment of human immunodeficiency virus infection. The compositions comprise engineered transcription activator like effector nucleases (TALENs) comprising a TALE DNA binding domain flanked by two spacer sequences, and a Fokl nuclease catalytic domain. Also, described herein, are methods of using TALENs to cleave nucleic acids; and methods of administering the TALENs to subjects at risk for or having an HIV infection.
Core Innovation
The patent describes engineered transcription activator like effector nucleases (TALENs) that comprise, from the N-terminus to the C-terminus, a first spacer sequence, a TALE DNA binding domain, a second spacer sequence, and a FokI nuclease catalytic domain fused to the C-terminus. The TALE DNA binding domain is made of TAL repeats and includes a C-terminal truncated TAL repeat, and is specific for binding to a nucleic acid sequence having at least 90% identity to a sequence of SEQ ID NOs: 4, 5, 6 or 7.
The TALENs further include TALE DNA binding domains with TAL repeat variants and spacer targeting, and the FokI nuclease catalytic domain is described as fused at the C-terminus. The FokI nuclease catalytic domain includes obligate heterodimer and homodimer forms, and FokI variant mutation options.
In addition to the engineered TALEN compositions, the patent discloses nucleic acid and vector/pharmaceutical compositions encoding the TALENs and methods for inactivating integrated retroviral (HIV) genomes in mammalian cells. The disclosed treatment and prevention methods include administering compositions to subjects at risk or infected, and the target is described as integrated HIV proviral DNA in mammalian cells, with target regions including HIV-1 TAR and 5′ and 3′ LTR target sites.
Claims Coverage
The partial claim set includes one independent claim. The independent claim is directed to an engineered TALEN structural composition with a specific nucleic acid binding specificity, and dependent claims further refine the inventive features by imposing additional identity, repeat architecture, and nuclease catalytic domain constraints, as well as additional claims directed to encoding and mammalian-cell genome cleavage using paired TALENs.
Engineered TALEN with N- to C-terminal spacer architecture
An engineered TALEN transcription activator like effector nuclease comprising from the N-terminus to the C-terminus a first spacer sequence, a TALE DNA binding domain, a second spacer sequence, and a FokI nuclease catalytic domain fused to the C-terminus.
C-terminal truncated TAL repeat in TALE DNA binding domain
The TALE DNA binding domain comprises TAL repeats and comprises a C-terminal truncated TAL repeat.
High-identity TALE binding specificity to SEQ ID NOs
The TALE DNA binding domain is specific for binding to a nucleic acid sequence having at least 90% identity to a sequence of SEQ ID NOs: 4, 5, 6 or 7.
Optional refinement by increased identity threshold
The TALE DNA binding domain is specific for binding to a nucleic acid sequence having at least 95% identity to a nucleic acid sequence of SEQ ID NOs: 4, 5, 6 or 7.
Defined TALE repeat count
The TALE DNA binding domain comprises 20 TAL repeats.
Defined repeat-variable di-residue composition
At least one TAL repeat has a repeat-variable diresidue (RVD) of NS.
Restricted FokI nuclease catalytic domain sequence options
The FokI nuclease catalytic domain has the sequence of SEQ ID NO: 13 or SEQ ID NO: 14.
Overall, the claim coverage centers on an engineered TALEN composition defined by N- to C-terminal spacer architecture, a TALE DNA binding domain with TAL repeats including a C-terminal truncated TAL repeat, and binding specificity to nucleic acid sequences with at least 90% identity to SEQ ID NOs: 4, 5, 6 or 7, with dependent refinements including higher identity thresholds, specific TAL repeat architecture, and restricted FokI nuclease catalytic domain sequence options.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treatment and prevention methods for HIV infection, including administering compositions to subjects at risk or infected.
Inactivation of integrated retroviral (HIV) genomes in mammalian cells by cleaving integrated HIV proviral DNA.
Cleavage of target nucleic acid sequences in a mammalian cell genome by introducing mRNAs encoding a pair of TALENs with different FokI nuclease catalytic domains.
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