RP2 and RPGR vectors for treating X-linked retinitis pigmentosa
Inventors
Wu, Zhijian • Swaroop, Anand • MOOKHERJEE, Suddhasil • HIRIYANNA, Suja
Assignees
US Department of Health and Human Services
Publication Number
US-10646588-B2
Publication Date
2020-05-12
Expiration Date
2036-03-11
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Disclosed are adeno-associated virus (AAV) vectors comprising a nucleotide sequence encoding RP2 or RPGR-ORF15 and related pharmaceutical compositions. Also disclosed are methods of treating or preventing X-linked retinitis pigmentosa, increasing photoreceptor number in a retina of a mammal, and increasing visual acuity of a mammal using the vectors and pharmaceutical compositions.
Core Innovation
The invention provides adeno-associated virus (AAV) vectors comprising nucleotide sequences encoding RP2 or RPGR-ORF15 proteins or their functional fragments or variants and related pharmaceutical compositions. These vectors include regulatory sequences such as a human rhodopsin kinase promoter, CMV/human β-globin intron, and a human β-globin polyadenylation signal, flanked by AAV2 inverted terminal repeats (ITRs). The vectors are capable of expressing full-length or functional forms of RP2 and RPGR-ORF15 proteins in photoreceptor cells, localized appropriately to connect cilia, and can be packaged into various AAV serotypes, preferably AAV8 or AAV9.
The invention addresses the lack of effective treatment for X-linked retinitis pigmentosa (XLRP), a hereditary retinal dystrophy characterized by progressive loss of photoreceptor cells leading to vision impairment or blindness. Mutations in RP2 and RPGR genes account for a significant proportion of XLRP cases, with RP2 mutations in approximately 15% and RPGR mutations in approximately 75% of patients. There exists a need for compositions and methods to treat or prevent XLRP by restoring or preserving photoreceptor function and viability.
The inventive vectors and pharmaceutical compositions mediate expression of RP2 or RPGR-ORF15 proteins in vivo, resulting in preserved photoreceptor function and structure in animal models. The methods of administration include subretinal delivery to effect treatment or prevention of XLRP, increase photoreceptor number, improve visual acuity, decrease retinal detachment, increase electrical response of photoreceptors, and increase protein expression and localization within the retina. The invention also encompasses methods of making the vectors and dosing regimens.
Claims Coverage
The claims describe three independent AAV vector claims directed to RP2-encoding vectors with specific regulatory elements, and associated methods of use and pharmaceutical compositions. The main inventive features encompass vector composition, regulatory control, packaging, and therapeutic applications.
AAV vector composition encoding RP2 under rhodopsin kinase promoter control
An AAV vector comprising a nucleic acid with a nucleotide sequence encoding RP2 or a functional fragment thereof, a human β-globin polyadenylation signal or fragment, a CMV/human β-globin intron, a human rhodopsin kinase promoter (SEQ ID NO: 10), and an AAV2 inverted terminal repeat or functional fragment, wherein the RP2 sequence is under transcriptional control of the rhodopsin kinase promoter.
Use of self-complementary AAV8 or AAV9 vectors for RP2 expression
The vector can be packaged into AAV8 or AAV9 serotypes and may be self-complementary to enhance gene expression.
Pharmaceutical composition including the RP2 vector
Compositions comprising the RP2-encoding AAV vectors and a pharmaceutically acceptable carrier.
Methods of treating XLRP and improving retinal function using RP2 vector
Methods of treating or preventing X-linked retinitis pigmentosa (XLRP), increasing photoreceptor number, increasing visual acuity, decreasing retinal detachment, increasing the electrical response of photoreceptors, and increasing RP2 expression in the retina by administering an effective amount of the RP2 vector.
The claims cover AAV vectors encoding RP2 with specific regulatory sequences including a rhodopsin kinase promoter, packaged preferably in AAV8 or AAV9 serotypes, self-complementary forms, pharmaceutical compositions thereof, and methods of administration for treating XLRP and associated retinal improvements.
Stated Advantages
The methods, vectors, and compositions improve the health and quality of the retina and reduce or prevent vision impairment associated with XLRP.
They enhance the ability of patients to carry out vision-guided activities such as driving and living independently.
Self-complementary vectors provide earlier onset and stronger gene expression.
Pharmaceutical compositions are formulated to protect AAV vectors from damage and extend shelf life, enhancing administration and transduction efficiency.
Documented Applications
Treating or preventing X-linked retinitis pigmentosa (XLRP) in mammals, including humans.
Increasing photoreceptor number in the retina of a mammal.
Increasing visual acuity in a mammal.
Decreasing retinal detachment in a mammal.
Increasing the electrical response of photoreceptors (rods and cones) in a mammal.
Increasing expression of RP2, cone opsin, or cone PDE6 proteins in the retina.
Localizing proteins such as rhodopsin or PDE6 to rod outer segments in the retina.
Interested in licensing this patent?