RP2 and RPGR vectors for treating X-linked retinitis pigmentosa
Inventors
Wu, Zhijian • Swaroop, Anand • HIRIYANNA, Suja • Li, Tiansen
Assignees
US Department of Health and Human Services
Publication Number
US-11617801-B2
Publication Date
2023-04-04
Expiration Date
2036-03-11
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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, designed to treat or prevent X-linked retinitis pigmentosa (XLRP). These vectors include specific regulatory elements such as a CMV/human β-globin intron and human β-globin polyadenylation signals, with the RPGR-ORF15 sequence under the transcriptional control of a rhodopsin kinase promoter. The vectors are packaged in various AAV serotypes, preferably AAV8 or AAV9, with inverted terminal repeats (ITRs) typically from AAV2.
X-linked retinitis pigmentosa (XLRP) is characterized by progressive photoreceptor cell loss, beginning with rod cell death and followed by cones, leading to impaired vision and eventual blindness. There are no current treatments for XLRP, which motivates the need for compositions and methods to address this condition. The vectors of the invention are capable of expressing full-length and functional RP2 or RPGR-ORF15 proteins in retinal cells, thereby preserving photoreceptor viability and function.
The invention further includes pharmaceutical compositions containing these vectors and methods for their use in mammals to treat or prevent XLRP, increase photoreceptor numbers, improve visual acuity, decrease retinal detachment, enhance photoreceptor electrical responses, and increase expression and proper localization of related proteins such as rhodopsin and PDE6 in the retina. The vectors have been demonstrated in mouse models to confer long-term expression and functional rescue when administered, especially by subretinal injection.
Claims Coverage
The patent contains independent claims directed to AAV vectors encoding RPGR-ORF15 and methods of using these vectors in treating XLRP and related outcomes. Two independent claim sets are identified.
AAV vector comprising RPGR-ORF15 coding sequence under rhodopsin kinase promoter control
An AAV vector includes a nucleic acid encoding RPGR-ORF15 or a functional fragment or variant thereof. The vector comprises a CMV/human β-globin intron and/or a human β-globin polyadenylation signal, and the RPGR-ORF15 sequence is under the transcriptional control of a rhodopsin kinase promoter, with the promoter having at least 99% identity to SEQ ID NO: 10.
AAV vector composition and packaging
The vector further comprises AAV2 inverted terminal repeats or functional fragments thereof and may be packaged in AAV8 or AAV9 capsids.
Pharmaceutical composition comprising the AAV vector
A pharmaceutical composition contains the aforementioned AAV vector and a pharmaceutically acceptable carrier.
Methods of treating X-linked retinitis pigmentosa using the AAV vector
Methods include administering an effective amount of the vector to a mammal to treat or prevent XLRP, increase photoreceptor number in the retina, increase visual acuity, decrease retinal detachment, increase photoreceptor electrical responses, increase RPGR expression, and localize proteins such as rhodopsin or PDE6 to rod outer segments.
Dosage and subject specifications
The vector is administered at about 5×10^6 to about 5×10^12 vector genomes per eye, and the subject is preferably a human.
The independent claims cover AAV vectors encoding RPGR-ORF15 under rhodopsin kinase promoter control with specific regulatory elements, their pharmaceutical composition, and methods of administration for treating XLRP and improving various retinal functions, including specified dosages and target subjects.
Stated Advantages
The inventive methods, vectors, and pharmaceutical compositions improve the health or quality of the retina and reduce or prevent vision impairment.
They improve a patient's ability to carry out vision-guided activities such as driving and living independently.
Formulations of the pharmaceutical compositions protect the AAV vectors from damage and extend shelf life, facilitating administration and increasing efficiency of treatment.
Documented Applications
Treating or preventing X-linked retinitis pigmentosa (XLRP) in mammals by administering AAV vectors encoding RP2 or RPGR-ORF15.
Increasing photoreceptor number in the retina of mammals via administration of the inventive vectors or pharmaceutical compositions.
Increasing visual acuity in mammals through administration of the inventive AAV vectors or pharmaceutical compositions.
Decreasing retinal detachment in mammals by administering the inventive vectors or compositions.
Increasing the electrical response of photoreceptors in mammals through administration of the inventive vectors or compositions.
Increasing expression of RP2, RPGR, cone opsin, or cone PDE6 proteins in retina of mammals after vector administration.
Localizing proteins such as rhodopsin or PDE6 to rod outer segments in the retina of mammals by administering the inventive vectors or pharmaceutical compositions.
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