Methods and compositions for treating leber congenital amaurosis
Inventors
Wu, Zhijian • Swaroop, Anand • MOOKHERJEE, Suddhasil • HIRIYANNA, Suja
Assignees
US Department of Health and Human Services
Publication Number
US-10351844-B2
Publication Date
2019-07-16
Expiration Date
2035-08-27
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Abstract
Expression vectors, viral particles and therapeutic methods of using such constructs to improve the visual function of a patient suffering from diseases of the eye, resulting from failure to produce a specific protein in the eye, or the production of a non-functional protein in the eye, particularly Leber Congenital Amaurosis (LCA) and CEP290-related LCA.
Core Innovation
The invention provides expression vectors, viral particles, and therapeutic methods for treating diseases of the eye caused by a failure to produce a functional protein, specifically Leber Congenital Amaurosis (LCA) related to mutations in the CEP290 gene. It is based on the discovery that only a portion of the CEP290 coding region, rather than the full-length gene, is necessary to restore proper CEP290 function and improve visual function in patients.
The problem addressed is the lack of effective treatment for CEP290-related LCA due to the large size of the CEP290 cDNA (7.4 kb) which hampers delivery to photoreceptor cells by gene therapy vectors. Previous gene therapy approaches successful for other LCA-causing genes like RPE65 were ineffective for CEP290 because the entire gene could not be efficiently delivered to the retina. The invention overcomes this by using portions of the CEP290 gene encoding functional fragments smaller than the full gene, thereby enabling successful delivery and therapeutic effect.
Claims Coverage
The patent contains one independent claim defining a viral vector encoding a specific CEP290 protein fragment to treat CEP290-related LCA. This claim covers key inventive features related to the nucleotide sequence, vector type, promoter, and regulatory sequences.
Viral vector encoding a CEP290 myosin tail protein fragment that restores visual function
A viral vector comprising a DNA molecule encoding a protein consisting of the amino acid sequence of SEQ ID NO:11, which, when expressed in photoreceptor cells of a patient with CEP290-related LCA, increases the patient's visual function.
Nucleotide sequence comprising the portion of the CEP290 ORF encoding SEQ ID NO:11
The nucleotide sequence encoding the protein consists of the nucleotide sequence of SEQ ID NO:10, representing a portion of the CEP290 open reading frame corresponding to the myosin tail domain.
Use of adeno-associated virus (AAV) vector for gene delivery
The viral vector is an adeno-associated virus vector, specifically including use of an AAV8 serotype vector known for efficient delivery to photoreceptor cells.
Inclusion of photoreceptor cell-specific and other promoters
The vector includes a promoter sequence functionally linked to the CEP290 ORF to drive expression, selected from rhodopsin promoter, rhodopsin kinase promoter, IRBP promoter, CMV promoter, and CMV intermediate-early promoter.
Incorporation of AAV inverted terminal repeats (ITRs) with Rep binding and terminal resolution sites
The viral vector further comprises at least one inverted terminal repeat nucleotide sequence containing an AAV Rep binding site and a terminal resolution site sequence to enable packaging and replication of the vector genome, with specific mention of an AAV2 ITR.
The claims cover a viral vector encoding a specific functional fragment of CEP290 protein suitable for gene therapy treatment of CEP290-related LCA, employing AAV vectors with appropriate promoters and regulatory elements to enable expression in photoreceptor cells and improve visual function.
Stated Advantages
Improved visual function in patients suffering from CEP290-related Leber congenital amaurosis by expression of a functional protein fragment.
Ability to deliver a therapeutic CEP290 gene fragment despite the large size of the full-length gene, overcoming previous delivery limitations.
Long-lasting therapeutic effects of the protein fragment expressed from the viral vector, maintaining improved visual function for many months.
Effective therapy across a wide dose range, allowing for flexible dosage administration.
Correction of photoreceptor protein mislocalization and restoration of normal protein expression patterns in the retina.
Documented Applications
Treatment of patients having CEP290-related Leber congenital amaurosis by administering isolated DNA molecules or viral vectors encoding portions of the CEP290 gene to improve visual function.
Use of viral vectors, especially AAV serotype 8, to deliver therapeutic CEP290 gene fragments to photoreceptor cells in the retina.
Methods of administration including subretinal injection, intravitreal injection, and sub-Tenon’s injection of naked DNA or viral particles to deliver CEP290 gene therapy.
Use of the invention in clinical or experimental gene therapy to ameliorate retinal dystrophies caused by CEP290 mutations, including improvements measured by electroretinogram and behavioral visual tests.
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