Methods and compositions for treating Leber congenital amaurosis
Inventors
Wu, Zhijian • Swaroop, Anand • MOOKHERJEE, Suddhasil • HIRIYANNA, Suja
Assignees
Usa REPRESENTED BY SECRETARY Dhhs AS • US Department of Health and Human Services
Publication Number
US-11421219-B2
Publication Date
2022-08-23
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
Leber congenital amaurosis (LCA) is a severe inherited eye disorder causing early-onset visual impairment due to mutations in specific genes, notably CEP290, which accounts for 20-25% of cases. No treatment was available, particularly for CEP290-related LCA, due to the challenges in delivering the large CEP290 coding sequence (7.4 kb) into retinal photoreceptors using gene therapy vectors.
The present invention addresses this problem by discovering that only a portion of the CEP290 coding region is sufficient to restore CEP290 function and improve visual function in patients with CEP290-related LCA. This portion encodes a protein fragment that, when expressed in photoreceptor cells, increases visual function.
Specifically, the invention provides isolated nucleic acid molecules encoding portions of CEP290 ORFs less than full-length, including sequences corresponding to the "myosin tail" domain, which can be packaged into viral vectors such as adeno-associated viruses (AAV) and delivered to the eye. Methods of administering these vectors, including subretinal or intravitreal injection, are disclosed to improve visual function in patients with CEP290-related LCA.
Claims Coverage
The patent includes one independent claim focused on a method of treating CEP290-related Leber Congenital Amaurosis (LCA) by administering a specific vector. The main inventive features relate to the vector composition, protein encoded, delivery method, and dosage.
Method of treating CEP290-related LCA by administering a vector encoding a specific CEP290 protein fragment
This method involves administering an effective amount of a vector containing a DNA molecule encoding the protein consisting of the amino acid sequence of SEQ ID NO:11, which increases visual function when expressed in photoreceptor cells.
Vectors delivered as naked DNA or viral particles
The vector can be delivered as naked DNA or encapsulated in viral particles for administration.
Specific routes of administration into the eye
The vector is administered by injection methods including subconjunctival, sub-Tenon's, intravitreal, subretinal, or intracameral injections.
Therapeutically effective dosage ranges
The vector is administered in dosages ranging between 3×10^8 and 1×10^13 nucleic acid molecules per eye.
Nucleotide sequence encoding the protein
The nucleotide sequence encoding SEQ ID NO:11 consists of the nucleotide sequence of SEQ ID NO:10.
Use of adeno-associated virus vectors, especially AAV8
The vector can be an adeno-associated virus vector, including AAV8 serotype.
Inclusion of promoter sequences to drive expression
The vector includes promoter sequences functionally linked to the nucleotide sequence, selected from rhodopsin promoter, rhodopsin kinase promoter, IRBP promoter, CMV promoter, and CMV intermediate-early promoter.
Inclusion of inverted terminal repeats containing AAV Rep binding and terminal resolution sequences
The vector further includes at least one inverted terminal repeat nucleotide sequence comprising an AAV Rep binding site and terminal resolution site, for example, from AAV2.
The claims cover a method for treating CEP290-related LCA by administering vectors encoding a CEP290 myosin tail protein fragment (SEQ ID NO:11), utilizing various delivery modes, specific vectors such as AAV8, defined dosage ranges, and vector constructs containing relevant promoters and AAV terminal sequences to achieve functional expression in photoreceptor cells and improve visual function.
Stated Advantages
Provides effective gene therapy for CEP290-related LCA by using only a portion of the CEP290 gene, overcoming prior delivery challenges due to the large size of the full-length gene.
Enables packaging of therapeutic DNA sequences into viral vectors such as AAV, facilitating gene delivery to retinal photoreceptor cells.
Demonstrates therapeutic efficacy across a wide dose range and prolonged duration of visual function improvement.
Allows multiple administration routes into the eye, enhancing clinical applicability.
Documented Applications
Treatment of patients suffering from CEP290-related Leber Congenital Amaurosis by administering gene therapy vectors encoding CEP290 protein fragments.
Use in gene therapy to improve visual function via photoreceptor cell expression of partial CEP290 protein sequences.
Treatment methods involving delivery of vectors by subretinal, intravitreal, and other ocular injection techniques.
Development of pharmaceutical compositions comprising vectors encoding CEP290 protein fragments for ocular administration.
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