Suprachoroidal AAV Formulations with Aggregates
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Solution Overview
Problem
Current ocular gene therapy methods, particularly those using adeno-associated viruses (AAV), are invasive and associated with complications such as increased risk of cataract, retinal detachment, and photoreceptor separation, necessitating a need for improved pharmaceutical compositions that enhance residence time in the suprachoroidal space for better efficacy.
Innovation Solution
A pharmaceutical composition comprising a recombinant adeno-associated virus (AAV) vector with an expression cassette encoding a transgene, formulated with an ionic strength of at most 200 mM and at least 3% aggregated AAV, designed for suprachoroidal administration to prolong clearance time, reduce circumferential spread, and increase transgene expression in the eye.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current ocular gene therapy methods (intravitreous or subretinal administrations) are used, then gene delivery can be achieved, but invasive procedures cause serious setbacks including increased risk of cataract, retinal detachment, and photoreceptor separation
Solution Approach 1:
The patent introduces the suprachoroidal space as an intermediary route for drug delivery. Instead of directly injecting into the vitreous or under the retina, the composition is delivered into the suprachoroidal space, which serves as a buffer zone that allows drug diffusion to adjacent tissues without direct contact with sensitive structures, thereby reducing invasive complications
Solution Approach 2:
The patent replaces invasive mechanical injection methods with a formulation-based approach. By using specific ionic strength formulations (at most 200 mM) and aggregated AAV compositions, the therapy achieves effective drug delivery through diffusion and absorption processes rather than direct mechanical penetration into sensitive ocular structures
2Duration of action of moving object
If drug solution is administered to suprachoroidal space, then drug can diffuse within SCS and be absorbed into adjacent tissues, but clearance time is too short leading to reduced efficacy
Solution Approach 1:
The patent changes the ionic strength parameter of the formulation to at most 200 mM, which optimizes the physical-chemical properties of the drug solution. This parameter change affects the osmotic pressure and diffusion characteristics, allowing the solution to remain in the suprachoroidal space longer before being cleared by physiologic processes
Solution Approach 2:
The patent uses aggregated AAV compositions as a composite formulation. The aggregation state of the viral particles creates a more complex formulation that interacts differently with the suprachoroidal space environment, prolonging residence time by reducing rapid clearance while still allowing controlled diffusion into adjacent tissues
3Duration of action of moving object
If aggregated AAV composition is used with ionic strength of at most 200 mM, then residence time in suprachoroidal space is prolonged and efficacy is improved, but formulation complexity increases
Solution Approach 1:
The patent establishes a clear parameter threshold (ionic strength of at most 200 mM) that defines the formulation requirements. This single parameter specification provides a straightforward guideline for formulation development and manufacturing, reducing complexity despite the aggregated composition requirements
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The composition achieves longer transgene expression, higher concentration, and increased rate of transduction in the eye, while reducing VEGF-induced vasodilation and vascular leakage, thereby improving the safety and efficacy of ocular gene therapy.
Implementation Method 1
The drug solution diffuses within SCS and is absorbed into adjacent tissues
Implementation Method 2
Capillaries in the choroid are permeable to low molecular weight osmolytes
Data Source
AI summary
Provided herein are pharmaceutical compositions for administration to a suprachoroidal space of an eye of a subject. The pharmaceutical compositions can include a recombinant adeno-associated virus (AAV) encoding a transgene. Also provided herein are methods for treating or preventing a disease in a subject by administering a therapeutically effective amount of the pharmaceutical compositions to the subject in need.