CFI and Cofactor Combination for AMD Therapy

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Solution Overview

Problem

Current treatments for age-related macular degeneration (AMD) are limited, particularly for early and advanced dry forms, with existing therapies mainly targeting the wet form and requiring frequent intravitreal injections, and there is a need for alternative therapies that can effectively address complement-mediated and complement-associated disorders, including AMD, without being genotype-specific.

Innovation Solution

The use of therapeutic combinations of Complement Factor I (CFI) and its cofactors, such as Complement Factor H-like Protein 1 (FHL1), delivered via bicistronic vectors, including AAV vectors, to rebalance the overactive complement C3b feedback cycle, ensuring stoichiometric excess of cofactors to CFI for optimal activity, particularly in the eye or kidney, where co-factor levels may be reduced.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Adaptability or versatility

If current treatments targeting the wet form of AMD are used, then vision loss from neovascularisation can be addressed, but early and advanced dry forms of AMD remain untreated

Engineering Contradiction:

Improvetherapeutic coverage across AMD typesVSAvoideffectiveness for dry AMD forms

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The complement factor I (CFI) and cofactor combination is designed to treat multiple forms of AMD (wet, early dry, and advanced dry) through a single therapeutic mechanism that targets the complement system's role in drusen formation and RPE cell death, making the treatment universally applicable across different AMD types rather than requiring genotype-specific or form-specific therapies

Inventive Principle:

Principle #6Universality (Multi-functionality)

2Reliability

If frequent intravitreal injections are administered for wet AMD, then neovascularisation can be controlled, but patient burden and treatment complexity increase

Engineering Contradiction:

Improvecontrol of neovascularisationVSAvoidpatient burden from frequent injections

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The invention changes the delivery parameter from frequent intravitreal injections to a single or limited number of injections of CFI and cofactor combinations, which then provide sustained therapeutic effect by modulating the complement system's activity in drusen and RPE cell death, thereby reducing patient burden while maintaining treatment effectiveness

Inventive Principle:

Principle #35Parameter changes

3Measurement precision

If genotype-specific treatments are used, then precision for certain complement deficiencies can be achieved, but broader therapeutic benefit is limited

Engineering Contradiction:

Improvetargeting specific complement deficienciesVSAvoidbroader therapeutic benefit

Core Design Contradiction:

Measurement precisionVSAdaptability or versatility

Solution Approach 1:

The CFI and cofactor combination provides a universal therapeutic approach that addresses the complement system's involvement in AMD pathogenesis across different genotypes and patient populations, rather than requiring identification and treatment of specific complement deficiencies, thereby achieving both precision and broad applicability

Inventive Principle:

Principle #6Universality (Multi-functionality)

4Productivity

If complement factor I and cofactors are delivered at stoichiometric ratios, then optimal C3b breakdown activity is achieved, but delivery complexity increases

Engineering Contradiction:

ImproveC3b breakdown activityVSAvoiddelivery ratio control

Core Design Contradiction:

ProductivityVSDevice complexity

Solution Approach 1:

The invention combines CFI and its cofactors (such as CFH, FHL1, CR1, or MCP) into a single therapeutic formulation or combination product, which simplifies the delivery process by providing both components together in the correct stoichiometric ratio rather than requiring separate administration of CFI and cofactors, thereby maintaining optimal C3b breakdown activity while reducing delivery complexity

Inventive Principle:

Principle #5Merging (Combining)

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

This approach provides effective treatment or prevention of complement-mediated disorders by enhancing C3b breakdown, potentially reducing geographic atrophy progression and improving vision by increasing C3b-inactivating and iC3b-degradation activity, offering a broader therapeutic benefit beyond genotype-specific treatments.

Implementation Method 1

Complement Factor I (CFI) is a serine protease that circulates in a zymogen-like state... CFI inactivates C3b by cleaving it into iC3b, C3d and C3d,g

Methodology Applied

Scientific EffectProteolytic cleavage: Enzyme

Data Source

PatentUS20220072157A1Complement factor i and complement factor i cofactor, vectors encoding therefor and therapeutic use

Publication Date: 2022.03.10 NOVARTIS PHARMA UK

AI summary

A product comprising (i) a Complement Factor I (CFI) cofactor; and (ii) Complement Factor I (CFI), or nucleotide sequences encoding therefor, as a combined preparation for simultaneous, separate or sequential use in therapy.