Modified MIS Protein for Ovarian Reserve and Uterine Protection

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Solution Overview

Problem

Existing methods fail to effectively arrest primordial follicle activation and protect ovarian and uterine tissues from damage during chemotherapy or other treatments, leading to premature ovarian failure and uterine complications.

Innovation Solution

Administration of recombinant Mullerian Inhibiting Substance (MIS) protein with specific amino acid modifications to enhance cleavage, using AAV9 gene therapy or recombinant protein, to achieve ovarian and uterine protection, including methods for ovarian protection, oncoprotection, and treatment of polycystic ovarian syndrome (PCOS).

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional methods are used to prevent premature ovarian failure, then ovarian protection is attempted, but they fail to effectively arrest primordial follicle activation and protect ovarian tissues from damage

Engineering Contradiction:

Improveovarian protection effectivenessVSAvoidprimordial follicle activation damage

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent modifies the MIS protein sequence by changing amino acid residues at positions 448-451 (specifically Q450R mutation) to enhance proteolytic cleavage and increase bioactive MIS levels. This parameter change in the protein structure enables more effective arrest of primordial follicle activation and better protection against chemotherapy-induced damage, resolving the contradiction between protection effectiveness and harmful factor prevention.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If superphysiological doses of MIS protein are administered to arrest folliculogenesis, then complete arrest is achieved, but the complexity of administration and monitoring increases

Engineering Contradiction:

Improvefolliculogenesis arrest completenessVSAvoidadministration and monitoring complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent uses AAV9 viral vectors to deliver and express MIS protein in the ovary, creating a self-sustaining system that copies the natural MIS function but with enhanced durability and effectiveness. This approach simplifies administration compared to continuous exogenous protein infusion while achieving complete and permanent folliculogenesis arrest throughout the reproductive lifespan.

Inventive Principle:

Principle #26Copying

3Reliability

If AAV9 vector expressing MIS protein is used for permanent contraception, then complete and permanent contraception is achieved, but the risk of off-target effects and safety issues increases

Engineering Contradiction:

Improvecontraception permanenceVSAvoidoff-target effects and safety risks

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent employs AAV9 vectors with ovarian-specific tropism, directing MIS expression specifically to the ovary through the virus's natural preference for ovarian cells. This local quality approach confines the therapeutic effect to the target tissue, minimizing off-target effects while achieving permanent contraception through sustained ovarian MIS expression.

Inventive Principle:

Principle #3Local quality

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 modified MIS protein achieves complete arrest of folliculogenesis, preserves ovarian reserve, protects ovaries from chemotherapy-induced damage, and reduces uterine complications, while also providing temporary contraception and controlling reproductive hormones.

Implementation Method 1

MIS, which is produced by granulosa cells of growing follicles, has been proposed as a negative regulator of primordial follicle activation

Methodology Applied

Scientific EffectProtein-receptor binding:

Implementation Method 2

using either an AAV9 gene therapy vector or administration of a recombinant MIS protein

Methodology Applied

Scientific EffectGene therapy:

Implementation Method 3

the 140 kilodalton (kDa) disulfide-linked homodimer of MIS is proteolytically cleaved to generate its active C-terminal fragments

Methodology Applied

Scientific EffectProteolytic cleavage:

Data Source

PatentUS12486309B2Mullerian inhibiting substance (MIS) proteins for ovarian and uterine oncoprotection, and ovarian reserve and uterine preservation

Publication Date: 2025.12.02 THE GENERAL HOSPITAL CORP

AI summary

One aspect of the invention provides a method of ovarian protection by administering to a female subject a composition comprising Mullerian inhibiting substance (MIS). Ovarian protection can be an induced arrest of folliculogenesis to preserve fertility. In some embodiments, ovarian protection is oncoprotection, the protection of the ovarian function during a cytotoxic treatment, e.g., chemotherapy. Another aspect of the invention relates to a method of treating PCOS, the method comprising administering to a female subject a composition comprising recombinant MIS protein.