Defense publication

Author: Byarugaba Umar
Caremax Clinic Limited, Kampala Uganda.
Correspondence: b.umarb2k@gmail.com

Date: 17 December 2025

Abstract

Dystrophinopathies, including Duchenne muscular dystrophy, are characterized by substantial genetic heterogeneity at the level of breakpoint architecture, intronic context, and transcript structure. Most antisense-based therapeutic strategies developed to date rely on exon-indexed paradigms, in which intervention eligibility and design are predetermined by reference to specific exon identifiers. While such approaches have demonstrated proof of concept in selected populations, they do not generalize across genetically diverse cohorts.

Here, a population-adaptive splice-modulation framework is described that departs from exon-indexed logic and instead operates on structural and functional properties of dystrophin pre-mRNA across heterogeneous mutation architectures. The framework integrates genotype-clustered therapeutic assignment, adaptive intervention refinement, and system-level manufacturing and clinical deployment considerations suitable for low-prevalence and genetically diverse populations. The principles articulated are disclosed to establish prior art and to prevent exclusive appropriation of population-adaptive splice-modulation systems, while preserving freedom to operate for independent implementers.

1. Background and Departure from Exon-Indexed Paradigms

Conventional antisense-based approaches to dystrophin restoration have largely relied on exon-indexed paradigms, wherein therapeutic eligibility and intervention design are predetermined by reference to a specific exon identifier. Implicit in this model is the assumption that exon identity alone constitutes a sufficient determinant of therapeutic behavior. Although such approaches have demonstrated limited success in selected cohorts, they fail to account for the diversity of mutation architectures observed across global populations.

Dystrophinopathies exhibit substantial variability in breakpoint configuration, intronic environment, and transcript-level architecture. Structurally distinct mutations affecting the same nominal exon may generate divergent splicing contexts and transcriptional landscapes, resulting in materially different therapeutic requirements. Consequently, exon-indexed paradigms are neither universally predictive nor extensible. The framework described here departs from exon-indexed logic and introduces population-adaptive splice-modulation systems that operate independently of predefined exon numbers.

2. Structural Determinants of Splice Modulation

The disclosed framework is grounded in the recognition that splice outcomes are governed by higher-order properties of pre-mRNA, including local and regional structural accessibility, folding dynamics, and spliceosome engagement behavior. Within this context, linear exon identity functions as a secondary descriptor rather than a primary determinant of splice modulation efficacy.

Structurally distinct mutations can reshape the RNA environment surrounding a splice decision point in ways that substantially alter therapeutic responsiveness, even when nominal exon identity is shared. Accordingly, splice modulation within the disclosed framework is defined by its influence on splice decision dynamics and transcript structural states, rather than by direct targeting or masking of predefined sequence motifs or canonical exon boundaries. This distinction establishes a broader, population-adaptive conceptual foundation that is independent of motif-centric or exon-centric approaches.

3. Genotype-Clustered Therapeutic Assignment

A central feature of the disclosed framework is the grouping of patients into functional therapeutic clusters based on shared structural and functional characteristics of their dystrophin transcripts. Patients are not assigned to treatment pathways solely by reference to specific deletions or exon numbers, but by convergence of properties such as reading-frame restoration potential, transcript architecture, and splice-decision behavior.

Therapeutic assignment within these clusters is adaptive rather than fixed. The framework permits reassessment and refinement of intervention strategies based on observed functional response, molecular indicators, and safety data within each cluster. This adaptive logic enables clinically meaningful intervention across genetically heterogeneous populations without reliance on rigid exon-indexed classifications.

4. Integration of Manufacturing and Deployment as a System

Manufacturing and clinical deployment are treated as integral components of the therapeutic system rather than ancillary processes. In populations characterized by genetic heterogeneity and low prevalence of individual mutation classes, therapeutic viability depends on adaptive, small-scale, and flexible deployment models rather than centralized, high-volume production.

Accordingly, the disclosed framework encompasses cluster-centric production and deployment logic, in which therapeutic constructs are prepared, supplied, and evaluated in alignment with functional patient groupings rather than global exon categories. This systems-based approach enables sustainable therapeutic intervention in settings where conventional large-scale manufacturing and trial models are impractical, without reliance on any specific chemistry, synthesis method, or delivery modality.

5. Clinical Evaluation Frameworks for Heterogeneous Populations

Clinical evaluation within the disclosed framework emphasizes longitudinal, within-patient and within-cluster assessment of functional outcomes, supported by molecular and physiological indicators. Functional stabilization or improvement, respiratory and cardiac trajectories, and safety profiles are integrated to assess therapeutic impact across heterogeneous genotypes.

Molecular measurements related to dystrophin expression or transcript behavior are treated as supportive pharmacodynamic indicators rather than sole determinants of efficacy. This approach aligns clinical evaluation with the adaptive, population-based nature of the framework and avoids dependency on exon-specific or chemistry-specific endpoints.

6. Regulatory and Ethical Deployment Considerations

The framework is compatible with adaptive clinical and regulatory models appropriate for rare diseases and genetically heterogeneous populations. Such models may include seamless phase transitions, interim reassessment of cohort composition, and integration of structured compassionate-use pathways into evidence generation. These features enable rigorous yet ethical evaluation in contexts where traditional large-cohort, placebo-controlled paradigms are neither feasible nor appropriate.

7. Prior Art Declaration and Public Dedication

The concepts articulated in this manuscript are disclosed to establish prior art for population-adaptive splice-modulation systems in dystrophinopathies and related disorders. Specifically disclosed are: population-adaptive splice-modulation independent of predefined exon identifiers; genotype-clustered therapeutic assignment based on transcript-level properties; adaptive refinement of interventions within functional clusters; and integration of manufacturing, deployment, and evaluation into unified systems suitable for genetically diverse and low-prevalence populations.

These system-level principles are dedicated to the public domain to prevent exclusive monopolization, while leaving open the development of specific algorithms, chemistries, therapeutic constructs, and deployment methods by independent implementers.

8. Closing Statement

This work establishes a conceptual and systems-level foundation for population-adaptive splice modulation in dystrophinopathies. While the principles described are made publicly available, their articulation does not limit independent innovation in implementation, execution, or therapeutic development consistent with these concepts