ATM Protein Variants for High-Efficiency Cellular Transduction
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Solution Overview
Problem
Current therapies for Ataxia Telangiectasia (AT) and ATM-related cancers are inadequate, with existing gene therapy vectors having low transduction efficiency and safety concerns, and treatments like dexamethasone causing significant side effects.
Innovation Solution
Development of synthetic ATM variants, such as ATM SINT (SEQ ID NO 1), which include additional domains beyond miniATM, for efficient transduction and restoration of ATM functions, using nanoparticles or vesicles for delivery to bypass the blood-brain barrier.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing gene therapy vectors are used to deliver ATM protein, then therapeutic function is provided, but transduction efficiency is low
Solution Approach 1:
The patent segments the ATM protein into different functional domains (kinase domain, FAT domain, PI3K domain, etc.) and creates variant proteins with specific combinations of these domains. This segmentation allows optimization of transduction efficiency by selecting variants with appropriate size and functional characteristics for efficient cellular uptake while maintaining therapeutic activity.
Solution Approach 2:
The patent applies parameter changes by modifying the amino acid sequence, molecular weight, and domain composition of the ATM protein variants. These parameter modifications enable improved transduction efficiency while preserving the essential DNA repair and cellular protection functions needed for therapeutic effectiveness.
2Reliability
If dexamethasone is used to treat AT patients, then neurological symptoms improve, but significant side effects occur
Solution Approach 1:
The patent extracts and utilizes specific functional domains of the ATM protein (such as the kinase domain and PI3K domain) that are responsible for the therapeutic effects observed with dexamethasone-induced miniATM production. By delivering these purified functional domains through gene therapy vectors, the treatment achieves neurological symptom improvement without the mineralocorticoid side effects associated with dexamethasone therapy.
Solution Approach 2:
The patent uses gene therapy vectors as intermediaries to deliver ATM protein variants directly to target cells, bypassing the need for dexamethasone administration. This intermediary approach allows selective restoration of ATM function in affected tissues without the systemic side effects of steroid therapy.
3Reliability
If full-length ATM protein is delivered, then complete function is restored, but vector cargo capacity is exceeded
Solution Approach 1:
The patent segments the full-length ATM protein into modular functional domains that can be independently expressed and assembled. This segmentation enables the creation of smaller protein variants that fit within vector cargo capacity limits while retaining essential functions for DNA repair and cellular protection.
Solution Approach 2:
The patent applies partial action by delivering protein variants containing only the essential functional domains needed for therapeutic effect, rather than the complete full-length protein. This partial delivery approach achieves sufficient functional restoration for treating Ataxia Telangiectasia while complying with vector size constraints.
Data Source
AI summary
The present invention relates to variants of the human ATM protein or derivatives thereof, said variant and/or derivatives for use in the treatment or in the prevention of diseases related to at least one mutation of the ATM gene, i.e. diseases caused or induced by said mutation/s, mRNAs and cDNAs, expression vectors coding for said variant of the ATM protein or derivatives thereof and composition or associations comprising them.