ZNF622 Targeting for Ribosomal Dysfunction in Stem Cells

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Solution Overview

Problem

Current treatments for bone marrow failure diseases associated with ribosomal dysfunction, such as Shwachman-Diamond syndrome, are inadequate in restoring hematopoietic regeneration and protein synthesis rates in CD34+ stem cells.

Innovation Solution

Administration of synthetic nucleic acid molecules, including shRNA, siRNA, and CRISPR guide strands, targeting ZNF622 to reduce its expression levels, thereby enhancing ribosomal subunit joining and protein synthesis in human stem cells, using vectors like lentiviral, plasmid, or adenovirus-associated vectors for delivery.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current treatments are used for bone marrow failure diseases, then patients receive standard care, but hematopoietic regeneration and protein synthesis rates in CD34+ stem cells are not restored

Engineering Contradiction:

Improvehematopoietic regenerationVSAvoidprotein synthesis rates

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The invention changes the molecular parameter of ZNF622 expression levels in CD34+ stem cells by introducing synthetic nucleic acid molecules (shRNA, siRNA, antisense oligonucleotides) that specifically target and reduce ZNF622 mRNA, thereby altering the cellular protein synthesis machinery to restore ribosomal function and improve both hematopoietic regeneration and protein synthesis rates

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention uses synthetic nucleic acid molecules as intermediary substances that mediate between the therapeutic goal and the target gene. These molecules (shRNA, siRNA, antisense oligonucleotides) act as intermediaries to selectively reduce ZNF622 expression without directly modifying the genome, enabling restoration of ribosomal subunit joining and protein synthesis in a controlled manner

Inventive Principle:

Principle #24Intermediary (Mediator)

2Productivity

If ZNF622 levels are reduced to improve ribosomal subunit joining, then protein synthesis rates increase, but delivery and stability of synthetic nucleic acids in vivo become challenging

Engineering Contradiction:

Improveprotein synthesis ratesVSAvoidin vivo stability and uptake

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The invention modifies physical-chemical parameters of the synthetic nucleic acid molecules by incorporating chemical modifications (e.g., phosphorothioate backbone modifications, 2'-O-methyl modifications) that enhance nuclease resistance, improve cellular uptake efficiency, and increase in vivo half-life of the therapeutic molecules while maintaining their ability to reduce ZNF622 expression

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention introduces delivery vehicles (lipid nanoparticles, conjugates with cell-penetrating peptides, viral vectors) as intermediary systems that facilitate the transport of synthetic nucleic acid molecules across biological barriers, protecting them from degradation and enabling their delivery to target CD34+ stem cells in bone marrow

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS20240301413A1Compositions and methods useful for the treatment of bone marrow failure diseases associated with ribosomopathies

Publication Date: 2024.09.12 THE CHILDRENS HOSPITAL OF PHILADELPHIA

AI summary

Compositions and methods for the treatment of ribosomopathies and regeneration of hematopoietic stems cells are provided.