TfR-Binding Acid Sphingomyelinase for CNS Delivery
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Solution Overview
Problem
Current treatments for acid sphingomyelinase deficiency (ASMD), such as olipudase alfa, do not effectively address central nervous system (CNS) manifestations and require frequent infusions, posing limitations in managing the disease.
Innovation Solution
Development of multidomain therapeutic proteins comprising a TfR-binding delivery domain fused to an acid sphingomyelinase (ASM) polypeptide, along with nucleic acid constructs that allow for the insertion of these proteins into a target genomic locus, such as the endogenous ALB locus, for enhanced expression and delivery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If enzyme replacement therapy (olipudase alfa) is used to treat ASMD, then the disease symptoms are managed, but the treatment does not address CNS manifestations and requires frequent infusions
Solution Approach 1:
The patent uses the transferrin receptor (TfR) as an intermediary to mediate the delivery of acid sphingomyelinase to the brain. The TfR-binding domain acts as a bridge that transports the enzyme across the blood-brain barrier, enabling CNS treatment while maintaining the enzyme's therapeutic function for peripheral tissues
Solution Approach 2:
The engineered acid sphingomyelinase is designed to perform multiple functions simultaneously: it treats peripheral ASMD symptoms through standard enzyme replacement and delivers CNS therapeutic effects through TfR-mediated brain uptake. This multi-functional approach resolves the limitation of current therapies that only address peripheral manifestations
2Reliability
If enzyme replacement therapy is administered frequently, then therapeutic levels are maintained, but patient convenience and compliance are reduced
Solution Approach 1:
The patent employs preliminary action by integrating the therapeutic acid sphingomyelinase into the patient's genome using CRISPR/Cas9 technology. This genetic integration creates a self-sustaining production system that continuously generates therapeutic enzyme levels without requiring repeated external administrations, thereby maintaining reliability while eliminating frequent infusions
3Reliability
If a TfR-binding domain is fused to acid sphingomyelinase, then targeted delivery to the brain is enabled, but the protein structure complexity increases
Solution Approach 1:
The patent divides the acid sphingomyelinase therapeutic into two functional segments: the original catalytic domain that breaks down sphingomyelin and a separate TfR-binding domain that enables brain delivery. This segmentation allows each component to perform its specialized function while maintaining overall therapeutic effectiveness and simplifying the design process
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 proposed solution enables targeted delivery and expression of acid sphingomyelinase within cells, potentially improving treatment outcomes for ASMD by addressing CNS manifestations and reducing the frequency of administrations.
Implementation Method 1
The TfR-binding delivery domain comprises an anti-TfR antigen-binding protein, wherein the antigen-binding protein binds to human transferrin receptor
Data Source
AI summary
Multidomain therapeutic proteins comprising a TfR-binding delivery domain fused to an acid sphingomyelinase polypeptide and nucleic acid constructs and compositions that allow insertion of a multidomain therapeutic protein coding sequence into a target genomic locus such as an endogenous ALB locus and/or expression of the multidomain therapeutic protein coding sequence are provided. The multidomain therapeutic proteins and nucleic acid constructs and compositions can be administered to cells, populations of cells, or subjects and can be used in methods of integration of a multidomain therapeutic protein nucleic acid into a target genomic locus, methods of expression of a multidomain therapeutic protein in a cell, methods of treating acid sphingomyelinase deficiency in a subject, and methods of preventing or reducing the onset of a sign or symptom of acid sphingomyelinase deficiency in a subject.