AAV Gene Therapy Redosing With Plasma Cell Depletion
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Solution Overview
Problem
The development of host antibodies against adeno-associated virus (AAV) vectors limits the efficacy of gene therapy by blocking transduction or affecting uptake, and the inability to re-dose AAVs due to sustained antibody responses prevents repeated dosing, rendering many patients ineligible for future treatments.
Innovation Solution
Administering a nucleic acid construct, a nuclease agent targeting a specific genomic locus, and a plasma cell depleting agent to cleave the target site and insert the construct, allowing for expression of a polypeptide of interest despite preexisting immunity, enabling subsequent administrations to achieve desired expression levels.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If AAV gene therapy is administered to treat genetic diseases, then therapeutic efficacy is improved, but host antibody response develops that blocks transduction and prevents re-dosing
Solution Approach 1:
The patent applies preliminary action by administering plasma cell depleting agents before AAV gene therapy to eliminate antibody-producing plasma cells in advance. This preemptive approach prevents the development of neutralizing antibodies that would otherwise block transduction and prevent re-dosing, thereby maintaining long-term therapeutic efficacy
Solution Approach 2:
The patent uses plasma cell depleting agents as intermediary substances that mediate between the AAV vector and the host immune system. These agents temporarily suppress the immune response by depleting plasma cells, creating a window of opportunity for successful AAV transduction and enabling re-dosing without triggering harmful antibody responses
2Productivity
If AAV re-dosing is attempted after antibody response, then transgene expression can be restored, but antibody-mediated blockade prevents successful transduction
Solution Approach 1:
The patent applies preliminary action by administering plasma cell depleting agents before re-dosing with AAV. This preemptive depletion of plasma cells removes the source of neutralizing antibodies, creating a permissive immune environment that allows successful transduction and restoration of transgene expression
Solution Approach 2:
The patent applies preliminary anti-action by using plasma cell depleting agents to counteract and neutralize the harmful antibody response before it can block re-dosing. This anticipatory countermeasure eliminates the obstacle to re-dosing, enabling restoration of therapeutic transgene expression
3Adaptability or versatility
If plasma cell depleting agents are administered, then antibody response is suppressed and re-dosing is enabled, but additional therapeutic agents and procedures are required
Solution Approach 1:
The patent applies universality by using plasma cell depleting agents that serve multiple functions: suppressing antibody responses to enable re-dosing, preventing neutralizing antibody formation, and creating a permissive immune environment for AAV transduction. This multi-functional approach consolidates several therapeutic needs into a single agent class
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
This approach facilitates sustained expression of therapeutic proteins by overcoming antibody-mediated blockades, allowing for effective treatment of enzyme deficiencies and reducing the onset of symptoms by enabling repeated dosing without antibody overshooting.
Implementation Method 1
the nuclease agent cleaves the nuclease target site
Implementation Method 2
administering a nucleic acid construct, a nuclease agent targeting a specific genomic locus, and a plasma cell depleting agent
Implementation Method 3
the nucleic acid construct is inserted into the target genomic locus
Data Source
AI summary
Provided herein are methods of inserting a nucleic acid encoding a polypeptide of interest into a target genomic locus in a cell or a population of cells in a subject, methods of expressing a polypeptide of interest from a target genomic locus in a cell or a population of cells in a subject, methods of treating an enzyme deficiency in a subject in need thereof, and methods of preventing or reducing the onset of a sign or symptom of an enzyme deficiency in a subject in need thereof. Some methods, such as when a subject has preexisting against an immunogen to be administered, use plasma cell depleting agents or combinations comprising plasma cell depleting agents to mitigate immune response and facilitate redosing of nucleic acid constructs encoding a polypeptide of interest and nuclease agents targeting a target genomic locus to achieve, for example, a step-wise increase in expression of a polypeptide of interest in a subject following insertion of the nucleic acid construct without overshooting. Other methods, such as when a subject has no preexisting immunity against an immunogen to be administered, use B cell depleting agents (e.g., anti-CD20×CD3 antibody or functional fragment thereof) to mitigate immune response and facilitate redosing of nucleic acid constructs encoding a polypeptide of interest and nuclease agents targeting a target genomic locus to achieve, for example, a step-wise increase in expression of a polypeptide of interest in a subject following insertion of the nucleic acid construct without overshooting.