Engineered Autologous HSCs With Modified HLA Alleles for Autoimmunity
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current treatments for autoimmune diseases primarily target symptoms rather than the root cause, leading to ineffective long-term remission and significant side effects, while existing stem cell transplants either fail to address the underlying issue or pose risks like graft-versus-host disease.
Innovation Solution
Engineering autologous hematopoietic stem cells (HSCs) to express modified HLA alleles with altered antigen binding affinity and specificity, targeting susceptible HLA alleles associated with autoimmune diseases, thereby reducing autoimmunity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments for autoimmune diseases target symptoms rather than the root cause, then short-term symptom relief is achieved, but long-term remission is ineffective and side effects are significant
Solution Approach 1:
The patent applies preliminary action by genetically modifying hematopoietic stem cells before transplantation to express HLA alleles with altered peptide-binding properties. This pre-modification ensures that the regenerated immune system is inherently resistant to autoimmunity from the outset, rather than treating symptoms after the autoimmune response has developed. The stem cells are engineered ex vivo with specific HLA allele variations that prevent binding of autoantigens, and then transplanted to regenerate the entire immune system with this protective characteristic built-in.
2Reliability
If stem cell transplants are used to address the underlying issue of autoimmunity, then the root cause may be targeted, but risks like graft-versus-host disease arise
Solution Approach 1:
The patent applies local quality by making targeted, specific modifications to the HLA alleles expressed on the stem cells rather than performing broad immunosuppression or using fully matched allogeneic transplants. The HLA alleles are engineered with specific amino acid substitutions in the peptide-binding groove that selectively alter antigen presentation capabilities while maintaining other immune functions. This localized genetic modification approach treats the root cause (autoantigen presentation) without requiring broad immune system disruption, thereby reducing graft-versus-host disease risk.
Solution Approach 2:
The patent uses an intermediary approach by employing autologous stem cells (from the patient's own body) rather than allogeneic donor cells. The patient's own stem cells are harvested, genetically modified to express HLA alleles with altered peptide-binding properties, and then retransplanted. This autologous intermediary approach eliminates HLA mismatching between donor and recipient, significantly reducing the risk of graft-versus-host disease while still enabling root cause treatment through HLA allele engineering.
3Reliability
If HLA alleles are engineered to alter antigen binding affinity and specificity, then autoimmune susceptibility is reduced, but the complexity of the treatment increases
Solution Approach 1:
The patent applies parameter changes by modifying specific physical-chemical parameters of the HLA protein structure, namely the amino acid sequence in the peptide-binding groove. Specific amino acid residues are substituted to alter the electrostatic, hydrophobic, or steric properties of the binding groove, thereby changing peptide-binding affinity and specificity. For example, changing charged residues to opposite charges or altering hydrophobicity at key positions modifies which peptides can bind, preventing autoantigen presentation while maintaining MHC class I or II function. This targeted parameter modification achieves autoimmunity prevention through precise molecular tuning rather than complex multi-component therapies.
Data Source
AI summary
Methods of preventing or treating autoimmune disease are disclosed. In some cases, subjects with having or at risk of developing autoimmune disease are identified as possessing one or more autoimmunity-susceptibility HLA alleles at one or more HLA loci. In many cases, the HLA loci are selected from Class I and Class II loci, for example Class I A, B, and C, and Class II DQ, DR, and DP. In many cases, subjects suffering from or at risk of developing an autoimmune disease may be administered a plurality engineered autologous HSCs modified to carry and express a variant susceptibility allele having at least one mutation in the antigen binding cleft that alters antigen binding and/or specificity of that variant HLA molecule. In many embodiments, the engineered HSCs are CD34+ immune cells that express one or more modified HLA proteins.