Chimeric Antigen Receptor Therapy Targeting Misfolded Proteins for Neurodegenerative Disease Treatment

In Alzheimer's disease and related dementias (ADRD), cells in the brain generate more misfolded/toxic protein variants than they can clear. The resultant toxic protein variants can kill neurons, and depending on which protein variants and which brain regions, can lead to AD or other ADRDs, or combinations of these diseases. There have been a significant number of clinical failures in the ADRD space, and new evidence suggests that targeting neurotoxic intracellularly generated protein variants may be a better approach versus trying to reduce plaque load in general.

 

Chimeric antigen receptor (CAR) therapeutics have revolutionized cancer treatment. The original construction was a CAR-T cell for targeting tumor cells. T cells can kill tumor cells by activating the immune system. Targeting the T cell to antigens dominant on cancer cells can direct the activity to cancer cells. The key to selectively targeting cancer cells is to utilize an antibody as the CAR part that selectively recognizes an antigen on the cancer cell surface. Current CAR therapeutics primarily target antigens that are enriched but not unique to cancer cells, therefore off target activity can be a substantial problem. Since neurodegenerative diseases already involve inflammation in the brain, such treatment must be very careful to minimize inflammation.

 

Prof. Michael Sierks, a pioneer in the neurodegenerative disease space at Arizona State University, has developed an innovative therapeutic approach utilizing a proprietary panel of highly specific antibody-based reagents to engineer chimeric antigen receptor constructs that selectively recognize and remove toxic, misfolded protein variants associated with neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and ALS. While CAR-T, CAR-NK or CAR-M may be utilized, employing natural killer or macrophage cells as CAR hosts may minimize harmful inflammatory responses common in traditional CAR-T treatments.

 

This system enables customizable, precise targeting of multiple pathogenic proteins simultaneously or tailored to individual patient profiles, offering a transformative advancement in treating neurodegenerative disorders.

 

Potential Applications

Benefits and Advantages

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