Augmenting Alfy levels for neurodegenerative diseases

This technology is a method to modify Alfy protein levels to modulate levels of protein aggregation and clearance in the brain and other tissues to prevent, inhibit or treat a proteinopathy.

Unmet Need: Therapeutic that reduces pathologic protein aggregates

Neurodegenerative conditions such as Alzheimer's, Parkinson's, and Huntington's Disease stem from the abnormal accumulation of proteins within neurons. Under normal circumstances, cells utilize a cellular process known as aggrephagy to identify and disassemble these protein clusters. However, in the context of disease, neurons struggle to efficiently activate aggrephagy, leading to the build-up of toxic protein aggregates. Consequently, these neurons perish due to the harmful protein accumulation, giving rise to the symptoms associated with neurodegenerative diseases in affected individuals.

The Technology: Modulating aggregate clearance with Alfy

This technology identifies increasing aggrephagy protein Wdfy3 (Alfy) expression via either augmentation or a single base change in its DNA coding sequence, as a method of improving aggregate protein clearance from cells. To modify Alfy, isolated nucleic acid or viral vectors are administered. This alternative protein sequence also targets specific protein aggregates implicated in many neurodegenerative diseases, leading to neuroprotection. Neurodegenerative mouse models with intrastriatal injections with Alfy experienced delayed symptom onset and better survival rates. As such, augmenting Alfy may inhibit or treat protein aggregation diseases, particularly within the context of neurodegeneration.

This technology has been validated in mouse models and human-derived cells.

Applications:

• Therapeutic for neurodegenerative disease
• Research tool for studying protein aggregation
• Research tool to assess effects of differential ALFY protein expression
• Research model for drug discovery related to neurodegeneration
• Research model for studying Huntington’s Disease, Parkinson’s disease, or Lou Gehring’s disease

Advantages:

• Modified version of a native protein
• Relatively simple synthetic method
• Compatible with viral delivery methods
• Compatible with the CRISPR/Cas9 system
• Effective in animal models
• Recognizes multiple types of protein aggregates

Lead Inventor:

Ai Yamamoto, Ph.D.

Patent Information:

Patent Pending (WO/2023/091943)

Related Publications:

• Fox LM, Kim K, Johnson CW, Chen S, Croce KR, Victor MB, Eenjes E, Bosco JR, Randolph LK, Dragatsis I, Dragich JM, Yoo AS, Yamamoto A. “Huntington's Disease Pathogenesis Is Modified In Vivo by Alfy/Wdfy3 and Selective Macroautophagy.” Neuron. 2020 Mar 4; 105(5): pp. 813-821

• Eenjes E, Dragich JM, Kampinga HH, Yamamoto A. Distinguishing aggregate formation and aggregate clearance using cell-based assays. J Cell Sci. 2016 Mar 15; 129(6): pp. 1260-70

• Filimonenko M, Isakson P, Finley KD, Anderson M, Jeong H, Melia TJ, Bartlett BJ, Myers KM, Birkeland HC, Lamark T, Krainc D, Brech A, Stenmark H, Simonsen A, Yamamoto A. The selective macroautophagic degradation of aggregated proteins requires the PI3P-binding protein Alfy. Mol Cell. 2010 Apr 23; 38(2): pp. 265-79

Tech Ventures Reference:

• IR CU22103, CU23286

• Licensing Contact: Beth Kauderer