Autophagy activating nucleotide sequence for neurodegenerative disease treatment

This technology is a nucleotide sequence for amplifying the expression of WDFY3 gene or its encoded protein, Autophagy-Linked FYVE (ALFY), that can be used to promote protein aggregate clearance in neurodegenerative diseases.

Unmet Need: Effective protein aggregate clearance for treating neurodegenerative diseases

Many adult-onset neurodegenerative diseases, such as Alzheimer’s, Huntington’s, and Parkinson’s diseases, share the pathological feature of misfolded protein aggregates in the brain. Current methods to treat neurodegenerative diseases have been targeting these aggregates. However, their efficacy has been limited in both reducing the aggregates and slowing disease progression. Neurons have the innate ability to selectively degrade protein aggregates with macroautophagy; activating this inherent mechanism can enable more effective clearance of aggregates and treatment of neurodegenerative diseases.

The Technology: Nucleotide sequence amplifies protein aggregate-specific degradation

This technology is a nucleotide sequence that activates the degradation of pathogenic protein aggregates by increasing the levels of Autophagy-Linked FYVE (ALFY) protein, encoded by the gene WDFY3. Universally expressed in the brain, ALFY is an adapter protein critical for the selective clearance of protein aggregates via the autophagy pathway. ALFY levels are increased by administering the truncated or full-length long-coding RNA WDFY3-AS2. Upregulating WDFY3-AS2 augments the expression of WDFY3 and ALFY. In mouse models of Huntington’s, Parkinson’s, and Alzheimer’s diseases, overexpressing ALFY decreased protein aggregate levels in the brain and protected against disease pathogenesis.

Applications:

• Prevention, inhibition, or treatment of diseases associated with misfolded protein aggregates, such as Huntington's and Parkinson’s diseases
• Research tool for studying protein aggregates, stress granules, or autophagy in homeostasis and disease
• Research model for studying neurodegenerative diseases
• Research model for drug discovery related to neurodegenerative diseases

Advantages:

• Selective for protein aggregates
• Effective for multiple types of pathological protein aggregates
• Compatible with multiple methods of delivery into cells
• Activates innate cellular pathway

Lead Inventor:

Ai Yamamoto, Ph.D.

Patent Information:

Patent Pending (WO/2024/233957)

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): 813-821.

• 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): 265-279.

Tech Ventures Reference:

• IR CU23286

• Licensing Contact: Kristin Neuman