Modulation of mitochondrial transport for neuropathy treatment

This technology proposes to modulate mitofusin-regulated microtubule acetylation for the treatment of peripheral neuropathy.

Unmet Need: Therapeutic target for the treatment of peripheral neuropathies

Mutations in Mitofusin-2 (MFN2) cause sensory loss in peripheral neuropathies like Charcot-Marie-Tooth Type 2A (CMT2A), with potential ties to a loss of acetylated tubulin. Mitochondria contacts with microtubules are hotspots of α-tubulin acetylation through the recruitment of α-tubulin acetyltransferase (ATAT1) by MFN2, and mutations of MFN2 that impact this activity cause CMT2A. While histone deacetylase (HDAC) inhibition has been identified as a promising therapeutic strategy for peripheral neuropathies, there are concerns about tubulin specificity. This suggests that targeting αTAT1 activity may offer a successful and tubulin-specific therapeutic approach for restoring sensory neuron function in CMT2A and potentially other related CMT subtypes.

The Technology: Modulation of mitofusin-regulated microtubule acetylation for neuropathy treatment

This technology describes methods for the modulation of acetyltransferase 1 (ATAT1) activity for the prevention of peripheral axonal degeneration caused by a disruption to acetylated tubulin-mediated mitochondrial transport. This technology proposes to target MFN2-mediated recruitment of ATAT1 to mitochondrial membranes to restore tubulin acetylation and mitochondrial transport using tubulin deacetylase inhibitors or tubulin acetylation activators. The identification of the importance of acetylation also enables risk assessment for patients with developing peripheral neuropathies. Modulation of mitochondrial transport through MFN2-dependent recruitment of ATAT1 potentially represents a therapeutic approach for CMT2A and other peripheral neuropathies.

This technology has been validated using primary sensory neurons isolated from mice and Drosophila.

Applications:

• Acetylated tubulin as a biomarker of peripheral neuropathies
• Therapeutic targets for CMT2A and other neuropathies
• Research tool for studying mitochondrial transport and tubulin acetylation in vitro and in vivo
• Intervention for mitochondrial disorders
• Treatment for Alzheimer’s and Parkinson’s diseases targeting microtubule-associated tau and a-synuclein clearance

Advantages:

• Versatile modulation system
• Highly specific to tubulin; no undesired side effects as for HDAC6 inhibitors
• Broad clinical relevance
• Straightforward small molecule design

Lead Inventor:

Francesca Bartolini, Ph.D.

Patent Information:

Patent Pending(US19/547,316)

Related Publications:

• Kumar A, Larrea D, Pero ME, Infante P, Conenna M, Shin GJ, Van Elias V, Grueber WB, Di Marcotullio L, Area-Gomez E, Bartolini F. “MFN2 coordinates mitochondria motility with α-tubulin acetylation and this regulation is disrupted in CMT2A.” iScience. 2024 May 15; 27(6):109994.

• Kumar A, Larrea D, Pero ME, Infante P, Conenna M, Shin GJ, Grueber WB, Di Marcotullio L, Area-Gomez E, Bartolini F. “MFN2-dependent recruitment of ATAT1 coordinates mitochondria motility with alpha-tubulin acetylation and is disrupted in CMT2A.” bioRxiv [Preprint]. 2023 Mar.

Tech Ventures Reference:

• IR CU24079

• Licensing Contact: Kristin Neuman