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) through an unknown mechanism. 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. Several lines of evidence suggest that the loss of acetylated tubulin plays a pathogenic role in CMT2A. Specifically, mutant MFN2 knock-in mice exhibit a deficiency of acetylated tubulin in the distal axons of their long peripheral nerves.

Moreover, HDAC6 inhibition has been identified as a promising therapeutic strategy for various toxic and hereditary peripheral neuropathies, including CMT2A. However, since HDAC6 deacetylates multiple lysine residues on α- and β-tubulin and has other substrates, this raises concerns about its specificity for tubulin. In contrast, ATAT1 is uniquely specific to tubulin as its substrate. Additionally, mutated forms of the formin INF2 are known to cause dominant intermediate CMT in conjunction with FSGS. INF2 positively regulates tubulin acetylation by influencing microtubule stability and αTAT1 expression. 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 axonal degeneration. Mutations in MFN2 cause axonal degeneration by sequestering ATAT1 at sites of mitochondria and microtubule contact and thus disrupting 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. 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.

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

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