Pharmacological inhibitors and mouse models of mitochondrial DNA depletion-deletion syndromes (MDDS)

This technology is a combined disease model and therapeutic strategy for the treatment of GUK1 mutation-associated mitochondrial DNA depletion-deletion syndrome (MDDS).

Unmet Need: Therapies for mitochondrial DNA depletion-deletion syndrome

Mitochondrial DNA depletion-deletion syndromes (MDDS) are a rare group of diseases that affect mitochondrial DNA through reductions in copy number or deletions, with pathologies impacting various organs, including the brain, central nervous system, liver, kidneys, and gastrointestinal tract. These diseases often occur in infants and young children, leading to developmental defects and early death. A subset of MDDS cases is attributed to nucleotide pool imbalances, resulting in mtDNA instability, deletions, and depletions. Evidence suggests this imbalance is associated with a mutation in GUK1. Currently, there are no FDA-approved treatments for MDDS.

The Technology: Disease model and therapy for GUK1 mutation-induced diseases

These technologies combine disease models and therapeutics for mitochondrial-DNA depletion-deletion syndromes (MDDS), caused by nucleotide pool imbalances due to GUK1 mutations. Knock-in and knock-out mouse models with GUK1 mutations are established, and monitoring of MDDS progression is established. Deoxyguanosine, forodesine, or a combination of the two therapeutics is used to restore the nucleotide pool balance and enable mtDNA repair and replication. Used together, this technology increases understanding and treatment options of MDDS.

This technology has been validated in mouse models.

Applications:

• Therapeutic for mitochondrial DNA depletion-deletion syndromes (MDDS) treatment
• Potential treatment for liver injury and acute lung injury caused by MDDS
• Preventive studies for MDDS-related multiple organ failure, specifically liver failure
• Preventive studies of mtDNA release induced by hemorrhagic shock
• Biomarker identification for progressing cardiovascular disease following an ischemia-reperfusion injury
• Potential treatments for other nucleotide metabolic imbalances

Advantages:

• Increased treatment options for MDDS patients
• Ability to study mitochondrial diseases that cannot be completed on non-mammalian animal models, such as peripheral neuropathy and leukoencephalopathy
• Nucleotide target for the treatment of faulty nucleotide metabolism

Lead Inventor:

Michio Hirano, M.D.

Patent Information:

Patent Pending (WO/2024/006595)

Related Publications:

• Hidalgo-Gutierrez A, Shintaku J, Ramon J, Barriocanal-Casado E, Pesini A, Saneto RP, Garrabou G, Milisenda JC, Matas-Garcia A, Gort L, Ugarteburu O, Gu Y, Koganti L, Wang T, Tadesse S, Meneri M, Sciacco M, Wang S, Tanji K, Horwitz MS, Dorschner MO, Mansukhani M, Comi GP, Ronchi D, Marti R, Ribes A, Tort F, Hirano M. “Guanylate Kinase 1 Deficiency: A Novel and Potentially Treatable Mitochondrial DNA Depletion/Deletions Disease.” Ann Neurol. 2024 Dec;96(6):1209-1224.

Tech Ventures Reference:

• IR CU23197

• Licensing Contact: Kristin Neuman