Pde5 Inhibitor for Use in the Treatment of Medical Conditions Associated with Mitochondrial Complex V Deficiency

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This invention proposes the use of phosphodiesterase 5 (PDE5) inhibitors, such as sildenafil or tadalafil, to treat or prevent medical conditions caused by mitochondrial Complex V (ATP synthase) deficiency. These conditions, which include Leigh syndrome, MILS, NARP, and similar disorders, are linked to genetic mutations affecting ATP production in cells. The patent shows that PDE5 inhibitors can improve symptoms, reverse some disease manifestations, and reduce disease progression by normalizing mitochondrial function at the cellular level.

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• Treatment of Leigh syndrome (including Maternally Inherited Leigh Syndrome, MILS) caused by Complex V deficiency.
• Therapy for NARP (Neuropathy, Ataxia, and Retinitis Pigmentosa) syndrome linked to mitochondrial defects.
• Prevention of metabolic crises and organ failures in children and adults with mitochondrial Complex V mutations.
• Reduction or reversal of symptoms in patients with muscle weakness, cardiomyopathy, developmental delay, and neurological complications related to ATP synthase deficiency.
• Adjunct therapy in patients with identified genetic mutations in Complex V subunits or assembly genes, both nuclear and mitochondrial.
• Potential preventive treatment in asymptomatic individuals genetically at risk for mitochondrial Complex V deficiency-related diseases.

BenefitsContent extracted from patent full text and abstract with AI.

• Provides a disease-modifying and, in some cases, symptom-reversing therapy for previously untreatable or poorly managed mitochondrial disorders.
• Can improve quality of life and survival, preventing need for palliative care in severe cases.
• Based on drugs (PDE5 inhibitors) with well-established pharmacological profiles and safety data.
• Reduces mitochondrial membrane potential and normalizes calcium signaling in affected neurons, addressing molecular disease mechanisms.
• May be administered orally, conveniently, and adjusted in dosage according to existing medical guidelines.
• Potential to significantly expand therapeutic options for rare, life-threatening neurological and metabolic disorders.

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Patent Abstract

The invention relates to a PDE5 inhibitor for use in the treatment and/or prevention of a medical condition associated with mitochondrial Complex V (ATP synthase) deficiency in a human subject. In embodiments, the mitochondrial Complex V deficiency comprises at least one mutation within a structural subunit gene, or within an assembly gene, of the mitochondrial Complex V (ATP synthase). In embodiments, the invention relates to PDE5 inhibitors, such as sildenafil or tadalafil, in the treatment and/or prevention of a Maternally Inherited Leigh syndrome (MILS), a Neuropathy, an Ataxia or a Retinitis Pigmentosa (NARP) syndrome, or a neurological syndrome associated with a mitochondrial Complex V deficiency. In embodiments, the invention relates to treatment of mitochondrial Complex V deficiency caused by at least one mutation in nuclear or mitochondrial DNA, preferably DNA mutations in the MT-ATP6 gene causing MILS or NARP. The invention further relates to a pharmaceutical composition comprising a PDE5 inhibitor for use in the treatment and/or prevention of a medical condition associated with mitochondrial Complex V deficiency.