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EP-4736888-A1 - COMPOSITION FOR PREVENTING, ALLEVIATING, OR TREATING MITOCHONDRIAL COMPLEX 1 DISORDERS, COMPRISING RECOMBINANT ADENO-ASSOCIATED VIRUS VECTOR LOADED WITH HYDRA NDI1

EP4736888A1EP 4736888 A1EP4736888 A1EP 4736888A1EP-4736888-A1

Abstract

The present disclosure relates to a composition for the prevention, alleviation, or treatment of mitochondrial complex 1 disorders, including a recombinant adeno-associated virus (AAV) vector loaded with Hydra NDi1. The inventors have confirmed that the scAAV-Hydra NDi1 of the present disclosure has an effect of restoring cellular respiration reduction caused by rotenone and an effect of inhibiting the apoptosis of LHON patient-derived cells by rotenone. Thus, the scAAV-Hydra NDi1 is expected to be useful for preventing, alleviating, or treating not only LHON but also diseases caused by abnormalities in mitochondrial complex 1.

Inventors

  • KEE, CHANG WON
  • SOHN, Seong Soo
  • PARK, KYUNG AH

Assignees

  • Samsung Life Public Welfare Foundation

Dates

Publication Date
20260506
Application Date
20240701

Claims (8)

  1. A pharmaceutical composition for preventing or treating mitochondrial disorder, comprising a recombinant viral vector loaded with a hydra NDi1 gene represented by SEQ ID NO: 1.
  2. The pharmaceutical composition for preventing or treating mitochondrial disorder of claim 1, wherein the recombinant virus is an adeno-associated virus.
  3. The pharmaceutical composition for preventing or treating mitochondrial disorder of claim 2, wherein the adeno-associated virus is a self-complementary AAV (scAAV).
  4. The pharmaceutical composition for preventing or treating mitochondrial disorder of claim 1, wherein the recombinant viral vector inhibits reduction of cellular respiration.
  5. The pharmaceutical composition for preventing or treating mitochondrial disorder of claim 1, wherein the recombinant viral vector inhibits apoptosis.
  6. The pharmaceutical composition for preventing or treating mitochondrial disorder of claim 1, wherein the mitochondrial disorder is caused by a mutation in one or more genes selected from the group consisting of NADH dehydrogenase subunit 1 (ND1), NADH dehydrogenase subunit 4 (ND4), and NADH dehydrogenase subunit 6 (ND6).
  7. The pharmaceutical composition for preventing or treating mitochondrial disorder of claim 1, wherein the mitochondrial disorder is selected from the group consisting of Leber's hereditary optic neuropathy (LHON), mitochondrial encephalopathy with lactic acidosis and stroke-like episode (MELAS) syndrome, neurogenic muscle weakness, myoclonic epilepsy with ragged red fiber (MERRF) syndrome, mitochondrial encephalomyopathy, Leigh syndrome, and Kearns-Sayre syndrome.
  8. A method for preventing or treating mitochondrial disorder, comprising administering to a subject a pharmaceutical composition for preventing or treating mitochondrial disorders comprising a recombinant viral vector loaded with a hydra NDi1 gene represented by SEQ ID NO: 1.

Description

[Technical Field] The present disclosure relates to a composition for preventing, alleviating or treating mitochondrial complex 1 disorders, including a recombinant adeno-associated virus vector loaded with Hydra NDi1. [Background Art] Mitochondrial genetic diseases caused by mutations in mitochondrial genomes were first reported about 30 years ago, and since then, there have been rapid advances in understanding numerous diseases caused by mutations in the mitochondrial genomes and mitochondrial genetics involved in the transmission of the mitochondrial genomes. Approximately thousands of mitochondrial genomes exist within a cell, and most mutated mitochondrial genomes are mixed with normal genomes within the cell, which is called heteroplasmy. The severity of disease symptoms varies depending on the proportion of mutated genomes, and the higher the proportion of mutated genomes, i.e. the higher the heteroplasmy, the more severe the symptoms. Mitochondrial genome mutations caused in the same manner are highly variable in heteroplasmy according to each tissue of the human body or each subject, and much research is still needed to elucidate mechanisms that control the heteroplasmy. Leber's hereditary optic neuropathy (LHON) is a mitochondrial disease that causes sudden, painless loss of vision in both eyes due to characteristic damage to the optic nerves at a young age, and was first described in 1871 by the German ophthalmologist, Theodore Leber. The LHON is mainly developed in men (about 80%) more than in women, and in the women, the LHON is developed later and more severely affected. The developed time is usually between the ages of 18 and 30, but the LHON may occur at all ages without warning, and cause simultaneous or sequential loss of vision in both eyes acutely or subacutely. The frequency of occurrence is not yet known exactly. The LHON is the first genetic disease discovered to be inherited due to mutations in mitochondrial DNA (mtDNA), and is a disease that is inherited only through the maternal line. Most patients have a family history from the maternal line, but 40% of the patients have spontaneous cases. Mitochondria are important intracellular organelles that produce energy (ATP) used for biological activities, and have independent genes, unlike nuclear genes. Most genetic diseases are caused by defects in genes within the nucleus, but some genetic diseases may be caused by abnormalities in mitochondrial genes. A pair of genes in the nucleus is inherited from parents, respectively, but mitochondrial genes are inherited only from the maternal line because mitochondria, which contain paternal genes in the sperm's tail, fall off during fertilization and do not enter the egg. The LHON accounts for 30 to 50% of idiopathic optic neuropathy occurring in both eyes and 2% of legal blindness. Approximately 90% of LHON has one of three point mutations of G11778A (approximately 70% worldwide), G3460A, and T14484C (most common in people of mixed French and Canadian descent), and several other point mutation genes have been identified. Most people have one mutated gene (homoplasic), but rarely have two or more mutated genes (heteroplasic). Although the exact pathogenesis of the disease is unknown, it is considered that a defective mitochondrial gene is involved in a normal cell division and a cell growth process, which causes problems with energy production in optic nerve cells, resulting in cell destruction. Although drug therapy administering vitamin C, vitamin B12 or idebenone may have an effect of alleviating damage to retinal ganglion cells in patients with the disease, the effect thereof is minimal, so that the drug therapy is not widely used in clinical practice, and has the limitation of not being able to fundamentally prevent the disease. Therefore, there is currently no suitable therapy, and only genetic therapy may be fundamental treatment. Accordingly, the present inventors produced a recombinant viral vector containing hydra NDi1 to effectively treat mitochondrial disorders, and experimentally demonstrated that the vector was used to prevent, alleviate, and treat mitochondrial disorders, and then completed the present disclosure. [Disclosure] [Technical Problem] An object of the present disclosure is to provide a pharmaceutical composition for preventing or treating mitochondrial disorders, including a recombinant viral vector loaded with a hydra NDi1 gene represented by SEQ ID NO: 1. Another object of the present disclosure is to provide a method for preventing or treating mitochondrial disorders, including administering to a subject a pharmaceutical composition for preventing or treating mitochondrial disorders including a recombinant viral vector loaded with a hydra NDi1 gene represented by SEQ ID NO: 1. However, technical objects to be achieved by the present disclosure are not limited to the aforementioned objects, and other objects which are not mentioned can be clearly understood to those