Mitochondria are found in all eukaryotic cells and are essential for basic cellular function due to their principal role in the production of energy. Mitochondria contain their own highly compact mitochondrial (mt)DNA encoding 37 intron-less genes. Mutations in mtDNA occur at a 10-fold or higher rate than in nuclear DNA possibly due to the lack of histones and the very limited mtDNA repair mechanisms. Another contributing factor to mutations in mtDNA is a high concentration of free oxygen radicals.
Each mitochondrion contains between 2-10 copies of mtDNA; an individual cell may have several thousand copies of mtDNA. Homoplasty occurs when all mtDNA copies are identical within a cell. Occasionally, two or more types of mtDNA can co-exist within a cell as a mixture of mutant and normal mtDNA, a phenomenon known as heteroplasmy. Heteroplasmy allows lethal mutations to persist, but when the mutant mtDNA load reaches a certain threshold the mitochondrial function is impaired. This can lead to serious human disorders, including premature aging, myopathies, neurodegenerative diseases, diabetes, cancer and infertility.
It is estimated that at least 1 in 200 individuals have a mitochondrial DNA mutation that may lead to disease. Mitochondrial disorders or diseases attributable to defects in oxidative phosphorylation are mostly severe disorders and affect at least one in 8000 individuals (Chinnery et al., Ann Neurol, 2000. 48(2): p. 188-93). These conditions can be fatal or cause chronic morbidity. Mitochondrial disorders often affect the tissues that utilize the most ATP, such as the central nervous system, heart, skeletal muscles, liver and kidney (Gropman, Curr Neurol Neurosci Rep, 2001. 1(2): p. 185-94).
Mitochondrial diseases can be caused by genetic alterations of nuclear- or mitochondrial-encoded genes involved in the synthesis of ATP. While disorders resulting from nuclear DNA mutations follow a Mendelian pattern of autosomal recessive, dominant or X-linked inheritance, conditions that result from mtDNA defects have unique characteristics. Affected individuals are usually heteroplasmic: there is a mixture of normal and mutant mtDNA. The level of the mutant mtDNA can differ among tissues. If the mutant load (the ratio of mutant to normal mtDNA) exceeds a tissue- and individual-specific threshold, clinical features become evident, although exact genotype-phenotype correlations usually vary even within families (Chinnery et al., supra). Unlike the chromosomes, which are inherited both paternally and maternally, mtDNA is transmitted maternally (Giles et al., Proc Natl Acad Sci USA, 1980. 77(11): p. 6715-9). There is a significantly higher number of mtDNA molecules in a mature oocyte (200,000 to 300,000 copies) compared to the sperm (approximately 100 mtDNAs) (May-Panloup et al., Hum Reprod, 2005. 20(3): p. 593-7; Spikings, et al., Hum Reprod Update, 2006. 12(4): p. 401-15). Generally, sperm mitochondria that enter via fertilization are eliminated specifically during early embryo development (Sutovsky, et al., Nature, 1999. 402(6760): p. 371-2). There is a need for a feasible, efficacious and safe reproductive option designed to minimize the occurrence of mtDNA-defects in an embryo.
USPTO Backgrounds
USPTO Backgrounds