Mitochondrial Complex I Deficiency

Researchers have identified a new therapeutic target that could lead to more effective treatment of glaucoma. Indiana University School of Medicine researchers have identified a new therapeutic target that could lead to more effective treatment of glaucoma. Glaucoma is a neurodegenerative disease that causes vision loss and blindness due to a damaged optic nerve. More than 200,000 people are affected by glaucoma in the United States each year. Unfortunately, there is currently no treatment. In a newly published paper in Communications Biology, researchers found neurons use mitochondria for a steady source of energy, and restoring mitochondrial homeostasis in the diseased neurons can protect the optic nerve cells from being damaged. "Age-related neurodegenerative disease, which includes glaucoma, Parkinson's disease, and amyotrophic lateral sclerosis (ALS), is the biggest global health problem," said Arupratan Das, PhD, assistant professor of ophthalmology and principal investigator of the study. "The fundamental mechanisms that we discovered can be used to protect neurons in glaucoma and be tested for the other diseases. We have identified a critical step of complex mitochondrial homeostasis process, which rejuvenates the dying neuron, similar to giving a lifeline to a dying person." The research team, led by Michelle Surma and Kavitha Anbarasu from the Department of Ophthalmology, used induced pluripotent stem cells (iPSCs) from patients with and without glaucoma as well as clustered regularly interspaced short palindromic repeats (CRISPR) engineered human embryonic stem cells with glaucoma mutation. Using stem cell differentiated retinal ganglion cells (hRGCs) of the optic nerve, electron microscopy and metabolic analysis, researchers identified glaucomatous retinal ganglion cells suffer mitochondrial deficiency with more metabolic burden on each mitochondrion. This leads to mitochondrial damage and degeneration. Mitochondria are the tube like structures in cells which produce adenosine triphosphate, cell's energy source. However, the process could be reversed by enhancing mitochondrial biogenesis by a pharmacological agent. The team showed retinal ganglion cells are highly efficient in degrading bad mitochondria, but at the same time producing more to maintain homeostasis. "Finding that retinal ganglion cells with glaucoma produce more adenosine triphosphate even with less mitochondria was astonishing," Das said. "However, when triggered to produce more mitochondria, the adenosine triphosphate production load was distributed among more mitochondrion which restored the organelle physiology. It is similar to a situation where a heavy stone is carried by fewer people versus a greater number of people -- each person will have less pain and injury, just like each mitochondrion will have less difficulty and damage." In the future, Das would like to test if these mechanisms protect the optic nerve in animal models under injury before testing in humans to hopefully lead to new clinical interventions.

CY6463 alleviated mitochondrial dysfunction and reduced inflammation in preclinical models of mitochondrial complex 1 deficiency Data provide support for ongoing CY6463 clinical studies in CNS diseases associated with mitochondrial dysfunction CAMBRIDGE, Mass., June 17, 2022 (GLOBE NEWSWIRE) -- Cyclerion Therapeutics, Inc. (Nasdaq: CYCN), a clinical-stage biopharmaceutical company on a mission to develop treatments that restore cognitive function, today announced research from preclinical studies demonstrating treatment with its lead soluble guanylate cyclase (sGC) stimulator, CY6463, was associated with improved cellular energetics and reduced inflammation in preclinical models of mitochondrial disease. The data will be presented today at the 10th International Conference on cGMP, taking place June 17-19, 2022, in Augsburg, Germany. “We’re excited to share results highlighting the beneficial impact of sGC stimulation in multiple preclinical models of mitochondrial disease,” said Juli Jones, Ph.D, Head of Disease Biology at Cyclerion Therapeutics. “These results are consistent with our recent clinical data in MELAS patients demonstrating that CY6463 was associated with improvements across multiple domains of disease activity, including mitochondrial function and inflammation, and further support the therapeutic potential of CY6463 to address a broad range of diseases characterized by mitochondrial dysfunction.” Data will be presented by Emmanuel Buys, Ph.D., Head of Network Excellence at Cyclerion Therapeutics in a poster titled, “CY6463, a CNS-penetrant sGC stimulator, elicits benefits in preclinical models of mitochondrial complex 1 deficiency” during today’s poster session. The poster is made available on the Cyclerion website on the following link. Presentation highlights: CY6463 significantly increased ATP levels in lymphoblasts derived from patients with mitochondrial complex 1 deficiency (Leber hereditary optic neuropathy or Leigh syndrome)CY6463 restored mitochondrial gene expression in lymphoblasts derived from patients with mitochondrial complex 1 deficiency (Leber hereditary optic neuropathy or Leigh syndrome)CY6463 significantly decreased the astrocytic marker, GFAP, linked to inflammation in a mouse model of mitochondrial complex 1 deficiency About CY6463CY6463 is the first CNS-penetrant sGC stimulator to be developed as a symptomatic and potentially disease-modifying therapy for serious CNS diseases. The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signaling pathway is a fundamental mechanism that precisely controls key aspects of physiology throughout the body. In the CNS, the NO-sGC-cGMP pathway regulates diverse and critical biological functions including neuronal function, neuroinflammation, cellular bioenergetics, and vascular dynamics. Although it has been successfully targeted with several drugs in the periphery, this mechanism has yet to be fully leveraged therapeutically in the CNS, where impaired NO-sGC-cGMP signaling is believed to play an important role in the pathogenesis of many neurodegenerative and neuropsychiatric diseases and other disorders associated with cognitive impairment. As an sGC stimulator, CY6463 acts as a positive allosteric modulator to sensitize the sGC enzyme to NO, increase the production of cGMP, and thereby amplify endogenous NO signaling. By compensating for deficient NO-sGC-cGMP signaling, CY6463 and other sGC stimulators may have broad therapeutic potential as a treatment to improve cognition and function in people with serious CNS diseases. About Cyclerion Therapeutics Cyclerion Therapeutics is a clinical-stage biopharmaceutical company on a mission to develop treatments that restore cognitive function. Cyclerion is advancing novel, first-in-class, CNS-penetrant, sGC stimulators that modulate a key node in a fundamental CNS signaling pathway. The multidimensional pharmacology elicited by the stimulation of sGC has the potential to impact a broad range of CNS diseases. The most advanced compound, CY6463, has shown rapid improvement in biomarkers associated with cognitive function and is currently in clinical development for Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like episodes (MELAS), Cognitive Impairment Associated with Schizophrenia (CIAS) and Alzheimer's Disease with Vascular pathology (ADv). Cyclerion is also advancing CY3018, a next-generation sGC stimulator. Forward Looking StatementCertain matters discussed in this press release are “forward-looking statements”. We may, in some cases, use terms such as “predicts,” “believes,” “potential,” “continue,” “estimates,” “anticipates,” “expects,” “plans,” “intends,” “may,” “could,” “might,” “will,” “should”, “positive” or other words that convey uncertainty of future events or outcomes to identify these forward-looking statements. In particular, the Company’s statements regarding trends and potential future results are examples of such forward-looking statements. The forward-looking statements include risks and uncertainties, including, but not limited to, the success, timing and cost of our ongoing or future clinical trials and anticipated clinical trials for our current product candidates; our ability to fund additional clinical trials to continue the advancement of our product candidates; the timing of and our ability to obtain and maintain U.S. Food and Drug Administration (“FDA”) or other regulatory authority approval of, or other action with respect to, our product candidates; the Company’s ability to successfully defend its intellectual property or obtain necessary licenses at a cost acceptable to the Company, if at all; the successful implementation of the Company’s research and development programs and collaborations; the acceptance by the market of the Company’s product candidates, if approved; and other factors, including general economic conditions and regulatory developments, not within the Company’s control. The factors discussed herein could cause actual results and developments to be materially different from those expressed in or implied by such statements. The forward-looking statements are made only as of the date of this press release and the Company undertakes no obligation to publicly update such forward-looking statements to reflect subsequent events or circumstance. For more information about Cyclerion, please visit cyclerion.com and follow us on Twitter and LinkedIn. Investors Carlo Tanzi, Ph.D. Kendall Investor Relations ctanzi@kendallir.com Media Amanda Sellers Verge Scientific Communications asellers@vergescientific.com

Recently, researchers with the Institute of Life in Athens, Greece, announced that a healthy baby boy was born who basically had the DNA from three people. The child was born to a 32-year-old woman who had failed in four cycles of in vitro fertilization (IVF). In the science fiction TV show, “ The Expanse ,” based on the books by James S.A. Corey, the main character , James Holden, is a Montana native born to eight parents as part of a genetic collective. Science fiction? Sure. But maybe not that far in the future. Recently, researchers with the Institute of Life in Athens, Greece, announced that a healthy baby boy was born who basically had the DNA from three people. The child was born to a 32-year-old woman who had failed in four cycles of in vitro fertilization (IVF). The boy was born from a technique known as maternal spindle transfer. In this procedure, the DNA found in the nucleus of a mother’s egg was removed. From a donor egg, the nucleus was emptied of DNA and the mother’s DNA was inserted. The donor egg with the mother’s genes was fertilized with sperm from the father, developed into an embryo, and transferred for pregnancy. So there was DNA from the original mother and DNA from the father. What about the third person’s DNA? That comes from mitochondrial DNA of the woman who donated the egg. Mitochondria are organelles found in the cytoplasm—not the nucleus—in most eukaryotic cells. They have numerous functions but are typically called the powerhouse of the cell for their role in energy production and respiration. There are several diseases related to mitochondrial dysfunction, as well as cardiac disease, heart failure and autism. They are also increasingly being implicated in some types of infertility. The key point is that because mitochondria are in the cytoplasm, they are not passed down by males, but are passed down in the eggs of females. In the Greece case study, the child inherited mitochondrial DNA from the woman who supplied the donor egg, as well as nuclear DNA from the mother and the father. The technique has been performed in the U.S. as well, but not for implantation. That is because of a 2015 congressional amendment, the 1996 Dickey-Wicker Amendment, that prevents the U.S. Food and Drug Administration (FDA) from considering human research “in which a human embryo is intentionally created or modified to include a heritable genetic modification.” In one case in the U.S., researchers at Columbia University in New York created similar embryos with genetic material from three people, but they have been frozen in hopes that a legal path forward might be found. In this case, Dietrich Egli, assistant professor of developmental cell biology at Columbia, used mitochondrial replacement therapy to create embryos for four female patients. All the women are carriers of mitochondrial genetic disorders, which is a different scenario than the one in Greece. Because the U.S. amendment prevents the use of federal funds for creating human embryos for research purposes, Egli and his team, which includes neurologist Michio Hirano, have turned to philanthropic funds. A STAT article also points out that a New York-based fertility specialist, John Zhang, went to Mexico in 2015 as a workaround of the U.S. law. Zhang transferred an embryo via mitochondrial replacement therapy into a woman who was a carrier of Leigh syndrome. She delivered an apparently healthy child in April 2016. Leigh syndrome is a severe neurological disorder that typically shows signs in the first year of life. It is characterized by progressive loss of mental and movement abilities, and usually causes death within two to three years, generally from respiratory failure. The disease can be caused by mutations in one of more than 75 different genes, most of which are found in the nuclear DNA. However, about 20% of Leigh syndrome patients have a mutation in mitochondrial DNA (mtDNA). For the case in Greece, the mother had gone through four rounds of IVF without becoming pregnant. Something in her egg apparently prevented a viable embryo from forming when it was fertilized. Although there are potentially many causes for that, problems with mtDNA can be part of it. Panagiotis Psathas, president of the Institute, stated, “We are now in a position to make it possible for women with multiple IVF failures or rare mitochondrial genetic diseases to have a healthy child.” Jonathan Tilly, chair of the department of biology at Northeastern University, told Time , “All the historical data, including preclinical animal data and clinical data with people, fall into line with the idea that something significant is going on that lends itself to infertility and poor egg and embryo quality—and the bulk of those data point to mitochondrial deficiency or mitochondrial dysfunction.” Although the motivations behind the U.S. federal government ban on these types of procedures are complex, often with religious objections, there are good reasons to question the wisdom of germ cell edits in embryos that have nothing to do with the abortion debate. The recent case of the Chinese researcher , He Jiankui, who used CRISPR gene editing within IVF to modify the CCR5 gene in human embryos, resulting in the birth of a set of twins and another pregnancy, is a good example. The CRISPR procedures were broadly condemned worldwide for violating moral and ethical standards. That was largely because the procedure was not medically necessary and that not enough was known about the technology, such as concerns about off-target CRISPR edits that might cause unforeseen problems, such as cancer. Also, when germline embryos are edited, if viable, the babies born would pass those same edits down to their children and so on. Some critics and ethicists are concerned that maternal spindle transfer and similar techniques will just lead to germline editing. That’s an argument that may not necessarily hold up to scrutiny and seems reminiscent of arguments against in vitro fertilization In the wake of the China CRISPR scandal, leading scientists worldwide have called for a moratorium on heritable genome editing. Whether that includes maternal spindle transfer remains to be seen, although it seems unlikely. Of the Greece case, however, Tilly told Time , “Success like this might lead to bypassing the need to use donor eggs at all and allow us to go back and fix the problems in the egg itself. There could be a whole host of things that are defective in the egg, from enzymes, lipids and anything that floats around in the cytoplasm. To me, that’s the exciting aspect of this—moving the science forward to understand what those factors are.”