Towards Mitochondrial Replacement Therapies
A great deal of evidence shows that declining mitochondrial function is important to the aging process. This is directly downstream of various forms of damage, such as to mitochondrial DNA. It is also a long way downstream from a range of other forms of age-related disarray that lead to epigenetic changes that impact mitochondrial function - far enough downstream that it is unclear as to how exactly the causes of aging produce this outcome. One common view is that the quality control process of mitophagy suffers as the result of reduced production of necessary proteins, and thus damaged mitochondria accumulate.
Thus we come to mitochondrial replacement as a form of therapy. Cells do take up mitochondria from the surrounding medium, and so it is possible in principle to deliver large numbers of mitochondria into the body and expect to see results. Some progress has been made in this direction; see the biotech startup Cellvie, for example. The big unanswered question for those of us interested in rejuvenation is the degree to which the effects of this therapy will last. Will fresh mitochondria quickly succumb to the same issues of the aged environment that lead to loss of native mitochondrial function? The fastest way to find out is to try.
Mitochondrial Transplantation as a Novel Therapeutic Strategy for Mitochondrial Diseases
In recent years, advances in molecular and biochemical methodologies have led to a better understanding of mitochondrial defects and their mechanisms as the cause of various diseases, but therapies for mitochondrial disorders are still insufficient. Mitochondrial transplantation is an innovative strategy for the treatment of mitochondrial dysfunction to overcome the limitations of therapies using agents. Mitochondrial transplantation aims to transfer functional exogenous mitochondria into mitochondrion-defective cells for recovery or prevention of mitochondrial diseases. Simply put, replacing an old engine with a new one to regain its function.
Recently, a considerable number of studies demonstrated the effectiveness of mitochondrial transplantation in various diseases. There are many reports of mitotherapy in tissues, animal models and even in patients, as well as in vitro. These include neurological diseases, drug-induced liver toxicity and liver disease, including fatty liver and myocardial ischemia-reperfusion injury. Several studies have evaluated the improvement in mitochondrial function via mitochondrial transfer in neurological disease models. Researchers intravenously injected mitochondria isolated from human hepatoma cells (HepG2 cells) into neurotoxin-induced Parkinson's disease (PD) mouse brain. The recipient mouse suppressed PD progression by increasing the activity of the electron transport chain (ETC), and reduced free radical generation and apoptotic cells.
To increase mitochondrial delivery efficiency, more advanced techniques have been used. One study showed the enhanced delivery and functionality of allogenic exogenous mitochondria using peptide-mediated delivery by conjugating a cell penetrating peptide, Pep-1. The result of transplanting Pep-1-labeled mitochondria into brain tissues of a PD rat model demonstrated that mitochondrial complex I protein and mitochondrial dynamics were restored in dopaminergic neurons, which also improved oxidative DNA damage. The removal of dopaminergic neuron degeneration due to a neurotoxin was also observed in the PD rat model.
I always think that Oisin's lipid nanoparticles would make a great mitochondria delivery vector.
@jimofoz
That works require much different lipid , to be able to encapsulate a mitochondrion, keep it alive and deliver it to the right cells. Ideally we need some genetically engineered cell line which homes to the desired tissues and while producing copious amounts of mitochondria. Once at the target that vehicle cells should burst and release the vesicles for absorption. Bursting will make sure the therapy effects are short lived in case something goes wrong.
Now on long vs short benefits. If we're subjective to the notion that age related deterioration is a vicious circle where reach damage reinforces the others than even a temporary relief of one type can help reduce the effects of others types too. Even if the improvements are short lived they still would be worth it if they are strong enough. And those therapies are actually perfect for the current business model of BIG PHARMA. Purple will require periodic , yet steady treatments. It seems that mitochondria will have much less immune rejection, so they could be mad produced, frozen and delivered on demand. Was a side benefit, if this whole thing works out we will have a (relatively) cheap and safe cure for many classes of genetics mitochondrial diseases.
It sounds really cool and exciting. Just a year ago , I would put this concept in the realm of science fiction.
Now it looks quite plausible.
The pharmaceutical companies should hurry up because the first to commercialize and patent this treatment will have a second Viagra killer product. Which will be needed by almost everybody above certain age.
It might turn out that even young athletes chips use it as steroid or doping.
Maybe this would be the 2nd rejuvenation treatment shortly after Senlytics.
@jimofoz: To quote Watson & Crick "It has not escaped our notice..."
@gary - always nice to see you in the comments. I'm a little surprised that you guys didn't go for any government funding with COVID as your lipid nanoparticles would also seem to be an ideal platform for getting a DNA vaccine into cells and producing proteins and actually working.
Or is the fusogenix protein in your nanoparticles actually difficult to manufacture?
The latest news on electroporosis of DNA vaccines:
https://spectrum.ieee.org/biomedical/devices/inovios-electrical-device-zaps-a-covid19-vaccine-into-the-body
"Despite the allure of nucleic-acid vaccines, none had been approved for commercial use in humans by medical regulators prior to the pandemic. In fact, most nucleic-acid-based vaccines hadn't made it past midstage clinical trials. The problem: Human cells don't readily take in foreign DNA or mRNA. After injection, much of the vaccine would remain inert in the body and eventually break down, without prompting much of an immune response.
Developers of mRNA vaccines recently resolved the issue by packaging the vaccine with chemicals. In one approach, researchers encapsulate mRNA within fat droplets called lipid nanoparticles, which fuse with the cell membrane and help the vaccine get inside.
Companies such as BioNTech, Moderna, and CureVac were in the midst of testing various mRNA vaccines against other viruses when the COVID-19 pandemic hit. Market pressure and billions of dollars from governments helped companies finish the job, and quickly. The mRNA vaccine from BioNTech, through a collaboration with Pfizer, was first to market in the United States and Europe, followed swiftly by the one from Moderna.
But the delivery strategies used for mRNA vaccines haven't worked out for DNA vaccines. That challenge has led to an outpouring of creative development and the eventual adoption of an electrical engineering approach."
Or is this a problem:
"The problem was getting the DNA, which is a big molecule, to penetrate not only through the cell's outer layers but also through the cell's nuclear membrane into the nucleus. Unlike an mRNA vaccine, which can function in parts of the cell outside the nucleus, a DNA vaccine can function only inside the nucleus. Some researchers reasoned that DNA vaccines worked well in small animals because the injection needle created pressure that damaged many surrounding cells, allowing DNA molecules to enter. But in the larger bodies of humans, the needle generates relatively little pressure, and fewer cells take in the vaccine."
Mitos already have a phospholipid outer layer
@jimofoz: We are peripherally involved in the Entos spinout, Aegis. See https://aegis.life
@gary - Ok I see Aegis are already all over it:
https://www.businesswire.com/news/home/20210416005430/en/Aegis-Life-Announces-Start-of-Phase-12-Trial-of-the-Entos-COVID-19-DNA-Vaccine-Covigenix-VAX-001-with-First-Participants-Dosed
"Aegis Life, Inc. announced today that the first participants have been dosed in a Phase 1/2 clinical trial with parent company Entos Pharmaceuticals' (Entos) Covigenix VAX-001, a novel DNA vaccine to stimulate immunity against SARS-CoV-2. Covigenix VAX-001 encodes the SARS-CoV-2 Spike (S) protein and uses novel Fusogenix technology for delivery. Using a next-generation gene delivery technology to the existing and approved mRNA vaccines, the VAX-001 DNA vaccine delivers the information needed inside cells to make the viral protein. In preclinical animal studies, VAX-001 induced a potent humoral immunity, and a balanced cell-mediated response against the novel coronavirus.
Fusogenix technology effectively and safely delivers nucleic acid cargo directly inside cells using advanced and proprietary lipid formulations, making it the ideal platform to develop and manufacture hundreds of millions of doses of safe, stable and effective vaccines. DNA vaccines also offer the advantage of stability at room temperature for one month and 4 to 8 °C for one year, which significantly simplifies shipping, storage and distribution. Aegis and Entos have also developed a second DNA vaccine candidate, in preclinical studies now, called Covigenix VAX-002, that is designed as a pan-coronavirus and emerging variant vaccine. "
Someone from Aegis' PR team should get in touch with Ieee Spectrum as this technology seems superior to that electroporosis vaccine as it is just a standard injection.
Thank you for this article.
Mitochondrial replacement is certainly promising...at our startup Mitrix we're pushing it as fast as we can! Our belief is that many different longevity treatments have great promise, but it's unlikely they will succeed if there isn't enough energy in the cell to effect changes. Essentially, the tissues in an elderly person are already "chronically energy depleted". In order for longevity treatments like Senolytics, Stem Cells, or Telomere lengthening to succeed, we need to remove that energy depletion. That's the goal of mitochondrial replacement: to provide the boost of energy that tissues as a foundation for regeneration.
We are alway interested in feedback from the Longevity community. Anybody who has ideas or wants to talk please contact Mitrix Bio any time.