GenSight Biologics has recently released data showing the effectiveness of GS010, the company’s gene therapy for Leber Hereditary Optic Neuropathy (LHON), a mitochondrial disease that can lead to blindness. Like in previous studies, this therapy had a bilateral effect.
Gene Therapy
In LHON, the mitochondrial protein ND4 is poorly expressed through mitochondrial DNA (mtDNA). GS010 is a gene therapy that causes this protein to be allotropically expressed in the nucleus, after which it is shuttled to the mitochondria through messenger RNA. This makes GS010 a partial treatment for mitochondrial dysfunction, which is one of the hallmarks of aging.
Scientists have made major strides when it comes to understanding the base code that underlies all living things—but what if we could program living cells like software?
The principle behind synthetic biology, the emerging study of building living systems, lies in this ability to synthesize life. An ability to create animal products, individualized medical therapies, and even transplantable organs, all starting with synthetic DNA and cells in a lab.
There are two main schools of thought when it comes to synthesizing life: building artificial cells from the bottom-up or engineering microorganisms so significantly that it resynthesizes and redesigns the genome.
With genetic engineering tools becoming more and more accessible, researchers want to use these synthesized genomes to enhance human health with regards to things like detecting infections or environmental pollutants. Bacterial cells can be engineered that will detect toxic chemicals.
And these synthesized bacteria could potentially protect us from, for example, consuming toxins in contaminated water.
Klotho, named after one of the Fates of Greek mythology, is the queen of anti-aging proteins. There are no close contenders at this time. Klotho gene therapy, like the one offered by Integrated Health Systems, has tremendous benefits. While it is produced primarily in the kidneys and brain, its soluble form circulates throughout the body. Many of the investigations so far have been done nephrologists interested in its prominent role in Chronic Kidney Disease (CKD), yet over the last decade its multifaceted role in the aging process has become a topic of intense research.
Klotho deficient mice show premature aging in multiple organs.
Inducing KL overexpression with a viral vector, like AAV, not only reverses this premature aging, but also enhances resistance to oxidative and ischemic damage. More impressive, KL outright extends the lifespans of mice, likely be inhibiting IGF and insulin signalling. Dubbed an “aging suppressor gene,” it can yield results similar to caloric restriction – what is, at this time, the most tried and true method of extending the lifespans of a variety of model organisms.
Bacterial vaginosis is a common infection in women that’s usually easily treated with antibiotics. But for those who develop recurrent infections, treatment options have been limited.
Now, Israeli researchers report they were able to put recurrent infections into remission in four out of five women who received a “vaginal microbiome transplant.” The transplant consisted of healthy bacteria collected from the vaginal fluid of donors without the condition, the researchers explained.
“Bacterial vaginosis, while not life-risking, is an exceedingly common female disorder that bears a severe toll on women’s lives, including severe discomfort, reduced self-esteem, problems in intimate relationships, social segregation and a variety of risks of developing infectious gynecological and obstetric complications,” said the study’s senior author, Dr. Eran Elinav.
When it comes to regeneration, some animals are capable of amazing feats — if you cut the leg off a salamander, it will grow back. When threatened, some geckos drop their tails as a distraction, and regrow them later.
Other animals take the process even further. Planarian worms, jellyfish, and sea anemones can actually regenerate their entire bodies after being cut in half.
Led by Assistant Professor of Organismic and Evolutionary Biology Mansi Srivastava, a team of researchers is shedding new light on how animals pull off the feat, and uncovered a number of DNA switches that appear to control genes for whole-body regeneration. The study is described in a March 15 paper in Science.
We recently had the opportunity to interview Dr. Amutha Boominathan from the SENS Research Foundation, at the Ending Age-Related Diseases 2019 conference about her research on mitochondrial repair therapies, the value of animal models, and her views on the future of aging research.
Dr. Amutha Boominathan received both her MSc and her PhD in Biochemistry from the University of Pune and the National Chemical Laboratory in India, respectively. She went on to do postdoctoral work in the U.S. relating to mitochondrial biogenesis at U. Penn and Rutgers University. She has extensively studied mechanisms of fusion and fission in mitochondria, Fe-S cluster biosynthesis, and protein import into mitochondria as part of her postdoctoral fellowship with the American Heart Association.
Currently, Amutha leads the MitoSENS program at SENS Research Foundation in Mountain view, California. Her research group is focusing on understanding mitochondrial DNA (mtDNA) mutations and restoring lost functionality as a result of these mutations by way of the allotopic expression of mitochondrial genes. Inherited mtDNA mutations can result in severe and debilitating diseases, such as NARP, Leigh’s syndrome and MELAS. Even in otherwise healthy individuals, mtDNA mutations accumulate with age. The MitoSENS team has already succeeded in stably expressing the ATP8 gene using their method and is looking forward to tackling each of the 13 mitochondrial protein genes in the coming years. Its goal is to develop safe and effective gene therapies for mitochondrial dysfunction.
The SENS Research Foundation science team is taking the next step in their work on moving mitochondrial genes into the cell nucleus, a process called allotopic expression. Having proven that they can carry out this task with the ATP8 gene in cells, they are now aiming at proof of principle in mice. This will require the production of transgenic mice, using a novel technology funded by the SENS Research Foundation called the maximally modifiable mouse. This mitochondrial project is being crowdfunded at Lifespan.io: you, I, and everyone else can contribute to advancing the state of the art one step further towards eliminating mitochondrial DNA damage as a cause of aging.
Mitochondria are the power plants of the cell, a herd of organelles descended from ancient symbiotic bacteria. They reproduce by replication and are recycled when damaged by cellular maintenance processes. Mitochondria carry the remnant of the original bacterial DNA, encoding thirteen genes vital to the process by which mitochondria package chemical energy store molecules. Unfortunately mitochondria generate reactive molecules as a byproduct of their operation, and this DNA is less well protected than the DNA of the cell nucleus. Some forms of damage to this DNA can break mitochondrial function in ways that allow the broken mitochondria to outcompete their functional peers, leading to dysfunctional cells that export massive quantities of damaging, oxidative molecules into the surrounding tissue. This contributes to conditions such as atherosclerosis, via the production of significant amounts of oxidized cholesterol in the body.
Allotopic expression of mitochondrial genes will work around this issue by providing a backup source of the proteins necessary to mitochondrial function. It has been demonstrated to work for ND4, and that project has been running for some years at Gensight Biologics to produce a therapy for inherited conditions that involve mutation of that gene. This work must expand, however, to encompass all thirteen genes of interest. So lend a hand, and help the SENS Research Foundation team take the next step forward in this process.
