Delivery Systems: Building In Rejuvenation Biotechnologies

The workhorse molecules of many rejuvenation biotechnologies are not classical small-molecule drugs, but proteins – and protein-based therapies face special challenges. For one thing, proteins usually can’t be given in pill form, but have to be injected, which can be inconvenient and cause discomfort. Also, most proteins are quickly degraded by the cell’s recycling machinery and other metabolic processes, making it very difficult in many cases to deliver the quantity of protein required to have a therapeutic effect, and to keep the local tissue concentration up to therapeutic levels. And there are similar problems with delivering RNA, the “working copies” of genetic instructions that tell cells how to build proteins on their own.

An additional challenge comes from the sheer number of different protein- (or  RNA-) based therapies, each of them removing or repairing a different kind of aging damage, that will be required to fully maintain the healthy vigor of youth – and to keep the full range of age-related diseases and disabilities at bay. If each of these many protein-based therapies had to be delivered via periodic injection, the complete panel of rejuvenation biotechnologies could entail an impractically-frequent regimen of trips to rejuvenation clinics to keep up with a person’s full schedule of regeneration sessions.

Even more challengingly, the sheer size of proteins would in many cases make it difficult to get protein-based therapies into the tissues where they’re needed to repair and rejuvenate the local cellular and molecular structures. The most important such case is the brain, which is protectively shielded from the rest of the body’s circulation; this shielding will likely present a barrier to the enzymes that will be needed to clear harmful wastes out of brain cells, as part of reversing age-related cognitive decline and preventing neurological diseases such as Alzheimer’s and Parkinson’s.

As an alternative to delivering therapeutic proteins (or RNA) via pills or injections, many rejuvenation biotechnologies can be produced directly in the very tissues where they’re needed.There are two primary ways to do this: transplantation of cells and tissues that have been engineered with the ability to produce the needed proteins built into them, and somatic gene therapy to engineer that ability into our existing tissues.

Transplantation

In any case where rejuvenating a tissue already requires replacing cells, tissues, or organs lost or irreparably damaged by aging, it will be a relatively simple matter to build into them the ability to express therapeutic proteins before transplanting them into the patient. This will be especially easy and uncomplicated in cases where we are able to use cells that can be taken out of a person, nudged to multiply in a lab, and then transplanted back in: such cells will be engineered to make the needed proteins when they are first taken out of a patient, and then all of those original cells’ legions of progeny will inherit the therapeutic genes and be delivered into their target tissues in the act of being transplanted back into the original patient/donor. In fact, in those tissues (like the skin, the blood, or the gut) that continuously lose cells are therefore continuously repopulated by pools of stem cells, this approach will be used to gradually upgrade the entire tissue, until all of its cells are fortified with the ability to make therapeutic proteins.

But in many cases, the cells in a tissue needing therapeutic proteins will not be amenable to this simple cycle (extract the cells harmlessly; build in the ability to express therapeutic proteins; nudge the enhanced cells to multiply; return the enhanced cells to the tissue en masse). Some of the target cells will be lacking in the tissue, or too few or too difficult to safely harvest; some will be unable to divide; and some are the very cells that will need to be therapeutically removed, because they are stuck in a permanent abnormal metabolic state that is harmful to the surrounding tissues.

In such cases, we can create the needed cells and tissues using the rapidly-progressing techniques of cell therapy and tissue engineering – a key rejuvenation biotechnology in its own right, which in these cases can serve an additional therapeutic purposes.

There is an additional hurdle to using this approach in tissues that do not have continuous renewal, such as most of the brain. Certainly, when we are transplanting new neurons into the brain as part of maintaining and restoring cognitive function and preventing Alzheimer’s and other dementias, those replacement neurons can be used to produce therapeutic proteins. For example, such neurons could be engineered to express enzymes with the ability to break down the wastes that build up over time inside aging neurons, bypassing the difficulty of getting those proteins into the brain by injection.

But transplantating therapy-expressing neurons will not be enough to provide all the brain’s neurons with the rejuvenating proteins they need. The relatively small number cells that will need to be transplanted at any given time, as compared to the very large number of neurons in the brain as a whole, as well as the complex web of connections amongst neurons that we will not want to disrupt, all mean that we will need additional strategies to supply the brain with all the therapeutic proteins it needs.

Fortunately, it’s not necessary that all therapeutic proteins be expressed by same kind of cell that needs them. Instead, we can in many cases introduce the genes for the desired proteins into a neighboring tissue that is more amenable to repleniSENS techniques, and arrange for them to be exported from the cells that make them and imported by the ones that need them. It is quite easy to modify genes so that their encoded protein will be secreted, and there are also techniques for targeting proteins in the circulation to particular organs.

As an example, let us return to the important case of the brain. Rather than coming up with ways to engineer neurons with the ability to produce the therapeutic proteins they need to maintain function, we can take advantage of the fact that the body already has systems for transporting some of the proteins specifically needed by the brain into it from the blood supply for the body as a whole.  We have a growing understanding of how this happens, and of how we could exploit that system to get new, therapeutic proteins across the barrier between the brain and the circulation system that supplies the rest of the body. Additionally, we could engineer the ability to synthesize and secrete therapeutic proteins into the cells that maintain and renew the brain’s own, internal blood vessels.

Somatic Gene Therapy

While it is convenient to be able to engineer new therapeutic properties into cells and tissues while they are in a Petri dish or bioreactor vat and then transplant them into a person who needs both cells and therapeutic proteins, several regenerative therapies for the diseases and disabilities of aging will almost certainly require that we introduce new genes into the cells that are already in the tissue and are not going to be replaced – so-called somatic gene therapy. This is a much harder task, for several reasons.

First, when scientists engineer a new gene in a cell or tissue in isolation in the lab, they can check whether the therapeutic gene was properly taken up by the cell (and that nothing harmful happened in the process) before the cells are transplanted into the recipient. By contrast, the existing techniques of somatic gene therapy are somewhat scattershot in terms of which and how many cells they modify in a target tissue, and in the process, they sometimes cause unwanted alterations in the genes surrounding the new, therapeutic genes. These challenges have so far relegated gene therapy to a highly experimental and risky procedure for patients, which has held back its enormous potential to cure diseases caused by inherited mutations, such as sickle cell anemia, cystic fibrosis, Tay-Sachs disease, and even the BRCA1 mutation that gravely increases the risk of early breast and ovarian cancers.

Therefore, improved techniques to safely and reliably engineer therapeutic genes into our existing cells and tissues is critical to our progress toward a comprehensive panel of rejuvenation biotechnologies. Fortunately, the potential of somatic gene therapy to cure disease, ease suffering, and improve quality of life is so enormous that it receives generous funding from the national health research institutes of industrialized countries, and is also attracting increasing numbers of biotech entrepreneurs. Several novel gene therapy methods are currently under intense investigation; and as you may have heard, there has been progress in using existing (and still relatively crude) forms of somatic gene therapy to treat actual patients, notably to restore some vision to children with several inborn diseases of the eye.

Germline Gene Therapy

Finally, a word about so-called “germline” gene therapy – that is, changing the genome of either a sperm or egg cell, or of a fertilized egg, so that people are born with a therapeutic gene already present in their cells. Some people think this would always be far too dangerous to be useful, while others have argued persuasively that these dangers can be overcome. SENS Research Foundation takes no position on this subject, because the answer isn’t actually important to our mission: whoever is right, even very safe germline therapies would not be an effective tool to address the humanitarian and economic challenge of degenerative aging that we are facing today. Any therapies to prevent or reverse age-related disease and disability that need to be engineered into people before they are even born would be of no use to those of us who are living today – and in particular, would abandon the “baby boom” generation to the sickness, suffering, and economic dependence that degenerative aging is about to impose on them and on the societies in which they live. Granted the timelines, germline therapies would also not come in time to help the equivalent swells of people that were born in the developing world a generation or so later, and are therefore at risk of age-related suffering and disease in large numbers in the years between 2030 and 2050.

And even for people in generations to come, germline therapies offer less benefit than one might at first think. This is because, while the cellular and molecular damage that eventually drives degenerative aging begins to occur while we are still in the womb, it takes many decades for the amount of such damage to become so extensive as to be harmful to our health.This means that there is no advantage to having rejuvenation biotechnologies be present and active in our tissues at birth, or even in our twenties and thirties: the amount of aging damage in our tissues in those decades is harmless, as is shown by the health and vigor of people in these age groups. The goal is not to prevent all aging damage from occurring, but to keep it from reaching the threshold at which it begins to harm us -- a threshold that we do not reach until our forties or so. Rejuvenation biotechnologies will deliver bona fide rejuvenation to human tissues, removing and repairing the damage of aging rather than slowing down its buildup; therefore, making its therapeutic proteins active in the bodies of newborn children and teenagers would be therapeutic overkill.

In sum, germline gene therapy is certain to become an important biomedical procedure in the future for a variety of inherited diseases – but not for combating the diseases and disabilities of aging.

Resources

SENS Research Foundation blog posts on protein delivery systems [Links here that redirects to CSO and other blog posts tagged ‘Delivery Mechanisms’]
Presentations on protein delivery systems from SENS Scientific Conferences
Scientific publications on this topic