In one of my favorite movies, Star Trek IV: The Voyage Home, the original crew of the Enterprise has traveled through time, back to the, to them ancient, city of San Francisco circa the 1980s. It’s all about Earth whales and alien cetaceans being none too pleased that we killed them all … And Klingons, of course. There must be Klingons. But what stuck in my young mind at the time was what Dr. McCoy did when walking through a hospital. He encountered an old lady in a wheelchair on her way to dialysis. The use of this “medieval” treatment, as he considered it, was intolerable to him, and he gave her a pill that helped her grow a new kidney. As crazy as it may sound, this scenario may not be fiction soon.
Back then, I couldn’t fathom how any technology could target a specific organ so precisely. And at that time, it was indeed impossible. But now, we have a solution. The development of viral vectors for genetic engineering using CRISPR technologies has sparked a revolution in medicine. These vectors have the potential to cure diseases like sickle cell anemia, transforming the lives of patients. However, they come with their own set of issues. They can trigger an immune response and disrupt host cell genes by splicing themselves into the DNA at the wrong place, potentially leading to mutagenesis and even cancer. This prompted the scientific community to explore other options.
Enter engineered extracellular vesicles (eEVs), a potential game-changer in the field of medicine. These are naturally occurring cellular particles that cells take up through endocytosis, first observed in the 1980s. By the early 2000s, they were recognized as possible carriers for DNA, RNA, and other molecules. Scientists next created cell lines that would produce EVs loaded with the desired cargo molecule or plasmid. The surface proteins of EVs were then engineered to display molecules that guided the EVs to different cell types. This is precision medicine, where instead of saturating the body with a medication, we deliver it only where it’s needed. It’s the realization of the long-awaited “magic bullet” for medicine.
A study from The Journal of Biomaterials described in SciTech Daily reveals a new technology that may give hope to many who suffer from chronic low back pain. As advanced as medicine has become, we are just now starting to develop technologies that truly enhance healing beyond aseptic treatment and antibiotics. Even these just give an optimal playing field for our body’s defenses to do their job. No antibiotic in the world is effective without a functional immune system. Immunotherapies are now becoming available with the advent of genetic medicine, and it looks like structural damage may be repairable through similarly advanced technology soon.
Low back pain is a leading cause of work limitations globally, and 50% to 80% of Americans experience at least one episode of low back pain in their lifetimes, with 15% to 20% suffering annually. Surprisingly, since men have a higher average body mass, it affects women more than men, 31.6% to 28%. It hits older people harder, with 37.3% aged 75 and older suffering, but it is still prevalent in those 18 to 44, what we might consider prime health years, at 24.4%. Chronic low back pain disables over 3 million Americans annually, costing the nation $100 billion each year. Physical therapy is the prime first-line treatment and helps reduce the overall cost of care by 72% in the first year, according to the CFAH.
The same source reports that over half of back pain patients, 56.7%, recover to their work capacity within six months, but 69% will have a recurrence within one year. When pain and debility just do not improve or get progressively worse, there can be several causes. About 5% will have sciatica, usually from a prolapsed or slipped disc, and the rest will be “nonspecific.” Included in the causes of nonspecific low back pain are listed work stress, money problems, difficult relationships, and bad mental health, but I disagree. I think those conditions make it harder for people to tolerate a low level of back pain that their brains “blocked” through descending pathways when things were going better.
According to the published study, about 40% of chronic low back pain is caused by intervertebral disc degeneration, which they refer to as “discogenic” pain, which sounds to me like something that should have been rampant in the 70s, but I digress. The intervertebral disc is a strong, flexible ring between the vertebrae with a gelatinous center that works as a shock absorber. These discs flex and twist with us, allowing vertebral movement. A tear in the ring will cause pain, especially on movement, and a significant tear may allow the swollen ring to press on a nerve or for the gel-like nucleus pulposus to extrude, which often causes cervicalgia in the neck or sciatica in the lower back.
From the study without abbreviations: The primary function of the intervertebral disc is mechanical as it distributes loads across the spinal column while also providing flexibility. As a consequence of intervertebral disc injury and degeneration, the disc undergoes significant changes in function; for example, a decrease in tissue hydration and increased matrix breakdown leads to a loss of pressurization within the nucleus pulposus and increased stresses being experienced by the annulus fibrosus. In degeneration, mechanical imbalances, loss of critical extracellular matrix components such as proteoglycans, increased catabolism, inflammation, and neurovascular invasion contribute to a detrimental shift in homeostasis that leads to the loss of tissue function and increased pain.
When this happens, healing does not always take place rapidly or even at all. The intervertebral disc is avascular and somewhat aneural, impairing the healing process. Inflammation starts, and increased catabolism with neurovascular invasion causes loss of function and increasing pain. Spinal injections with steroids are used by interventional pain and other specialists to help reduce the inflammation and slow the process, but these are mainly effective for sciatica with very low efficacy for other causes of low back pain, except stenosis. 87% of sciatica sufferers and 42% of those with severe spinal stenosis get significant relief, although it only lasts about 90 days.
There are also limits to how often a patient can have a high-potency steroid injection as these have secondary effects like osteoporosis and weight gain that can exacerbate the problem. What we need is a way to go in and fix the disc itself. This was realized long ago, and spinal disc surgery started in the 1930s at the Massachusetts General Hospital, where Dr. Barr and Dr. Mixter performed the first removal of a herniated lumbar disc, giving significant relief to the patient. Since then, vertebral fusions and laminectomies have become commonplace, and while these stabilize the spine and can reduce pain in some patients, many others continue to suffer from debilitating pain.
Even today, with the advent of minimally invasive techniques, microsurgery, laser and radiofrequency ablation, artificial discs, arthroscopy, and even robotic surgery, it still does not heal the underlying problem. That may change. The critical need for methods that restore tissue structure and function has produced a plethora of techniques, including growth factor injections like TGF-beta and GDF6, cell-based therapies like stem cell injection, and now, genetic interventions. The last includes delivery with viral vectors carrying the SOX9 protein, which has had some success in vitro and in animal studies, but a new approach is to utilize transfection vectors like Brachyury and Forkhead Box F1 (FOXF1).
These are markers of healthy immature nucleus pulposus cells and are involved in their growth and development. The theory was that targeting these markers could reprogram damaged nucleus pulposus cells to revert to a pro-anabolic stage and heal the damage. This was to be accomplished using “engineered extracellular vesicles,” or eEVs, which would carry a FOXF1 gene into the NP cells. These eEVs are made to penetrate tissues and share molecular identification markers specific to the targeted donor cell. So, the eEVs used would deliver FOXF1 to the injured disc to stimulate healing by resetting the cells to an earlier stage, allowing them to grow again and heal the injury. This study was in mice.
To help differentiate vector effects from the active gene, a “control gene” was needed. For this purpose, the researchers chose pCMV6. The plasmid containing pCMV6 carries the cytomegalovirus promoter, which increases gene expression in mammalian cells and is often used as a control plasmid. This can help differentiate the effects of the vector from the active gene being studied, in this case, FOXF1. Experiments were first performed in mouse embryonic fibroblasts, and vector action and gene expression were studied and quantified. Then, studies were performed on animals. These animals were chosen to be “young adults” by murine standards but not elderly and were treated right after injury.
The mouse would be given a controlled intervertebral disc injury by needle puncture. Half the randomly selected mice could go through the normal healing process while the rest got eEVs with either FOXF1 or pCMV6 containing plasmids. They were then assessed over a twelve-week period by observing pain response behaviors and with the use of imaging, such as CT scans and MRI machines, to calculate disc height and structural integrity. I truly do want to see an MRI machine designed for mice but not how the researchers get them to stay still. They also did a microscopic analysis of the discs of all the mice: control, injured, injured pCMV6, and injured FOXF1.
The study demonstrates that “FOXF1 eEVs have the potential to restore the structure and function of the injured mouse IVD in vivo …” In the dry parlance of science. That means it worked. Restoring disc height, tissue hydration, and proteoglycans, resulting in not just structural but functional improvement that was not evident in the pCMV6 controls. The cells of the nucleus pulposus were returned to a pro-anabolic phenotype, allowing healing beyond that brought about by inflammation and scar tissue formation. Other studies have confirmed the use of eEVs to create a similar effect in other progenitor cells. This is a long way from growing an entirely new kidney, but it is clearly the first step in that direction.
L. Joseph Parker is a distinguished professional with a diverse and accomplished career spanning the fields of science, military service, and medical practice. He currently serves as the chief science officer and operations officer, Advanced Research Concepts LLC, a pioneering company dedicated to propelling humanity into the realms of space exploration. At Advanced Research Concepts LLC, Dr. Parker leads a team of experts committed to developing innovative solutions for the complex challenges of space travel, including space transportation, energy storage, radiation shielding, artificial gravity, and space-related medical issues.
He can be reached on LinkedIn and YouTube.
