Gene therapy is starting to come into its own, and it will change medicine more profoundly than anything that came before. Just like when antibiotics were discovered almost exactly a century ago, we are on the cusp of another revolution in medicine. One that is orders of magnitude greater than antibiotics.
Recently, in China, five of six children born with an autosomal recessive otoferlin deficiency deafness were cured by the injection of a gene therapy. These children had suffered from a condition called DFNB9, which is a mutation in the OTOF gene that causes complete deafness. The gene codes for the protein otoferlin, which is necessary to translate sound waves into electrical signals in the human cochlea. One of the scientists who developed this therapy was Dr. Zheng-Yi, who happens to have trained at Harvard Medical School.
The corrected gene was inserted into the cells in the cochlea by a viral vector. Viruses can become biomicrosyringes when their DNA is removed and replaced with therapeutic DNA. The OTOF gene is so big that it must be cut into two halves and spliced into the cell’s DNA in different places. The completed protein is then assembled from these two sets of instructions by the cell.
Within a few weeks, there were signs of hearing changes, and by 26 weeks, the older children were able to recognize speech and have a telephone conversation. Remember that this is after a lifetime of complete deafness.
America is also working on genetic solutions. Both with the same therapy used in China and with new ones. The Food and Drug Administration has approved two gene therapies for sickle cell anemia in the last few months. As every medical student knows, sickle cell anemia is caused when someone inherits both copies of a recessive gene for this condition. Having one copy gives some protection from malaria, presumably why this gene was selected in some parts of the world; having two copies will make the red blood cells become crescent or “sickle” shaped in a low oxygen environment. This causes unbelievable pain as cells deep in organs and bones start to suffer hypoxia and die.
I have treated many chronic pain patients with this terrible disease, and it is one of the worst things to have in my opinion. Especially since it is most common in patients of color, who are often treated inadequately for their pain. Finally, there might be some relief for them, as all we had before was oxygen, fluids, and morphine. These new treatments are called CASGEVY and LYFGYNIA, for exagamglogene autotemcel and lovotibeglogene autotemcel respectively.
Autotemcel is a type of therapy where cells are collected from a patient, modified in the lab, and then infused back into the patient. It is a combination of the word “auto” as in self, and temcel, which seems to have been put there to confuse those of us not in this field. CASGEVY uses CRISPR-Cas9 technology to splice a gene into blood cells, producing stem cells harvested from bone marrow, so they can start making fetal hemoglobin again, bypassing the defective sickle gene. LYFGYNIA uses a lentiviral vector to deliver a healthy adult hemoglobin gene to the stem cells.
These therapies are not cheap. $2.2 million and $3.1 million, respectively, but if you add up the cost of the disease over the patient’s lifetime and factor in human suffering, this is a bargain. There is hardly any other disease in America that will make you suffer more and be treated worse than this condition.
And that brings me to severe chronic pain. Severe chronic pain is a multifactorial problem, but we are slowly starting to elucidate some of its causes. It turns out that metabolic gene polymorphisms are associated with many chronic pain conditions. Some of these seem to be related to the metabolic control of energy production and biosynthesis, through the regulation of signal transduction and gene expression. Altered metabolic states cause aberrant gene signaling and transcription in diseases like cancer, neurodegeneration, and even cardio and cerebrovascular disease.
Some of this signaling is associated with increased levels of a polypeptide hormone called nerve growth factor (NGF); though we are not sure how, we do know that NGF is upregulated in chronic pain conditions. A recent study was able to show that intraplantar injection of NGF caused increased expression of lactate dehydrogenase A (LDHA) and pyruvate dehydrogenase kinase 1 (PDHK1), affecting mitochondria, which contributed to the development of allodynia. Allodynia is a medical condition where any sensory stimulus causes severe pain.
Mitochondria are the unique bacteria-like organelles that produce ATP and control our metabolism, providing energy for our cells and keeping us alive. Blocking these enzymes prevented NGF-induced allodynia while reducing them sped up the resolution of the condition. This strongly indicates that mitochondria impaired by pyruvate oxidation may be a major factor in the development of intractable pain and could be a key target for future gene therapies.
Mitochondria have their own DNA, about 16,000 base pairs stored in a ring like a bacterial plasmid, causing many scientists to believe that it is the remnant of ancient symbiotic bacteria. The study goes on to show that mitochondrial pyruvate oxidation impairment in the dorsal root ganglia is a critical mechanism for the development of severe chronic pain. Gene therapies are being developed for mitochondrial diseases, and If we can make mitochondria more resistant to the effects of these chemicals, we might be able to short-circuit this defective process.
Allowing us to reverse this condition, too, and perhaps other neuropathic pain conditions. Neuropathic pain affects up to 17.9 percent of the American population at some time in their lives, and up to 50 percent of sufferers will experience allodynia. Having an effective treatment would dramatically help these people live more productive, higher-quality lives.
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.