Gene therapy has been used recently to cure previously incurable diseases, including sickle cell anemia. It is a horrible disease that I have seen so many times in the ER that it haunts me at night, especially one patient. He was a sweet man with a loving and patient demeanor who tolerated the agony he suffered on a weekly basis with saintly patience. My daughter was helping out in the clinic that day, and it was my third chance to get a doctor out of the brood after one writer/producer and a graphic artist. But when I put the large bore needle in the port in his chest, which I knew was there from long experience, I heard a loud thump behind me and realized maybe not. She now has an international business degree and is fluent in Mandarin. But gene therapy will soon send my experiences the way of the dinosaur, at least in countries wealthy enough to afford the Casgevy or Lyfgenia treatment. What other diseases will fall to the CRISPR cannon?
Could what have often been seen as “psychological” problems also be cured with gene therapy? That’s a good question. And if our evolutionary cousins are any indication, the answer is yes. Alcohol is well known to be a type of addiction. With the understanding that I define addiction here not as just a habit or compulsion but as an irresistible compulsion to repeat the use of a substance or action to generate a feeling of euphoria that causes upregulation of the gene that codes for DeltaFosB in the nucleus accumbens of the brain. The nucleus accumbens, as I’m sure you remember, is associated with desire targeting, motivation, pleasure, and addiction. DeltaFosB is a transcription factor that affects genes related to synaptic plasticity, neurotransmitter receptor production, and, thereby, neuronal communication. Many neuroscientists consider DeltaFosB the “molecular switch” for addiction because it accumulates in the brain following repeated exposure to addictive substances and some activities like gambling.
DeltaFosB also interacts with a protein called brain-derived neurotrophic factor (BDNF). These are both gene expression regulators. While deltaFosB seems to “set” learning patterns increasing short-term learning, BDNF seems to be more associated with long-term potentiation, or LTP, by promoting synaptic strength and helping to maintain newly learned information. Both of these have been implicated in addiction-related behaviors, including relapse. These changes have been known for quite some time, but one I was much less familiar with is called glial-cell-derived neurotrophic factor (GDNF). Glial cells are almost equal in number to neurons in the brain, and they help remove toxins and create a favorable environment. There is also evidence that glial cells take part in neuronal signaling with neurotransmitters and long-term memory storage. GDNF has been found to play a critical role in the survival and function of neurons throughout the brain but is particularly important in the ventral tegmental area (VTA) and nucleus accumbens (NAc), which make up the brain’s reward targeting system.
The VTA projects dopaminergic neurons to the nucleus accumbens, creating a sensation of euphoria. All addictive substances seem to function through this system. GDNF increases the survival and activity of dopaminergic neurons in the VTA and modulates synaptic transmission and plasticity in the nucleus accumbens. When GDNF is administered into the nucleus accumbens, it increases dopamine release and promotes reward-seeking behavior. This is the system that goes awry in addiction. The brain focuses on the substance to the exclusion of other things in their lives, even food, relationships, and family. Once the addiction becomes set, the nucleus accumbens starts reacting to the drug only, ignoring most other cues, causing the person to crave the alcohol and suffer anhedonia when it is not available. Breaking this link once it is formed can be very difficult, with relapse extremely common.
A recent study focusing on alcohol use disorders infused an adeno-associated virus vector encoding human glial-derived neurotrophic factor (AAV2-hGDNF). So, the use of a potentially addicting substance first increases dopamine release in the NAc and then drops it whenever the substance is not present, reducing it until the two choices of behavior are miserable or really miserable. The study used eight rhesus monkeys who had been exposed to alcohol to the point of addiction. Four had the active vector put into their VTAs, while the four received the vector only but no active gene. The increased expression of GDNF wiped out the alcoholic behavior in the four receiving the active gene, as the increased activity of dopaminergic neurons allowed the brain to lock on to other targets of reward, thereby wiping out the hypodopaminergic state that is associated with addiction. Even re-exposure to alcohol did not cause a return to alcoholic behaviors or relapse.
The authors suggest that this could be a viable treatment for alcoholism, which has been indicated, but the same theory should apply to almost all addictions. I don’t think directly implanting a virus into the brain will be a popular treatment, but intranasal administration of a viral vector selective for cells in the NAc might be effective. The point is that it seems to work, and perhaps we will have a truly effective treatment for addiction soon.
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.
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