05/21/2025
MESSAGE from Dr. Boles:
“Many have read about the latest in genetic engineering in which a patient with a urea cycle defect essentially was cured by using the child’s own CRISPR-edited cells. They understandably wonder if this technique could be used in their children, or in themselves. Unfortunately, for the vast majority of people with neurodevelopmental (e.g., autism, ADHD) and neurofunctional (e.g., chronic fatigue, pain, nausea/vomiting, dizziness) disorders, the answer is “no”, either in the near- or in the medium-time future.
In the neurodevelopmental disorders, the primary reason for this is that these disorders generally involve degrees of cell signaling (too little or too much results in disease), under specific conditions, in specific neurons, and at specific times (e.g., in brain development). Neurodevelopmental disorders also tend to be polygenic, meaning that in each patient, DNA sequence variants/mutations are important in more than one gene.
CRISPR and other known genetic engineering techniques work when:
1. Health is greatly improved when just a small amount of the protein is available.
2. An extreme amount of the protein is not toxic.
3. The technique can get the gene to the location where the protein can do what it needs to do.
4. Fixing that one gene removes most disease manifestations.
The child with the CRISPR-treated urea cycle defect has CPS1, a monogenic disorder, meaning it caused by mutation in a single gene. In CPS1, individuals are healthy when they have only a small proportion of the protein, even 10 to 20% of normal being sufficient. Also, having a 10-fold higher amount of the protein is not a problem. Finally, since the protein circulates in the blood, it matters little where the corrected cells are located.
The situation is vastly different for the vast majority of individuals with neurodevelopmental disorders. Following genetic engineering, some cells would have far too little protein available. Other cells would have far too much protein available. It's essentially a shotgun approach. Again, the primary problem in neurodevelopmental disorders is generally too little or too much, often by subtle amounts. Genetic engineering would likely make the situation far worse. The polygenic aspect in most people with these conditions also complicates matters.
Neurofunctional disorders appear to be almost-always polygenic. These conditions are also multifactorial, in which several environmental components apply as well. Correcting one gene is unlikely to make a significant difference, and dosing effects (too little or too much results in disease) are generally present as in the neurodevelopmental disorders.
The good news is that there are a lot of people with monogenic disorders that can be helped by this technology. However, for now and in the foreseeable future, they are unlikely to be those with neurodevelopmental and neurofunctional conditions.”
