View Full Version : Possibility of gene therapy for neurological disorders.

01-05-13, 09:59 PM
Another fine presentation from UC Davis. Yes, I watched the whole thing, but not all in one sitting. It was well worth it. The presenter is Dr. David Segal, Associate Director of Genomics, UCD Genome Center.

In part one, he goes over some of the basics of the "pieces" of genetics that are significant, the history of genomic sequencing, and the cost of various technologies and how they are evolving.

At around 9 minutes in, he explains that our DNA has about 3 billion base pairs, about 26,000 genes, and that 99.5% of it is identical. The differences that matter are SNPs (Single Nucleotide Polymorphisms) CNVs (Copy Number Variations) Inherited Deletions, and De Novo Mutations. SNPs are useful in detecting similarities in population and certain types of disease risk. CNVs are longer protein sequences that are significant because of their duplication or deletion in an individual's DNA. They are inherited from parents, and can be passed down to children, and are less common than SNPs.

He goes over a number of factors that influence what is testable, why, how easy it is to correlate or not, and how likely that correlation will relate to risk.

At about 31 minutes, he puts up a graphic that illustrates the importance of determining phenotypes, above and beyond simple gene sequencing. I would suggest just going to it and listening for a few minutes, rather than me trying to translate it for you. It gives both information and perspective on the roles of each piece of genetics and environment that are relevant to phenotype.

He goes over some practical applications of genetic testing. In addition to testing for disease and disease risk, it is also being used to assess response to medications, since certain proteins take many forms and would indicate a possibly predictable response to entire classes of medications (he uses much more technical language, so I'm trying to paraphrase this some.)

There are 2,000-6,000 monogenic diseases that are easy to test for, and states in the US require neonatal testing for about 10-30 of them depending on state. Diseases that are more complex are harder to test for genetically, obviously, but ethical issues also drive whether or not the genetics of these diseases should be researched or tested for because of whether or not they are preventable or treatable or would result in some form of discrimination.

Despite the size of the genome, only about 2% of it actually codes for protein - that's the part that's making our cells and replacing the ones that are worn out, so practically, we could test only partial sequences of DNA in order to perform genetic diagnoses. He goes further into ethics, noting that every individual's DNA contains 2 or more mutations, and since some of these would be probabilistic rather than predictive, would doctors be required to inform patients? If the probability looks significant, but actual risk is not much more than the general population, should the information be disclosed?

At about 1:06, he begins to describe work that has been going on with gene therapy for neurological disorders. Angelman Syndrome is genetic and highly testable, an Imprinting Disorder that results from the same gene sequence, UBE3A, being turned on from the father's side, but inactivated in the same place from the mother's side (again, paraphrasing because he gets technical here.) What makes this significant besides its testability is that this happens only in the brain - the gene is active elsewhere in the body, so the effect is strictly on neuronal cells.

In order to test mechanisms for gene therapy, mice were bred with this genetic mutation. There is a possibility that drugs could be used to treat the symptoms caused by this syndrome, but they would not correct it. Some gene therapy has worked by using viruses to implant corrected genetic code into the DNA, but the problem here is that viral gene therapy does not effectively cross the blood-brain barrier - making it not terribly useful for a condition that expresses itself only in the brain tissue.

They tried the viral method, injecting the altered genes directly into the brains of the mice, but it didn't spread to the whole brain. What Dr. Segal's group is working on is a Artificial Transcription Factors that will bind to the protein-producing segments of DNA (and eventually to very specific sequences of protein-producing DNA) upstream of the damaged segment so that the proteins created will activate or deactivate the segment, and will use a cell penetrating peptide to spread the action across membranes such as the blood brain barrier. It has worked in the lab on mice, and now they are working on figuring out exactly how and why so it can have broader use and possible real world applications.

Just a synopsis in case people want to discuss before committing to almost 90 minutes of viewing!

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01-05-13, 10:02 PM

I mentioned the possibility of gene therapy for ADHD should genetic causes be better understood in another thread. The only example I had on hand, however, was gene therapy for cystic fibrosis. I am glad to see that the notion is at least somewhat viable.

11-28-13, 08:56 PM
Gene therapy for ADD might be possible now but many feel it akin to creating designer babies because it's not a serious disorder in comparison to Huntington's Disease, Parkinson's, Alzheimer's, etc. the fact that many with the disorder have been able to survive and thrive proves no need for intervention other than Adderall or Ritalin.

However, if it were to exist minus the issue of designer babies, I would take advantage of it for my children. I would hate for them to suffer like I did as a child and continue to as an adult. I want them to be able to succeed in any capacity and to experience an even playing field. So I would be happy of it were possible to prevent children from acquiring ADHD since it seems to be mostly attributed to the parents. I don't want my children (if I live that long or have any) to blame me for their problems with the insidious disorder. I have blamed my mother incessantly to the point where she embraces it and has wished that she wasn't born!

I don't want to be the cause of my child's failure. Just because nature hasn't corrected itself yet doesn't mean children have to suffer because of it. But then again modern genertics could create designer babies almost perfect children and prevent psychiatric disorders and homosexuality features that make us unique. So it's a Catch-22 if you will.