Teddy visited Dr. Morava at Mayo Clinic today for his first annual follow up. She is following him through her natural histories study, and we're so grateful for the opportunity to see and consult with her. She is a world-renowned expert in CDG, and she's absolutely brilliant. She's also phenomenal with Teddy and takes the time to explain things to us in a way that makes sense ... as much as this highly scientific stuff can.
So I'm going to use this blog post to summarize what we discussed, both for the benefit of other PIGN-CDG families and our family but also to help cement the information in my brain. My warning is that this is my understanding and recollection, so anything inaccurate is clearly my error.
Dr. Morava provided us a chart similar to what she used last time and covered again the basics of GPI-anchoring disorders. Each cell uses sugar chains to build antennas that have protein on top. That is how cells communicate and function together at the most basic level. PIGN-CDG right now is the at the 7th step in the process of building of the sugar chain, with I believe 18 GPI-anchoring CDGs known. So, essentially Teddy's cells start building the sugar chain but stop before the chain is complete. That is why Teddy is globally affected because his brain's cells can't communicate and execute as intended without the proper antenna structure.
As she explained before, it's a tough diagnosis to develop treatment for because the sugar-chain building occurs deep inside the cellular level, and it's a very specific need. You can't simply provide more of the sugar molecules needed because that's like trying to shovel more snow with a broken shovel ... more does you no good.
She's aware of the drug-repurposing research we are pursuing with other PIGN-CDG families. She thinks that is a very good thing, not only for PIGN but also for potentially other PIG CDGs and GPI-anchoring CDGs. The goal with the GPI anchor disorders will be to target drugs that can cross the blood/brain barrier, as that is where they will need to do their work.
Dr. Morava is extremely familiar with drug repurposing, as she is involved with drug repurposing for the most common CDG, PMM2. They started approximately 4 years ago and are just now approved for clinical trials. Believe it or not, that's extremely fast for the use of a drug. They actually got rare direction from the FDA to skip phase 2, which is an extended study of the safety of the drug in patients, and move right to phase 3, which is a controlled test with both drug and placebo. Dr. Morava explained there's both pros and cons to that situation, and it's not the normal process but happened due to the known safety of the drug as it's been in use for 40 plus years. In the PMM2 study, they saw improvement in the earlier testing in about 80% of the cases. They started with yeast cells, just as we intend to, and then moved on to worms and then skin biopsies.
Dr. Morava said that with drug repurposing they can test 200 known drugs at a time to work their way through the 2,000 FDA-approved drugs. There is a difference between what is approved in the US and what is approved in other countries. So clinical trials may not cross country lines perhaps, but they can do work in parallel with other countries. For example, there are some studies where they hand off the different stages. This can be helpful as there are limited CDG experts. In the US, there are 4 (Dr. Edmundson in Philadelphia, Dr. Lam in Seattle and Dr. Scaglia in Baylor whose plate is full, in addition to Dr. Morava).
Dr. Morava said one of the challenges with drug repurposing is identifying the biomarker to test. One possibility may be the truncated GPI anchor, but they need to identify something they can clearly measure in each of the tests to see if there's improvement with each drug.
Another type of potential treatment aside from drug repurposing that does get a lot of attention is gene therapy. There's excitement over that possibility for PIGA as that type of gene therapy already exists in animal models for that gene. If you've heard of CRISPR, that's gene therapy. Essentially gene therapy changes your genetic makeup forever, which is great in the sense of correcting a damaging mutation. However, the long-term impacts aren't known yet because it's such a new therapy. There is the possibility that the genetic rewrite to fix one gene may create other issues, so Dr. Morava cautioned that while it may make sense for diagnoses with no hope, she doesn't view it as the best option for PIGN, particularly individuals like Teddy who are doing well.
The last type of potential treatment we discussed is the idea of using MRNA, which would essentially be temporary genetic therapy. You've all heard of MRNA, as that's how the COVID vaccines were developed. The idea with MNRA is that you inject the correct version of the gene to build the sugar chain and protein correctly. The advantage of this type of therapy is that it should work on all PIGN individuals, regardless of the specific and different mutations. (That's one of the weird things about PIGN is that most of our children have different mutations ... they're all messed up but in a lot of different ways.) The reason is you're simply overwriting whatever the error in the code is with the correct code. The disadvantage of MRNA is that it's temporary. It only lasts about 2 weeks, so it would be a continual process. However, that's also an advantage in the sense that if detrimental side effects are noticed, the process can be stopped and things go back to baseline. (Although Dave and I talked about how incredibly hard it would be to see progress and then regression.)
The MRNA is being tested in terms of proof of concept with a glycogen storage disease. It's not a type of CDG, but it is another glycosylation disorder. It will be interesting to see and learn what happens.
Of course, all these treatments are literally years down the road. But it's exciting that science is happening, and that people are interested in GPI anchor disorders and these types of CDGs. That's the biggest challenge is finding the right people to be interested and champion for our children by doing the work.
The main focus Dr. Morava has currently in her research is biomarkers to diagnose CDGs with a biochemical diagnosis rather than a genetic array that results in likely pathogenic results. Right now we have a likely pathogenic result for Teddy from his genetic testing that indicates that his PIGN mutations are likely the cause of his symptoms and disorder. Her focus, with a study of 200 patients, is to develop a blood test that will provide a functional diagnosis for CDGs. This would also, at least in my mind, provide biomarkers that can be used in further research, drug testing and treatment development.
Whew, that is my entire page of notes around the very complex chart she provided, in addition to the much simpler GPI anchor chart she gave us. I haven't touched the 20-page booklet of GPI Anchor Disorders: A Subtype of Congenital Disorders of Glycosylation, but I will. Also, as soon as I get a digital version of that, I'm happy to share it with you if you're interested in learning more (and will share it on our PIGN page.)
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| Teddy loves to visit Dr. Morava ... and he "locked" the dietician in the corner. |
