Pictured: Dr. Sonja Sucic from the Medical University of Vienna presenting on pharmacochaperoning at the Creatine Deficiency Workshop in Rotterdam in September 2019
Being a CCDS/CTD mom, I understand that it can be very easy to put a huge amount of hope in the idea of prospective treatments. The exciting news is that it’s not just a cliché to say that we can each make a difference. Our individual participation in the research process is vital and necessary to help researchers in the quest to find a cure for CTD. There are researchers around the world working on innovative new ideas for therapies that could really work to help our loved ones. Providing access to patient data is in our hands as parents and caregivers, and it is not an understatement to say that if we don’t do our job, the researchers can’t do their jobs.
Overall, there are a few very specific ways we can all participate in the research process:
- Upload your genetic reports into the patient registry to ensure that our mutations are represented in larger datasets like ClinVar.
- Donate biosamples to Coriell so researchers can work with each mutation.
I recently heard about an intriguing presentation at the Creatine Deficiency Workshop in Rotterdam in September 2019. “Rescue by 4-Phenylbutyrate of Several Misfolded Creatine Transporter -1 Variants Linked to Creatine Transporter Deficiency Syndrome,” was presented by Dr. Sonja Sucic and discussed a new mechanism that sounded promising for patients with CTD. The approach is called pharmacochaperoning. This is the process of being able to save misfolded proteins with particular compounds.
We received a genetic test report that explained our son, Cadman, has a mutation on the SLC6A8 gene, which means he has CTD. The report also mentioned more specifics about his specific mutation, but nearly 3 years later, I still do not understand what it all means. With CTD, there is a mutation on the SLC6A8 gene, but there are a lot of differences between each specific mutation, and researchers are still in the process of understanding how those differences affect each patient, and what it means for finding treatment options. Dr. Sucic’s research suggests the potential of one day having mutation-specific treatments for CTD, making an understanding of my son’s mutation especially important to me.
You can learn more about the types of mutations here.
The ACD asked Dr. Sucic to help us understand more about pharmacochaperoning and her work in the Q&As that follow.
Pharmacochaperoning Q&A – What does it mean for CTD?
Dr. Sucic, co-author of the research paper, “4-Phenylbutyrate rescues folding-deficient creatine transporter-1 variants linked to the creatine transporter deficiency syndrome”
Q: What is Pharmacochaperoning?
A: Pharmacochaperoning is used to rescue some point mutations, which impair the folding of proteins (e.g. CRT-1) and cause their retention in the endoplasmic reticulum. This is achieved by employing different ligands (“pharmacochaperones”) that interact with the transporter and subsequently enhance its delivery to the cell surface.
Q: What is a missense mutation? How do I know if my loved one has this type of mutation?
A: In a missense mutation, a single nucleotide change leads to a codon, that codes for a different amino acid residue in a protein. This, in turn, sometimes causes functional changes/defects in the protein. For further information, please check the information provided here.
Q: Can all missense mutations be rescued?
A: Unfortunately, not all missense mutations can be rescued.
Q: Could pharmacochaperoning work for CTD?
A: *Pharmacochaperoning appears to work in laboratory studies for several CTD variants examined in our recent study.
*Note from ACD: These laboratory studies were not performed in humans.
Q: For what mutations does 4-PBA seem to work?
A: **We showed that 4-PBA-treatment works quite well on the following mutations: R391W, A404P, G424D, V539I, P544L and P554L.
**Note from ACD: These laboratory studies were not performed in humans. These results point to the potential importance of studying and understanding each CTD mutation, but do not guarantee safety or efficacy in humans.
Q: What mutations did you test?
A: In our study, we examined 16 mutants of human CRT-1: Y80H, G87R, G132V, G253R, C337W, G356V, P382L, P390L, R391W, A404P, G424D, A448D, C491W, V539I, P544L and P554L.
Q: The drug you used to rescue transporters is already FDA approved–can patients use it?
A: 4-PBA is FDA-approved for other conditions. However, if given (for CTD), this would be an off-label use that should be done very carefully, under strict pediatricians’ guidance. More research is needed to determine use in CTD including dosage.
Q: When does protein misfolding occur and what does it mean?
A: Protein misfolding is caused by mutations in proteins and it often means that the function of the protein is impaired (the protein cannot effectively do the job it was supposed to do).
Q: What are the drawbacks, if any, to Pharmacochaperoning?
A: If pharmacochaperoning works for a given misfolded variant, this is a very promising result (providing that the drug in question is safe to use (approved) and causes no serious side effects). Drawbacks are difficult to foresee, perhaps one would be possibly the cost aspects of the life-long therapy.
Q: What do you believe is most important for CCDS families to know about Pharmacochaperoning?
A: Pharmacochaperoning may represent one, novel, way of treating diseases caused by protein misfolding. Our work on several creatine transporter variants provides a proof-of-principle that some CTD mutations are amenable to pharmacological rescue by 4-PBA treatment.
I hope other families find this Q&A as helpful and educational as I did! It’s important to really understand the research that’s out there for our disorders and even more critical to understand your own genetic information so that you can know how particular research studies may impact you. Even though a potential treatment like this might not be ready right now like we all wish it could be, and it is not the right fit for every CTD patient, it’s an excellent example of the fact that there could be many ways to approach a treatment for CTD and the importance of giving researchers access to as much information as possible. I feel empowered knowing that I can do something to help the research process, and I’m happy to report that Cadman’s blood sample and skin biopsy have been submitted to Coriell and his specific mutation can be studied and hopefully included in any ongoing or upcoming research that could one day help improve his quality of life.
*It is important to understand that no human clinical trials have been completed to confirm the safety or efficacy of 4-PBA treatment for the treatment of CTD. As described above, the research performed so far has been “proof-of-principle”. It is not advised that caregivers administer 4-PBA or any other “promising” treatment prior to scientific research that clearly proves the safety of the treatment for the disorder it is being used for.
A prescribing physician should be involved in any changes made to a patient’s care plans, especially to monitor the patient’s health during all treatments and treatment changes. It is important to understand that there are potential undiscovered side effects and risks when using any drug off-label (not approved for the specific disease). This could be especially important to consider with the neurological and gastrointestinal symptoms patients with CTD often experience.
Please feel free to contact the ACD at firstname.lastname@example.org with any questions you have on participating in our efforts to support ongoing research.
*We thank Dr. Sonja Sucic for her work and taking the time to talk to our community.