PDCD RESEARCH
SMALL MOLECULE THERAPY
What is Small Molecule Therapy?
Small molecule drugs, as their name suggests, are chemical compounds that have low molecular weight – a single molecule of a small molecular drug typically contains only 20 to 100 atoms. They can enter cells easily where they interact with molecules within the cell. They are typically drugs that enter your system, pass through your liver, and need to be taken repeatedly to manage symptoms.
Most of the medications that are currently in use are small molecule drugs. For example, pain relief medications, antibiotics and almost all over-the-counter medications are small molecule drugs. Vitamins and nutritional supplements are also small molecule drugs.
Thiamine (vitamin B1)
The standard of care for treatment of PDCD is supplementation with thiamine. For some patients, additional cofactors including carnitine and lipoic acid may be added separately or may be components of a ketogenic formula. Thiamine is important for people with PDCD because thiamine is a cofactor of PDC. That means that part of the pyruvate dehydrogenase complex. It both helps it work as well as possible, but also, having extra thiamine can help stabilize the complex if there is a variant that changes the structure. Some patients with PDCD have “thiamine-responsive” disease, meaning that thiamine can quickly improve symptoms. The dose of thiamine given is typically higher than routinely found in multivitamins (“high-dose” thiamine).
Dichloroacetate
The activity of PDC is controlled by other enzymes in our body that activate and inhibit it. In particular when a cell has plenty of ATP and does not need to oxidize pyruvate, the pyruvate dehydrogenase kinase inhibits the function of PDC. This is a normal regulatory process that helps our cells conserve energy. Dichloroacetate inhibits the pyruvate dehydrogenase kinase. Another way of saying this is that it keeps the PDC active all the time and doesn’t let the body shut it off. This lets people with PDCD get as much out of their PDC as possible. DCA is currently under investigation as a phase 3 clinical trial. It is not yet routinely available. Because people on DCA have their PDC active all the time, the body uses up thiamine more quickly, so it is very important that people on DCA take thiamine to prevent deficiency.
Dichloroacetate (DCA) is an investigational drug for the treatment of genetic mitochondrial diseases. Its primary site of action is the pyruvate dehydrogenase (PDH) complex, which it stimulates by altering its phosphorylation state and stability. DCA is in a Phase III clinical trial for PDCD, sponsored by Saol Therapeutics. For more information about Dichloroacetate and it’s use for PDCD, please visit clinicaltrials.gov.
C7 (aka triheptanoin, triheptanoic acid, Doljovi)
C7 is a type of medium chain triglycerides. Medium chain triglycerides are fats that our bodies can quickly convert to energy. Pyruvate dehydrogenase complex deficiency (PDCD) is a disorder where people cannot break down sugars & carbohydrates for energy, but can use fats properly, so fat-enriched diets are a common treatment for PDCD.
What is special about C7 is that it is made up of odd-chain (7 carbon) fats. Naturally occurring fats that we eat have an even number. Odd chain fats can be used by our body to make chemicals that our bodies need, like myelin, which is essential for normal brain function, so it is thought that C7 may help children with PDCD reach their best development potential. C7 is not currently routinely used to treat PDCD, but is headed to a clinical trial in 2023. For more information about what C7 is used for, please visit clinicaltrials.gov.
The Hope for PDCD Foundation would like to thank Dr. Rebecca Ganetzky for providing information about small molecule therapies and making this information accessible to non-clinicians.