Overview

1. Audience

2. Implementation

3. Safety and Challenges

Audience

A probiotic to control excess BCAA intake is most effective in patients whose dietary protein intake is difficult to control. Newborn children are generally put on a strict diet of BCAA-free formula, which is easier for parents to regulate, yet this formula is not readily available all over the world. Thus, our long-term goal will be to treat toddlers and young children, whose diets are generally difficult to control. This is also generally the age range when children begin to diversify their diet and want to try a wide range of foods, leading parents to constantly try to come up with new low protein recipes. When speaking to Dr. Vockley, a specialist in liver transplantation for MSUD in children from UPMC Children’s Hospital of Pittsburgh, he indicated that crisis years, in which patients with MSUD may inadvertently cause tremendous irreversible neurological damage, occur when those afflicted reach from age 5 to 12, and can pick up beginning after age 2. While this demographic is arguably the most crucial to treat, there is also a need for older patients who have milder cases of MSUD, are unable to undergo liver transplantation, or require an aid in buffering their BCAA intake while waiting for a liver transplant. Some patients with non-classical MSUD may also be unwilling to undergo such an invasive procedure, which may have complications due to long-term immunosuppression or result in secondary malignancies, and thus need an alternative treatment.

Implementation

As B. subtilis is already a probiotic on the market with proven safety, the most straightforward way to deliver our probiotic to patients is through a pill or incorporate it into baby formula. Studies show that B. subtilis probiotic strain DE111 germinates within the gut 3 hours after ingestion (1), however, we are inclined to package vegetative B. syruptilis or B. syruptilis spores in a capsule and manually induce their germination before ingestion so it can start working immediately in the gut. We especially liked the 2016 Vilnius Lithuania team’s idea of creating a capsule with two layers - the outside layer with the inducer molecule and the inside layer with the bacteria - and squeezing the capsule to induce constitutive expression in B. syruptilis. Additionally, spores of B. subtilis are able to last in the gut of humans for up to 8 hours (and potentially longer) which means that our probiotic would likely need to be ingested with every meal, allowing patients to eat intermittently between meals as well.

Safety and Challenges

While we used B. subtilis JMA222 for experimentation, if we were to move forward with this project we would look into acquiring a probiotic strain with proven safety and health benefits such as DE111. Of course, as we are creating a therapeutic product, it is necessary to get consumer input on whether or not they would actually use our product. While talking to a parent of a MSUD patient, she mentioned that MSUD patients would be willing to take a probiotic with every meal or daily but it would have to allow almost entire freedom of diet. While liver transplants are the most comprehensive solution to allowing freedom of diet and avoiding metabolic decompensation, there are lots of hurdles to getting a transplant, including location, and patients who receive transplants might reject the organ. Another challenge would be getting FDA approval, as we would need to first demonstrate efficacy and safety in an older group of patients before working our way down to our target demographic of children.