Phenylalanine Ammonia-Lyase (PAL)-Containing Drug Formulation, Methods of Preparing, Using the Same

Unmet Need

Phenylketonuria (PKU) is an inherited disorder that increases levels of phenylalanine in the blood. Phenylalanine is an amino acid obtained through diet and found in all proteins and in some artificial sweeteners. If PKU is not treated, phenylalanine can build up to harmful levels in the body, causing intellectual disability and other serious health problems. Occurrence varies by ethnic group and geographic region worldwide. In the US, PKU occurs in 1 in 10,000 to 15,000 newborns.

Currently, the primary treatment for phenylketonuria includes a lifetime diet with very limited intake of protein-rich foods containing phenylalanine and a PKU (nutraceutical) formula to provide sufficient essential protein (without phenylalanine) and nutrients crucial for growth and general health.   Current guidelines require diet therapy to be started during the first few weeks of life and to be continued throughout life. However, non-compliance is a major problem due to the poor organoleptic properties of the diet and its high cost. Non-compliance is associated with adverse consequences in PKU patients and especially severe teratogenic consequences in pregnant women with PKU. There is a continued need to develop a more comprehensive therapy for PKU patients.

Opportunity

The D’mello laboratory has developed a novel approach to managing phenylketonuria (PKU) utilizing innovative microcapsule technology. These microcapsules taken orally function as miniature factories, rapidly and selectively removing phenylalanine from the diet, thus providing a new level of dietary control. Designed not for absorption, they pass through the gastrointestinal tract and are eliminated in feces, maintaining safety while effectively reducing phenylalanine absorption. This platform technology offers a promising solution for PKU patients, enabling a more normal diet without the lifelong restrictions of synthetic, unpalatable foods.

The D’mello lab’s PKU microcapsule system employs encapsulated enzymes, such as phenylalanine ammonia lyase, to target and metabolize phenylalanine directly within the gut. Taken alongside meals, these microcapsules selectively break down phenylalanine in the small intestine, lowering its absorption and therapeutic levels in the body. This innovative method allows patients greater dietary flexibility and improved quality of life, while ensuring optimal metabolic control.

By leveraging enzyme encapsulation, the D’mello lab’s platform technology extends beyond PKU management. It can be adapted to encapsulate various enzymes involved in drug metabolism, enabling oral administration of enzyme-based therapeutics alongside medications. This approach unlocks new possibilities for targeted nutrient removal and enhanced drug efficacy, transforming dietary and pharmacological interventions.

The microcapsule manufacturing process has been modified to use organic solvents that are relatively non-toxic and all materials used to construct microcapsules are approved by the FDA as Generally Regarded As Safe. The manufacturing process also has been optimized to maximize encapsulation of phenylalanine ammonia lyase within and minimize its leakage out of the microcapsules. In vitro testing has shown that microcapsules can deplete phenylalanine in an aqueous solution.

Unique Attributes

• Microcapsules in the low micron size present a large surface area for rapid metabolism of phenylalanine.
• The core of the microcapsules is formulated with co-encapsulants and presents a nurturing microenvironment to maximize the activity of encapsulated phenylalanine ammonia lyase.
• The semi-permeable membrane does not permit larger molecular weight gastrointestinal proteases to diffuse into the microcapsules and protects the encapsulated phenylalanine ammonia lyase from proteolytic degradation
• A novel buffer system that is retained within the microcapsule, buffers the core of the microcapsules at a pH of 8.5, which is the pH of maximal activity of phenylalanine ammonia lyase.
• A novel protein-based approach completely relieves phenylalanine ammonia lyase from product inhibition and ensures sustained activity during its transit in the gut.
• By leveraging enzyme encapsulation, the platform technology extends beyond PKU management and can be adapted to encapsulate various enzymes involved in drug metabolism, enabling oral administration of enzyme-based therapeutics alongside medications. The method unlocks multiple possibilities for targeted nutrient removal and enhanced drug efficacy, transforming dietary and pharmacological interventions.

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