Providing Solutions for Diseases with Unmet Medical Need

Aeglea is built on the concept of developing next generation engineered human enzymes to target and degrade metabolites in the blood, providing potential therapies for the treatment of diseases with unmet medical need.

By using our breakthrough bioengineering approach, we can engineer human enzymes with therapeutic potential across a number of areas of great medical need beginning with:

RARE GENETIC DISEASES (OR INBORN ERRORS OF METABOLISM)

Currently we have multiple drug candidates in development. Each targets a different amino acid for potentially life-changing benefit.

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Pegzilarginase | ACN00177  | Publications

Next Generation Enzyme Therapeutics

Our innovative approach of developing enzyme solutions to treat diseases with unmet medical need achieved its origins in the laboratory of Professor George Georgiou at the University Texas at Austin. Our in-house team of protein engineers develops next generation enzyme therapeutics by either enhancing the catalytic or pharmacokinetic properties of existing enzymes or generating enzymes with novel activity from alternative human enzyme scaffolds. Examples of metabolites that are targeted using our novel enzymes include:

Amino acids are critical to cell function. By reducing excesses in amino acids through targeted degradation, our engineered human enzymes have the potential to be applied to a variety of diseases, including inborn errors of metabolism. Our most advanced rare genetic disease focus is on Arginase 1 Deficiency.

Unlike microbial enzymes, engineered human enzymes may not be recognized as foreign by the body and may be less likely to elicit an immune response — potentially providing more tolerable, more flexible treatment options for patients.

Pegzilarginase: Modulation of Arginine Levels

Our lead product candidate, Pegzilarginase (AEB1102), is derived from human Arginase 1. Engineered modifications, which include the substitution of cobalt for the manganese cofactor and PEGylation, gives Pegzilarginase both increased catalytic activity and serum stability compared to native human Arginase 1, making it potentially suitable as a therapeutic for the degradation of arginine.

Pegzilarginase has a potential immunogenicity advantage over microbial enzymes with arginine degrading activity. The Pegzilarginase amino acid sequence is derived from the native human amino acid sequence. We believe the human immune system will be less likely to mount an immune response since it will not recognize Pegzilarginase as a foreign molecule. This is in contrast to microbial enzymes that are commonly seen as foreign by the human immune system.

Hyperargininemia Resulting from Arginase 1 Deficiency:

Arginase 1 Deficiency is a rare genetic disorder caused by a mutation in the Arginase 1 gene that leads to the inability to degrade arginine. This results in excessively high levels of arginine in the blood, referred to as hyperargininemia. Arginase 1 Deficiency is a urea cycle disorder with a reported incidence of 1:350,000 to 1:1,000,000 live births. Patients with this disease are predisposed to neurologic symptoms including cognitive deficits, seizures and spasticity, loss of ambulation, and severe intellectual disability.

High levels of blood arginine are believed to be the key driver of the clinical manifestations that develop in patients with Arginase 1 Deficiency. Although the medical literature suggests that disease progression can be slowed with strict adherence to dietary protein restriction, there is no approved therapeutic agent that addresses the cause of Arginase 1 Deficiency. Pegzilarginase is intended to replace the Arginase 1 missing in patients and lower blood arginine levels, which is anticipated to slow or halt the progression of disease.

ACN00177

ACN00177 – Homocyst(e)inase: Targeting homocysteine for classical homocystinuria

Classical homocystinuria is a rare disease resulting from the hereditary genetic deficiency in cystathionine beta synthase. It has been estimated to impact up to 1 in 344,000 people worldwide, however, its prevalence is significantly higher in some countries. The most common medical conditions associated with classical homocystinuria are cardiovascular complications including an increased risk of blood clots.  Other symptoms include skeletal abnormalities, dislocation of the lens in the eye, and development and learning defects.

Currently available treatments for classical homocystinuria include high doses of vitamin B6 and betaine (N,N,N-trimethylglycine) to reduce homocysteine levels.  Although these treatments are effective for some patients, responses fluctuate significantly due to the variations in the genetic mutation driving the disease.  As a result, there exists an opportunity to develop a therapy that addresses the need of all patients by reducing blood homocystine levels back to the normal range.

Our program to develop an engineered human enzyme designed to treat homocystinuria has delivered clinical candidate ACN00177. We anticipate that enzyme replacement therapy with ACN00177 will degrade homocysteine and the oxidized form  homocystine, returning blood levels to the normal physiological range. Normalization of homocystine/homocysteine levels may halt or slow the progression of the symptoms of the disease in these patients.

Scientific Publications and Presentations

Sharing data and discoveries is a cornerstone of scientific and medical research. To review some of our research, please see our past events page.