Engineered enzyme therapy for targeted reduction of plasma homocysteine in metabolic disorders

This technology is a specially engineered human enzyme, modified and PEGylated to break down excess homocysteine in the blood, offering a new treatment for homocystinuria and hyperhomocysteinemia with improved effectiveness and dosing flexibility.

Background

Homocystinuria and hyperhomocysteinemia are metabolic disorders characterized by elevated levels of homocysteine in the blood, primarily due to genetic defects affecting enzymes involved in methionine metabolism, such as cystathionine β-synthase (CBS). These conditions can lead to a wide range of serious health problems, including vascular complications, skeletal abnormalities, developmental delays, and increased risk of thromboembolism. The management of these disorders is crucial because persistently high homocysteine levels are toxic and can have life-threatening consequences. The field of metabolic disease therapy has long sought effective interventions that can safely and sustainably lower plasma homocysteine, thereby reducing morbidity and improving quality of life for affected individuals.

Current treatment approaches for homocystinuria and hyperhomocysteinemia are limited and often unsatisfactory. Standard therapies include strict dietary restriction of methionine, supplementation with vitamins such as pyridoxine (vitamin B6), and use of adjunct agents like betaine to promote alternative metabolic pathways. However, these regimens are challenging for patients to maintain due to dietary complexity and poor palatability, leading to issues with compliance. Additionally, many patients are unresponsive to vitamin supplementation , and betaine therapy can have undesirable side effects, such as gastrointestinal discomfort and increased methionine levels, which may themselves be harmful. These limitations highlight a significant unmet need for more effective, targeted, and patient-friendly treatments that can reliably control homocysteine levels without imposing a substantial burden on patients’ daily lives.

Technology description

This technology is a therapeutic enzyme solution designed to treat homocystinuria and hyperhomocysteinemia. At its core is a modified human cystathionine-gamma-lyase (CGL) enzyme, engineered with eight specific amino acid substitutions to enhance its specificity and catalytic activity for degrading homocysteine and homocystine, while minimizing off-target effects on related amino acids like methionine and cysteine. The enzyme can be conjugated with polyethylene glycol (PEG) to extend its serum half-life and improve pharmacokinetics, and may also be fused with affinity tags for easier purification.

The formulation is provided as a liquid in vials, with concentrations ranging from 1 to 50 mg/mL, and is administered intravenously or subcutaneously at flexible dosing regimens tailored to patient needs. The primary therapeutic goal is to reduce plasma homocysteine levels to clinically desirable targets, with administration protocols supported by preclinical efficacy and pharmacokinetic data.

This solution is differentiated by its rational protein engineering approach, which tailors the enzyme’s substrate specificity and activity through targeted amino acid substitutions, resulting in superior homocysteine degradation compared to the native enzyme. The optional PEGylation further distinguishes it by significantly enhancing the enzyme’s stability, circulation time, and reducing immunogenicity, enabling less frequent dosing and improved patient compliance. Unlike current therapies that rely on restrictive diets or adjunctive agents with variable efficacy and side effects, this enzyme-based therapy directly targets the underlying metabolic imbalance, offering the potential for more consistent and robust control of homocysteine levels. The detailed development plan, including preclinical validation in disease models and a structured clinical trial strategy, underscores its readiness for clinical translation and its promise as a transformative therapy for patients with limited treatment options.

Benefits

Enhanced specificity and activity for degrading homocysteine and homocystine, improving treatment efficacy for homocystinuria and hyperhomocysteinemia
Extended serum half-life and improved pharmacokinetics, allowing less frequent dosing and sustained therapeutic effects
Reduced off-target activity toward other amino acids like methionine and cysteine, minimizing potential side effects
Flexible administration routes (intravenous and subcutaneous) and dosing regimens tailored to patient needs
Demonstrated preclinical efficacy including improved survival, reversal of liver pathology, and reduction of plasma homocysteine levels
Potential to improve patient compliance and quality of life by enabling dietary liberalization compared to current treatments
Produced via recombinant expression with engineered amino acid substitutions, ensuring consistent quality and scalability

Commercial applications

Treatment of homocystinuria
Treatment of hyperhomocysteinemia
Adjunct to dietary management
Reduction of plasma homocysteine

Additional information

A modified human cystathionine-gamma-lyase enzyme incorporates eight specific amino acid substitutions to enhance homocysteine and homocystine degradation. Optionally PEGylated for extended serum half-life, it is formulated as a liquid (1-50 mg/mL) for intravenous or subcutaneous administration. This therapeutic agent aims to reduce plasma homocysteine levels in homocystinuria or hyperhomocysteinemia.