Enzyme Replacement Therapy For Gaucher Disease

Introduction

A rare, inherited metabolic disorder known as Gaucher disease is caused by a lack of the enzyme glucocerebrosidase, which leads to the accumulation of toxic amounts of specific fats (lipids), namely the glycolipid glucocerebroside, throughout the body, particularly in the liver, spleen, and bone marrow. Gaucher disease symptoms and physical characteristics differ significantly amongst individuals. While some people experience minimal or no symptoms (asymptomatic), others could experience major consequences.

Enzyme replacement treatment (ERT) and substrate reduction therapy (SRT) are two FDA-approved medication therapeutic options available at this time. For those with Gaucher disease type 1, enzyme replacement therapy (ERT) has proven beneficial. Notably, anaemia and low platelet counts have improved, spleen and liver enlargement have significantly decreased, and skeletal abnormalities have improved in ERT investigations. When ERT is administered to patients with Gaucher disease types 2 and 3, these systemic signs also become better.¹

Understanding Gaucher disease

Gaucher disease is inherited autosomally recessively, meaning that one defective gene is passed down from each parent to their offspring. The GBA gene is found in two copies in every person. Individuals who carry a single defective copy of the gene are referred to as carriers. Individuals with Gaucher disease do not have a single functional copy of the gene; instead, they receive a mutant copy of the gene from each of their parents. The odds of a child being born with Gaucher disease, becoming a carrier, and not having the condition or being a carrier are 1 in 4 and 1 in 2, respectively, if both parents are carriers.²

Patients with Gaucher disease, a hereditary lysosomal storage disorder, have low glucocerebrosidase (GCase) levels. This enzyme is in charge of glucocerebroside's breakdown. If there is insufficient GCase enzyme, fat can be collected in specialized immune cells called macrophages, which amass in the liver, spleen, and bone marrow, leading to inflammation and organ dysfunction. The illness is brought on by mutations in the GBA gene and the GCase action is disrupted by this gene mutation.²

Symptoms of Gaucher disease

The different symptoms include:³

• Bleeding because of low platelet count (most common symptom)
• Bone pain and fractures
• Cognitive impairment (decreased thinking ability)
• Easy bruising
• Enlarged spleen
• Enlarged liver
• Fatigue
• Heart valve problems
• Lung disease (rare)
• Seizures
• Severe swelling at birth
• Skin changes

Types of Gaucher disease

• Type 1: the most prevalent kind of Gaucher illness is Type 1. About 90% of those who have the illness are affected by this type of disease. Patients have low platelet count and may become easily bruised and experience extreme weariness as a result. Symptoms may be seen at any age. Enlargement of the spleen and kidneys as well as lung, bone, or kidney issues is also possible⁴
• Type 2: this type affects babies between three and six months old. Children typically don't live past the age of two, hence, it is lethal⁴
• Type 3: skeletal issues, abnormalities in the movement of the eyes, seizures that worsen with time, blood disorders, respiratory issues, and enlargement of the liver and spleen are among the symptoms⁴

Enzyme replacement therapy (ERT)

ERT is designed to be highly targeted, addressing the specific enzyme deficiency associated with a particular disorder. This precision distinguishes ERT from other therapeutic approaches. The goal is to correct the biochemical imbalance at the molecular level, leading to improvements in symptoms and overall health.⁵

ERT uses a modified form of the glucocerebrosidase (GCase) enzyme to counteract low levels of the enzyme. The fatty substance known as glucocerebroside, which builds up in the bodies of Gaucher disease sufferers, is broken down by this enzyme. (The therapy is known as enzyme replacement since this makes up for the lost enzyme.) ERT is administered to patients via IV infusion, which typically takes one to two hours. The first ERT was authorized by the US Food and Drug Administration (FDA) in 1991.

Depending on the patient, an ERT infusion is usually required every two weeks. There are advantages and disadvantages to receiving ERT at home, in a Gaucher disease treatment facility, or at an infusion centre.⁶

There are several ERTs currently available for Gaucher disease, namely:⁷

Cerezyme (imiglucerase)

A recombinant enzyme called Cerezyme was created by Sanofi Genzyme to replace beta-glucocerebrosidase, which was approved by the FDA in 1994 as the replacement for Ceredase.

VPRIV (Velaglucerase alpha) 

Another long-term ERT created by Shire with a unique gene activation technique is called VPRIV. The FDA authorized it in 2010 for the treatment of type 1 Gaucher disease.

Elelyso (taliglucerase alpha) 

Pfizer created Elelyso, a recombinant ERT based on plant cells that can replace human beta-glucocerebrosidase that isn't working properly. The FDA gave it its approval in 2012.

ERT administration and monitoring

Administration methods 

Enzyme replacement therapy (ERT) is administered using various methods, depending on the specific disorder being treated, the characteristics of the enzyme, and patient considerations. Here are some common administration methods for ERT:⁸

Intravenous infusion (IV)

Intravenous infusion is a common method for delivering enzyme replacement therapy. The enzyme is typically administered directly into the bloodstream through a vein. This allows for a controlled and consistent delivery of the enzyme throughout the body. Infusions are usually performed in a clinical setting, such as a hospital or infusion centre.

Subcutaneous injection (SC) 

Some enzyme replacement therapies can be administered through subcutaneous injections, where the enzyme is injected under the skin. This method is often preferred for certain disorders as it can be done at home, reducing the need for frequent hospital visits. It may involve the use of an autoinjector or pre-filled syringe, making it more convenient for patients.

Intrathecal administration 

In some cases, especially for lysosomal storage disorders affecting the central nervous system, the enzyme may be delivered directly into the cerebrospinal fluid through an intrathecal injection. This method aims to target the enzyme to the affected areas of the central nervous system.

Oral administration

While not as common, oral administration is explored for certain enzyme replacement therapies. However, enzymes are often broken down in the digestive system, and the challenges of stability and absorption make this method less common for many ERTs.

Targeted delivery systems

Researchers are continually exploring targeted delivery systems, such as nanoparticles or liposomes, to enhance the effectiveness of ERT. These systems can improve the stability of the enzyme, increase its circulation time in the body, and allow for more specific targeting of affected tissues.

The choice of administration method depends on various factors, including the nature of the disorder, the characteristics of the enzyme, patient preferences, and the potential for home-based treatment. The goal is to achieve optimal therapeutic outcomes while minimizing inconvenience and discomfort for the patient.

Dosage and frequency of ERT

Doctors who are experienced in treating patients with Gaucher disease should oversee Cerezyme therapy.

Cerezyme dose recommendations vary depending on the severity of the disease; they range from 2.5 units/kg three times a week to 60 units/kg once every two weeks. Give the diluted Cerezyme solution to patients weighing 18 kg or more for one to two hours. Infuse the diluted Cerezyme solution over 2 hours for patients weighing less than 18 kg. Based on the patient's therapeutic objectives and the clinical presentation of the condition, titrate the dosage.⁹  

Monitoring and assessment of treatment effectiveness

• Regular monitoring is essential to assess the patient's response to treatment and to detect any adverse effects
• Dosage and frequency may be adjusted based on monitoring results, changes in the patient's condition, or new developments in the field of enzyme replacement therapy¹⁰

Potential side effects and complications of ERT

Although ERT is frequently the only successful treatment available for a particular lysosomal storage disease, there are a few drawbacks and adverse effects to take into account, including:¹¹

• Exorbitant treatment costs. The annual cost of ERT treatments can reach hundreds of thousands of dollars. For the majority of people, this calls for significant insurance support
• Reaction of the immune system against the injected enzyme. Depending on the body's response to the infused enzyme, ERT can set off immunological reactions. Individual differences will exist in these impacts
• The emergence of enzyme resistance. If the body becomes resistant to the replacement enzymes, some ERTs may lose some of their efficacy over time
• Not a remedy. With any ERT, lifetime treatments are required, occasionally even in the event of negative side effects. To lessen the symptoms of having a lysosomal storage disorder, medications must be administered for the entirety of a patient's life. Although ERT can replace missing enzymes, it does not create in the body the ability to synthesize them
• Inhomogeneous biodistribution. This indicates that the body's replacement enzyme is not dispersed equally across its organs. As a result, the therapy's efficacy might be restricted to particular body parts, and some LSD symptoms might endure through treatment

Summary 

Enzyme Replacement Therapy (ERT) has emerged as a transformative and life-changing treatment for individuals with Gaucher's disease. Gaucher's disease, a rare lysosomal storage disorder, is characterized by the deficiency of the enzyme glucocerebrosidase, leading to the accumulation of lipid substances in various organs. ERT, specifically designed to address this enzymatic deficiency, has shown remarkable efficacy in alleviating symptoms and improving the overall quality of life for patients.

Through targeted administration, typically via intravenous infusion, ERT aims to replenish the deficient enzyme, facilitating the breakdown of accumulated lipids and preventing further organ damage. The therapeutic benefits of ERT extend beyond symptom management, encompassing reductions in hepatosplenomegaly, improvements in haematological parameters, and enhanced bone health.

The success of ERT in Gaucher's disease underscores the importance of personalized treatment plans, with dosages and frequencies tailored to individual patient needs. Home administration options for some ERTs further contribute to patient convenience and adherence.

However, challenges such as the need for lifelong treatment, potential immunogenicity, and access to therapy remain considerations in the ongoing management of Gaucher's disease. Ongoing research and advancements in ERT technology aim to address these challenges and enhance treatment outcomes.