Enzyme replacement therapy2018-09-28T10:35:53-04:00

Enzyme Replacement Therapy

Enzyme replacement therapy (ERT) is used to compensate deficiencies of production of specific enzymes within the patient’s body—usually resulting from specific genetic defects—by delivering the missing protein on a periodic basis.

This method is used to treat a range of inherited diseases, but for the most part these are focused on the 50+ lysosomal storage diseases that affect relatively small numbers of people and are considered rare/orphan diseases. Lysosomes are cellular organelles responsible for the metabolism of many different macromolecules and proteins within the cell. The lysosomes utilize enzymes to break down these macromolecules, which are then recycled or disposed. If genetic mutations prevent the production of certain enzymes used in the lysosomes, this often leads to a build-up of the substrate within the body. The accumulation of substrate can result in a variety of symptoms, many of which are severe and can affect the skeleton, brain, skin, heart, and the central nervous system. Increasing the concentration of missing enzyme in the blood provides cells the ability to correctly process these substrates.

Some of the more prominent lysosomal storage diseases include:

Gaucher’s disease occurs when certain fatty substances build up in certain organs, particularly your spleen and liver. This causes these organs to enlarge and can affect their function. Specifically, Goucher’s disease is a genetic disorder in which glucocerebroside (a sphingolipid, also known as glucosylceramide) accumulates in cells. It exists in three forms: type 1, also called non-neuronopathic Gaucher disease because the brain and spinal cord are usually not affected; type 2, which affects the nervous system and usually causes life-threatening medical problems beginning in infancy; and type 3, which also affects the nervous system but it tends to worsen more slowly than type 2). Signs and symptoms include hepatomegaly and splenomegaly, joint pain, neurological issues and osteoporosis.

This is a rare autosomal recessive lysosomal storage disease where the body does not produce enough active lysosomal acid lipase (LAL or LIPA) enzyme. The lack of the LAL enzyme can lead to a build-up of fatty material in a number of body organs including the liver, spleen, gut, in the wall of blood vessels and other organs. Symptoms include feeding difficulties, vomiting, diarrhea, weight loss and abdominal distension.

A rare lysosomal disease resulting from deficiency in the enzyme alpha-glucosidase (GAA). Pompe may present in childhood (early-onset) or in adulthood (late-onset). Symptoms include diminished muscle weakness, hypertrophic cardiomyopathy, liver enlargement, respiratory difficulties and hearing loss.

People with MPS II are deficient in the enzyme iduronate-2-sulfatase that helps breakdown glycosaminoglycans (GAG). Build up of GAG can lead to a plethora of symptoms although the more severe cases are characterized by stunted growth, coarse facial features, stiff joints, and intellectual disability. MPS II affects mainly boys and symptoms often begin around age 2-4 years of age. The severe form often results in progressive cognitive impairment and limits the lifespan to about 12-15 years. In more mild forms, the condition may go undiagnosed for many years as it does not result in intellectual impairment or regression. Other symptoms include hearing loss, joint stiffness and thickening of heart valves.

Patients with MPS IV produce an insufficient amount of active N-acetylgalactosamine-6-sulfatase enzyme (GALNS) or have inactive GALNS. As a result, damaging levels of keratan sulfate and chondroitin-6-sulfate accumulate in the tissues and organs, causing pervasive skeletal and joint abnormalities, cardiopulmonary disease, and other clinical manifestations.

Caused by a deficiency in arylsulfatase B (ARSB). Signs and symptoms include neurological complications such as clouded corneas, deafness, pain from compressed nerves and thickening of dura matter. Signs and symptoms include abnormal heart development, large fingers, dwarfism, widely spaced teeth and compression of spinal cord.

ERT is used to minimize symptoms and prevent permanent damage to the body from substrate buildup

ERT is used to minimize symptoms and prevent permanent damage to the body from substrate buildup. Typically, recombinantly-produced enzymes—either replicating the natural protein or modified versions that can function similarly—are provided to the patient via periodic intravenous injection. ERT administration typically requires one to two hours and is repeated multiple times per month. Infusions are usually administered at an infusion centers but under certain conditions can be administered at home by a nurse.

The development of these complex therapies for markets of dozens, hundreds or a few thousand people has resulted in pricing that typically ranges between $150,000 to $300,000 per patient per year. Many of these diseases would be amenable to the use of a nucleic acid-based therapy where the gene for the protein is given and the patient produces a sufficient level of protein that suffices for the missing or deficient protein.

The current economic model for orphan drugs is unsustainable

Successful gene-encoded therapeutics would prolong the period between treatment and eliminate the infrastructure of infusion now required to deliver these proteins, thus freeing these patients from a significant burden of therapeutic administration and lowering the overall cost of care for these patients.

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