PATIENTS AND FAMILIESLysosomal Disorders

Lysosomes are important organelles or structures, located inside the cell. They have multiple functions including the recycling of cellular materials. When lysosomes malfunction, recycling slows or halts, and otherwise harmless molecules build up to toxic levels. This accumulated material, known as substrate, can cause tissue and organ damage and related disease symptoms.

There are about 50 lysosomal disorders. In each, a different type of molecule builds up in the lysosome, disrupting normal cell function.

The severity of a lysosomal disorder depends on which cells, tissues and organs accumulate the most toxic molecules.

• Many lysosomal disorders affect the heart, kidney, spleen, liver and/or bones
• About half of these disorders also affect the central nervous system, which includes the brain and the spinal cord
• Lysosomal disorders are chronic and progressive, meaning they worsen over time. People with these disorders may have life-limiting symptoms and a significantly shortened life span

Although there are currently no cures for lysosomal disorders such as Fabry disease, Gaucher disease, Pompe disease and cystinosis, there are several approved treatments. Each approach has its own advantages and limitations.

Enzyme replacement therapy, or ERT, is the standard of care for lysosomal disorders. As the name implies, ERT is designed to replace the enzyme that is missing or defective in people with lysosomal disorders.

Among the advantages of ERTs:

• They slow progression of disease and in some cases can reverse damage to certain organs.
• ERTs can significantly improve symptoms. For example:
  • In people living with Gaucher disease, ERTs can dramatically reduce the size of enlarged spleens and livers.
  • In people living with Fabry disease, ERTs can slow decline in renal function and improve peripheral neuropathy (pain, numbness, or tingling in the hands or feet).
• ERTs have established a favorable safety profile and are generally well-tolerated over decades of use.

ERTs also have limitations:

• Enzyme replacement does not address the underlying cause of lysosomal disorders and does not halt the overall progression of disease.
• ERTs do not cross the blood-brain barrier and therefore cannot address neurological symptoms that may result from disease progression. For example:
  • People living with Fabry disease may continue to experience impairment of executive function, which can affect their ability to plan, focus and remember instructions. Patients sometimes refer to this impairment as "Fabry fog."
  • People with Gaucher disease type 1 have a significantly higher risk of developing Parkinson’s disease.
• Once ERTs are infused, the body begins to immediately break them down in the liver as well as in the circulation. That’s why people on ERT typically must undergo lifelong biweekly infusions of the enzyme treatment.

Chaperone therapy, used to treat Fabry disease, is an oral medication that "chaperones" mutated lysosomal proteins to assist them in processing, or "digesting," the molecules that would otherwise build up in toxic quantities. Chaperone therapy is used in people with specific mutations that respond to these medications.

Substrate reduction therapy, or SRT, is designed to limit the production of the specific toxic molecules that build up within the cell. This type of oral medication is approved for the treatment of Gaucher disease and is typically given to people with less severe forms of the disease.

In addition to ERT, chaperone therapy, and SRT, individuals living with lysosomal disorders may also take medications to help with symptoms such as pain, high blood pressure or depression.