Are there treatments available for patients with LSDs?
- The treatment of LSDs can be divided into supportive/symptomatic and specific treatment (Fig.2).
- Both treatment modalities complement each other, and together they aim the best quality-of-life for the affected patients and their families.
- Supportive treatment involves the multi-disciplinary care of different specialties. Usually, the multiple problems that LSD patients develop require symptomatic/supportive treatment to address the secondary effects of the accumulation of a substance in lysosomes. Several specialties have an essential role in determining the clinical outcome and quality of life for patients with LSDs, including cardiology, anesthesia, orthopedics, otorhinolaryngology, ophthalmology, neurology, neurosurgery, as well as paramedical groups including physiotherapy, occupational therapy, nutrition, audiology, speech therapy, and psychology.
Figure 2 – Principles to understand Lysosomal Storage Diseases. Lysosomal storage diseases (LSDs) are genetic diseases caused by specific enzyme deficiencies that result in the buildup of undegraded substance inside cell organelles called lysosomes, which are sac-like structures present in every cell in our body. Lysosomes are recycling units, i.e., they are responsible for breaking down lipids, sugars, and proteins into small units that can be re-utilized by the cell. Lysosomes and related endosomes are responsible for intracellular trafficking that is essential for cell function. The figure shows a blood cell from a healthy individual and a patient with an LSD, showing the enlargement of several lysosomes containing the undegraded substance. Enlargement of lysosomes ultimately results in the impairment of lysosomal function and consequently cellular function in multiple organs and systems. Therefore, LSDs manifest as systemic diseases in patients with multiple and progressive neurological, renal, cardiovascular, gastrointestinal, musculoskeletal, ophthalmological, cutaneous and respiratory problems.
Hematopoietic stem cell transplantation (HSCT)
- The aim is to use donor-derived cells as a source of enzyme.
- The cell source can come from bone marrow, or umbilical cord donor macrophages can infiltrate diverse patients’ tissues including the central nervous system. These donor-cells secrete a normal lysosomal enzyme (able to break down the accumulated substrate) which is uptake by patients cells, reaching their enlarged lysosomes directly and cleaning them as the defect.
- When done before a patient with severe form of disease starts to develop neuroregression, HSCT has shown to be efficacious in one specific LSDs, MPS type 1 and a treatment algorithm is described. However, it has not been proven to have the same result in most LSDs. Also, most data available is anecdotal or is based. In Krabbe disease and metachromatic leukodystrophy, the initial benefit has demonstrated, preventing the fulminant course of these neurodegenerative diseases.
Enzyme-replacement therapy (ERT)
- Eight LSDs are treated with ERT – Gaucher disease, Fabry disease, mucopolysaccharidoses types I, II, IV and VI, lysosomal acid lipase deficiency
- ERT was initially developed for Gaucher disease type 1 (without neurological problems) using glucocerebrosidase purified from human placentas. The development of recombinant enzyme produced in cultured cells increased the scale of the production. The primary limitation of ERT is its inability to treat neurological symptoms of most LSDs since the ERT agent is unable to cross the blood-brain barrier, which is a physiological barrier located in blood vessels located in the brain and spinal cord
- Patients on ERT require administration of the recombinant enzyme diluted in normal saline intravenously every one or two weeks.
- Evaluating different clinical outcomes for 6-12 months can note the response to ERT. Some patients develop infusion-related reactions which consist of
Substrate Reduction Therapy (SRT)
- SRT is based on reducing the production of the accumulating substance of a deficient lysosomal enzyme in LSDs
- Miglustat and eliglustat are SRT FDA-approved agents to treat patients who are unable to tolerate ERT for Gaucher disease
- It reduces the production of several SRT agents
- In patients with Niemann–Pick type C disease, miglustat demonstrates stabilization of disease progression and is now licensed in Europe for the treatment of this disease
Enzyme enhancement therapy
- In most LSDs, the disease causes health problems only once the enzyme efficiency is below 10–15% of normal enzyme
- Enzyme-enhancement therapy is based on specific small molecules, which enhance the activity of the deficient enzyme when delivered to lysosomes. Increasing residual enzyme activity by only a few percentage may have profound clinical effects.
- The drugs are still in clinical trials, but they can be available for this type of treatment
What are the limitations of the current treatment for LSDs?
- The ERT is not able to treat neurological problems
- The decision to start ERT for Fabry disease, Gaucher disease (type I) and late-onset Pompe disease is based on patients symptoms or deterioration of those over time in each affected patient. The treatment decision is made in conjunction with patient and their family members
- Early initiation of treatment for mucopolysaccharidosis MPS-I, MPS-II and MPS-VI results in clinical benefit for patients with these conditions
- Although ERT is not effective for treating neurological problems, it may bring significant improvement in the quality of life of patients with severe clinical forms of MPS-II, MPS-II, MPS-III and neuronopathic Gaucher disease
- Pregnancy is not considered a contraindication for ERT in non-neuronopathic Gaucher disease type I and Fabry disease. At present, there are no reports evaluating the ERT during pregnancy in mucopolysaccharidosis MPS-I, MPS-II and MPS-VI
- For MPS-I, specific criteria for offering HSCT and ERT are well-established