Introduction

The cell is the functional unit of life. It’s like a colony that shelters many members, called cell organelles. Each organelle is assigned specific duties to perform, allowing for the smooth functioning of the cell. Lysosomes are the organelles that play a vital role in cell signaling, metabolism, growth, programmed cell death, autophagy, protein processing, and maintaining cellular homeostasis. They contain degradative enzymes, such as proteases, lipases, and nucleases, which function at acidic pH (called Acid Hydrolases).⁷ Lysosomes are suicidal bags, which degrade old, unnecessary cell components and recycle the cell debris.¹

What are Lysosomal Storage Disorders (LSDs)?

When there is a mutation in the genes that encode the lysosomal enzymes, the microenvironment of the lysosome gets disrupted. Disruption of the normal function of the lysosome results in abnormal storage and degradation of macromolecules, such as sphingolipids, mucopolysaccharides, and mucolipids, which triggers oxidative stress, autophagy dysfunction, inflammation, and altered membrane transport. These events cause irreparable damage to the cell, leading to premature death.^1,3

Inheritance

The majority of these disorders are inherited in an autosomal recessive pattern, except Mucopolysaccharidosis (MPS) type II, Fabry, and Danon disease, which follow X-linked inheritance.³

Lysosomal Storage Disorders(LSDs) comprise more than 70 inborn errors of metabolism disorders, and these occur in 1 in 5000 live births.¹

The common Lysosomal Storage Disorders(LSDs), which occur due to enzyme defects, are listed in the table below:⁸

These disorders can also occur due to a processing defect of lysosomal enzymes after their synthesis, inefficient transport of synthesised enzymes to the lysosome, or a defect in soluble lysosomal proteins.⁸

Clinical features

The clinical profile of LSD patients can be extremely variable depending on the type of storage material and physical distribution throughout the body. The majority of these disorders manifest in infants and young children, and they affect various organ systems like bones, connective tissues, and brain, causing enlargement of the liver and spleen. More than 70% of all LSDs are associated with neuronal damage leading to impaired memory, motor defects, behavioural problems, sleep disturbances, blindness, deafness, hyperactivity, and seizures.^3,8

Diagnosis of Lysosomal Storage Disorders (LSDs)

The gold standard technique for the diagnosis of LSDs is the demonstration of deficient enzyme activity in peripheral blood leukocytes (white blood cells) in dried blood spot (DBS) samples or cultured skin fibroblasts. The option of measuring accumulated substrate concentration in a specific disorder is also available. For example, the measurement of glucosphingosine (lyso-Gb1) concentration in Gaucher Disease. Genetic testing for mutations in genes such as GBA1, SMPD1, and LIPA confirms the diagnosis.⁵

Various therapies available are:

• Pharmacological therapy
• Enzyme replacement therapy (ERT)
• Gene therapy
• Transplantation
• Lysosomal drug targeting (LDT)¹

Enzyme replacement therapy (ERT)

Enzyme replacement therapy is the process by which the specific enzyme that is absent or inactive in affected persons is replaced with a functional enzyme. 

The recombinant enzymes (functional enzymes) are produced in continuous human fibroblasts or animal cell lines (Chinese hamster ovary (CHO) cells) and plant cells. Recombinant enzymes are the purified form of the lysosomal enzymes.⁶

There is no effective treatment available for the majority of the LSDs. ERT was first developed for the treatment of Gaucher disease and is also available for the treatment of other LSDs. In ERT, the functional recombinant enzyme, produced by utilising recombinant DNA technology, is administered intravenously to the patients. The enzyme enters the cells through the mannose-6-phosphate receptor pathway and is then directed to the lysosomes. In the lysosomes, these functional enzymes degrade the accumulated substances, which alleviates LD symptoms.^1,3

Benefits of ERT

The ERT is effective in reducing the amount of accumulated substrates, preventing further accumulation, reversing organomegaly (enlarged organs), improving growth by reducing bone deformities, increasing the range of motion of joints, improving lung capacity, heart health, hearing, vision, and the overall quality of life.

These benefits can be achieved if ERT is started at an early age after diagnosis. However, the effects of starting ERT early on cognitive function are not clear from the research.⁶

ERT can be administered in hospitals or at home. Hospital-based therapy is under medical supervision, where patients can be managed immediately in case adverse effects occur. However, patients may face the challenges of long-distance travel for frequent hospital visits, which is inconvenient for them and puts a financial burden on them.

Based on patient needs, resource availability, and safety considerations, home therapy was introduced. Home therapy is more comfortable, cost-effective, and improves the quality of life of patients as they can independently manage their treatment. Patients or caregivers should be well-trained to self-cannulate, stop the infusion, and identify the potential adverse effects.²

Limitations of ERT

1. The recombinant functional enzymes can not effectively cross the blood-brain barrier, as it is impermeable to larger molecules
2. These enzymes have a short plasma half-life; hence, they are rapidly cleared from the blood. That's why the patient requires frequent infusions 
3. The patients may develop immunological reactions and produce antibodies against the infused enzyme, diminishing the treatment efficacy and compromising patient safety¹
4. High cost and frequent hospital visits for administration of ERT limit the patient’s compliance with the treatment²
5. There are some countries or regions where home ERT is not approved or not reimbursed²

Methods used to overcome limitations of ERT

1. To improve the efficacy of transport of enzymes to the brain, two approaches have been used: 
   • Direct administration of recombinant enzyme via intrathecal (IT) or intracerebroventricular (ICV) routes bypasses the blood-brain barrier (BBB) completely
   • Modification of the enzymes by fusing them to molecules that recognise specific blood-brain barrier (BBB) carrier proteins, such as ApoB, ApoEII, Fc antibody fragments, and IGFII, permits improved transport across the BBB by receptor-mediated transcytosis (RMT). The encapsulation of enzymes into nanoparticles also facilitates their transport across the blood-brain barrier by RMT
2. Enzymes with long plasma half-life are being developed so that the patient requires less frequent dosing of ERT
3. To alleviate skeletal manifestations, bone-targeting enzymes are developed that would penetrate better into the bones 
4. To reduce the financial burden on patients, alternative production methods are devised to reduce the cost and improve availability 
5. To improve the efficacy of ERT, efforts are made to pair ERT with gene therapy or substrate reduction therapy (SRT)
6. The incorporation of lysosomal enzymes with nanoparticles overcomes the risk of immunologic reactions and biodegradation. Moreover, this technique increases drug absorption, extends enzyme release, and improves the biological response¹
7. Immune tolerance induction(ITI) regimes are used as an effective approach in patients to address the issues of the development of immunological reactions. These can benefit patients therapeutically by diminishing the levels of pre-existing antibodies. Tolerance induction involves balancing the elimination or deactivation of antigen-reactive cells and the emergence of regulatory cells⁴

Summary

Lysosomal storage disorders are inherited conditions that impact multiple organs, including the bones, liver, spleen, brain, and eyes. These disorders arise from impaired lysosomal function, leading to the accumulation of substrates within the cells. Neurological symptoms are among the most common manifestations due to the frequent involvement of the brain. The severity of clinical signs and symptoms depends on the distribution of the substrate and its type in various tissues within our body. Diagnosis typically involves detecting deficient enzyme activity in the cells.

Enzyme replacement therapy (ERT) works by supplying a functional version of the deficient enzyme. It is usually administered intravenously, either in a hospital setting or at home. Despite its benefits, ERT faces several limitations, such as high treatment costs, the inability of therapeutic enzymes to cross the blood-brain barrier, and the risk of immune responses or anti-drug antibody formation. To overcome these challenges, research should be conducted to explore the enhanced forms of ERT in combination with other approaches, including substrate reduction therapy, chaperone therapy, exon skipping, and gene therapy.