What are lysosomal storage disorders?

Lysosomal storage disorders (LSDs) are a group of more than 50 inherited conditions caused by missing or non-functional enzymes inside cellular structures called lysosomes. Lysosomes are the cell's recycling centre; they break down waste molecules so the cell can reuse the components.

What goes wrong. When an enzyme is missing or broken, the molecules it normally processes build up inside lysosomes. Over time, this accumulation damages organs in different patterns depending on which enzyme is affected. Common features include enlarged liver and spleen, bone problems, heart issues, and in many cases progressive neurological problems.

The enzyme replacement approach. For decades, scientists have been able to manufacture the missing enzymes and infuse them into patients. The patient's cells take up the enzyme through specific receptors, the enzyme travels into the lysosome, and the substrate buildup begins to clear. Enzyme replacement therapy has transformed the outlook for many LSDs that affect organs outside the brain.

The brain problem. The blood-brain barrier is a tight layer of cells that protects the brain from many circulating molecules, including therapeutic enzymes. Standard enzyme replacement therapy does not cross the barrier in meaningful amounts, which means LSDs with significant brain involvement (MPS II, MPS IIIA, several others) have not been well served by the standard approach.

The new approach. Engineered enzymes designed to cross the blood-brain barrier (often by attaching them to a transporter that carries molecules into the brain) are now in late-stage development. If they work, they would address the unmet need that has defined LSDs with brain involvement for decades.

Gene therapy, substrate reduction therapy (small-molecule drugs that reduce production of the harmful substrate), and other approaches are also part of the modern LSD therapy toolkit.