For those whose lives are touched by Gaucher disease types 1 and 3, ERT (enzyme replacement therapy) and SRT (substrate reduction therapy) are often part of their regular routines. But in 1991, when the FDA approved the first form of ERT, this breakthrough felt miraculous, radically easing the disease’s signs and symptoms. This was followed by orally administered SRT, which can make for more convenient treatment. But how do these drugs function within the body? And when will a drug that treats brain-related symptoms be available? A thorough understanding of the main forms of Gaucher disease therapy can help empower patients and their families.
ERT and SRT: The Drain and the Faucet
When talking about Gaucher disease therapy to people outside the medical field, Dr. Gregory Grabowski, Professor Emeritus at University of Cincinnati College of Medicine and a world-renowned expert on Gaucher disease, uses a metaphor from daily life. The lysosome can be compared to a bathtub, he says, while the GCase enzyme can be said to “open the drain.” The substrate glucocerebroside is like water coming out of the faucet. In Gaucher disease, it is as if the drain has been constricted, but the water continues to flow. While enzyme therapy opens the drain, allowing the substrate to be diminished, substrate reduction therapy turns the faucet down, inhibiting the flow of glucocerebroside into the tub and allowing the body to reach a healthy equilibrium. A doctor with expertise in treating Gaucher disease will be able to work with each patient to decide on a personalized plan of care involving one of these two therapy options.
Enzyme Replacement Therapy: The First Line of Defense
Most people experience painful or debilitating signs and symptoms before being diagnosed with Gaucher disease. At that point, physicians will usually start enzyme therapy, which quickly gets the signs and symptoms under control. “It is extremely rare to have a failure of enzyme therapy,” says Dr. Grabowski. During a period of six to nine months, treatment is typically given at an infusion center, or a Gaucher disease treatment center, so the small percentage of patients who develop adverse effects can be treated as needed. Once doctors determine ERT is safe for an individual, the patient can receive infusions closer to home, or even in the home, in the case of a visiting or home health nurse. The next step is determining the right dose, which is different for everyone. While some people do well on a low dose, others “need a lot more enzyme – even greater than the recommended 60 units per kilogram every two weeks,” according to Dr. Grabowski. In addition, doctors can adjust the frequency of infusions. That can help those who feel great immediately after an infusion, but start to feel tired a week later. “Not everybody is going to respond the same to the identical dose of enzyme given at the same frequency. You have to personalize it for the individual,” says Dr. Grabowski.
Substrate Reduction Therapy: The Right Choice for Some
Once signs and symptoms of Gaucher disease are under control, an SRT, taken orally, may be an option. Currently, it is available only for adults. More research is needed to determine whether it is a safe therapy for use in children. The SRT Eliglustat is as effective as enzyme therapy for use in adults and has minimal side effects, but the dosing can be complex because of how some genes metabolize it. As with enzyme therapy, dosing needs to be personalized to be most effective. In the future SRTs and ERTs may be combined. There is some evidence to suggest that when doctors administer the two treatments simultaneously they can treat certain kinds of rapidly progressing childhood variants of the disease.
Coming Soon: An SRT that Treats Neurological Symptoms
While both drugs control a wide range of signs and symptoms, they have been largely ineffective against neuronopathic forms of the disease, such as those that are present in Gaucher disease type 3. Within the next five years, that is set to change. Scientists are currently developing a new form of SRT, a derivative of Eliglustat, which may be able to penetrate the central nervous system. Although researchers have just begun recruiting participants for clinical trials, data from experiments involving mice indicates this drug can cross the blood-brain barrier, reducing the level of substrate and stopping effects of the disease in the brain, explains Dr. Grabowski. The big question is whether those findings are transferable to humans.
Taking the Long View: What Does the Future Hold for These Treatments?
What are the long-term effects of these forms of Gaucher therapy? According to Dr. Grabowski, even after many years of enzyme therapy, it is possible that some parts of the bone, lymph nodes and lungs may still have traces of the disease, despite the amazing rates of success. Adding substrate therapy or applying a combination of enzyme and substrate therapies may be part of future care plans, as treatments for Gaucher disease are refined further.
