By Bethany Bridge
Gaucher disease is a rare genetic disorder caused by a mutation in the GBA1 gene and a subsequent deficiency in the enzyme glucocerebrosidase, which is responsible for breaking down the fat glucosylceramide into glucose and ceramide. This deficiency leads to a harmful accumulation of glucosylceramide in lysosomes, small organelles within cells. Though Gaucher disease is rare, it is more common in the Ashkenazi Jewish population, with 1 in 800 births affected and around 10% of the population being carriers of the GBA1 gene mutation.
Symptoms of Gaucher Disease
There are three types of Gaucher disease. Type 1 is the most prevalent in the western world and symptoms can include: 
- Hepatosplenomegaly: Enlargement of the liver and spleen, causing discomfort.
- Cytopenia: A decrease in blood cells, leading to fatigue, anaemia, and a higher risk of infections.
- Severe Bone Involvement: Pain, fractures, and osteopenia.
In addition to these symptoms, for Types 2 and 3, there is also neurological involvement. Due to early onset of this neurological involvement, Gaucher Type 2 is fatal, often causing death before 2 years of age. Type 3 has a more gradual onset than Type 2 and is the most common type in the Middle East, China, and India. Neurological symptoms of Type 3 Gaucher can include seizures and poor coordination.
Current Treatments for Gaucher Disease
Current treatment options aim to either replace the missing enzyme or reduce the production of glucosylceramide:
- Enzyme Replacement Therapy (ERT): ERT involves intravenous infusions of modified glucocerebrosidase such as imiglucerase or velaglucerase alfa every two weeks. These infusions help reduce symptoms by increasing enzyme levels in the body.
While effective, ERT has limitations, such as the inconvenience of regular infusions and the long-term safety concerns related to infusion ports. Additionally, enzyme levels are highest at the time of infusion and decrease over time, leaving some patients feeling fatigued between treatments. - Substrate Reduction Therapy (SRT): SRT uses oral medications to reduce the production of glucosylceramide, thereby reducing its harmful accumulation in lysosomes. Eliglustat and miglustat are examples. This therapy was previously available only to adults, but eliglustat was recently approved in the UK for children aged 6-18 (as of January 2025).
While more convenient than ERT, SRT can cause side effects like diarrhoea and neuropathy. Additionally, drug interactions are a challenge, as certain medications may interfere with SRT’s effectiveness or lead to additional side effects. Adherence to treatment is another challenge, as patients must remember to take a daily oral medication, which may be difficult for some and can sometimes lead to inconsistencies in dosing.
Importantly, neither ERT nor SRT can address the neurological impairment seen in Gaucher Types 2 and 3, as these treatments cannot cross the blood-brain barrier. Patients with Gaucher Type 3 can receive treatment for other symptoms, but this has little to no effect on neurological involvement.
Gaucher Disease and Parkinson’s Disease: A Surprising Link
A notable connection between Gaucher disease and Parkinson’s disease has been discovered in recent years. Parkinson’s disease affects about 1.5% of people over age 65, causing tremors and stiffness. The comorbidity between Gaucher and Parkinson’s was first noted in the 1990’s, and a 2008 study revealed that Parkinson’s patients were over five times more likely to be Gaucher carriers than control subjects. Although the exact cause of this comorbidity is unclear, it suggests a shared underlying mechanism potentially related to lysosomal dysfunction. This has spurred interest in developing treatments that can cross the blood-brain barrier, potentially benefiting patients with both diseases, particularly those with Gaucher Types 2 and 3.
Innovative Treatment Approaches
- Gene Therapy: Gene therapy aims to introduce healthy copies of the GBA1 gene into patients using viral vectors, such as lentiviral or adeno-associated virus (AAV) vectors. Trials for gene therapies, including FLT-201 by Spur Therapeutics and PR001 by Prevail Therapeutics, show promise, offering hope for treating the disease at its genetic root.
- Small Molecule Chaperones: Chaperones help enzymes fold correctly, ensuring they function properly. In Gaucher disease, they can protect the glucocerebrosidase enzyme from degradation. One promising chaperone, ambroxol, can cross the blood-brain barrier and is currently being investigated in Parkinson’s and Type 1 Gaucher disease patients.
Looking Ahead
Despite current treatment limitations, new advancements in gene therapy and small molecule treatments are creating hope for more effective therapies for Gaucher disease. Researchers are actively exploring ways to target the root causes of the disease, offering the potential for improved outcomes. As these innovative treatments move closer to clinical use, individuals living with Gaucher disease may soon have access to more effective and less invasive options.
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