Is Gaucher disease curable?

Scientists have been searching for a cure for all genetic diseases, including Gaucher disease, for more than 40 years. Since inherited genetic disorders result from an altered sequence of genes located on chromosomes within each cell in your body, a cure must permanently reverse the underlying genetic mutations that cause Gaucher disease⁽¹⁾.

There is currently no cure for Gaucher disease. However, the lives of patients with the disease have already been transformed as scientists work toward a permanent or semi-permanent cure utilizing advancements in gene therapy. Beginning in the early 1990s, patients with Gaucher disease have experienced substantial increases in quality of life and overall health as a result of expanding treatment options.

How far have we come toward curing Gaucher disease?

In the early days of treatment, doctors managed Gaucher disease according to each patient’s unique symptoms selecting from treatment options including surgical removal of the spleen, orthopedic procedures like hip replacements, liver transplants, blood transfusions, and bone marrow transplants ⁽²⁾. However, scientists weren’t able to effectively address the actual cause of Gaucher disease, the lack of the enzyme glucocerebrosidase (GCase) which breaks down glucocerebroside.

In 1991, the U.S. Food and Drug Administration (FDA) approved enzyme replacement therapy (ERT) for Gaucher disease type 1, which revolutionized patient treatment. To this day, if you have Gaucher disease type 1, you can receive ERT every two weeks via intravenous (IV) infusion. ERT works by replenishing low levels of GCase enzyme with a modified version of the normal enzyme found in most people.

ERT allows your body to break down accumulated glucocerebroside, a fatty material that can accumulate throughout your body and blood stream. Left untreated, this material will reach toxic levels, activating the immune system and ultimately result in the Gaucher symptoms.⁽³⁾. Dr. Pramod Mistry, Professor of Medicine and Pediatrics and the Director of the Center of Excellence at Yale School of Medicine, says, “ERT has saved lives. It has prevented devastating complications, it has alleviated pain and suffering, and stopped the need for surgical procedures. In that way, lives of patients have been dramatically transformed.”

While ERT has been transformative for Gaucher disease type 1 in many respects, it involves life-long intravenous infusions every 2 weeks. Hence, there have been efforts to develop oral treatment that works by slowing down production of glucocerebroside. The first such treatment, called the substrate reduction therapy (SRT) was approved in 2003 for patients with mild-to-moderate Gaucher disease who were unable to take ERT. Recently, the FDA approved a more targeted and potent form of SRT for adults with type 1 Gaucher disease as an initial treatment or switch from ERT. Instead of IV infusions, patients can take oral medications once or twice a day to slow the production of glucocerebroside.

“Remarkably, (SRT) is as effective as ERT, whether or not patients have the severe, most advanced forms of Type 1 Gaucher disease. The burden of IV infusions has been alleviated, because patients now have the option of going on the oral medication,” says Dr. Mistry. “This is a huge milestone in the history of Gaucher disease, and it opens the door for next generation treatments that cross the blood brain barrier to tackle neurological forms of Gaucher disease, including Parkinson disease which complicates type 1 Gaucher disease.”

What obstacles stand in the way of curing Gaucher disease?

In Western countries, almost 95 percent of people with Gaucher disease have type 1, which is especially common among people of Jewish descent. However, type 2 and type 3 Gaucher disease are the most common forms of the condition worldwide. In many cases, people with type 2 and type 3 experience a variable degree of neurological symptoms, ranging from mild eye movement abnormalities to severe problems, such as seizures and cognitive problems.

“About 5 to 6 percent of patients with Gaucher disease type 1, and also carriers of the genetic mutation for Gaucher disease, are at risk of developing Parkinson’s disease and Lewy Body Dementia,” says Dr. Mistry. “Both conditions appear to be increasingly connected to the buildup of lipids that is so characteristic of Gaucher disease.”

Unfortunately, available treatments – including ERT and SRT – are not effective in stopping the progression of any neurological complications associated with Gaucher disease type 2 and 3, as well as Parkinson disease associated with Gaucher mutations.  These aspects of Gaucher disease are devastating, but now there is a ray of hope for these individuals with the launch of several clinical trials investigating the next generation of SRT medications. Each of these medications can cross the blood-brain barrier to control neurological problems.

How could gene therapy help us reach a cure?

In the 21^st century, there has been a noticeable shift in focus toward gene therapy as a new way to permanently correct the mutations that lead to inherited disorders such as Gaucher disease. The idea behind gene therapy is to replace the defective gene with the normal gene or to fix the specific genetic abnormality that underlies Gaucher disease. While there has not yet been definitive research that shows this new treatment will work for Gaucher patients, clinical trials involving people with other genetic diseases have been successful.

To date, research into gene therapy has advanced, all of which could have a broad impact on people who are suffering from any number of genetic diseases, including Gaucher disease. Scientists believe these new therapies could be anything from a one-time injectable cure to a treatment that is only required once every few years.

• Adeno-associated virus (AAV) vector therapy

Adeno-associated viruses (AAV) contain a single strand of DNA. They have been disabled, meaning that they will not cause infection within your body. Instead, these viruses act as vehicles (vectors) to transport copies of normal genes, such as the normal copy of the gene that is defective in Gaucher disease⁽⁴⁾.

AAV vectors for gene therapy can be infused intravenously into a person suffering from a genetic disease. The AAV vector travels to the liver, where the normal genes drive the production of normal enzymes. The normal enzyme is then secreted by the liver into the patient’s bloodstream, eventually taken up by other organs throughout the body.

For Gaucher patients, AAV could be used to exploit the liver as a “bioreactor” capable of producing enough GCase enzyme to restore health. “Some studies for lysosomal diseases have shown that this AAV vector can drive the production of so much enzyme that it is taken up by all cells in the body – it may even get to the brain,” says Dr. Mistry.

• Lentiviral vector gene therapy

With this new type of gene therapy, doctors collect bone marrow cells from the patient via a needle inserted into the bone marrow. In the laboratory, this crude preparation is manipulated to purify cells capable of giving rise to all types of blood cells. Scientists infect these progenitor cells with lentiviral vectors, a type of disabled virus that can act as a vehicle to deliver the normal gene into the cell⁽⁵⁾.

These vectors are capable of carrying normal genes for many different types of genetic diseases. First, the cells with correct copy of the gene are intravenously infused back into the patient. Then, the cells hone into the bone marrow to produce blood cells with normal GCase activity. This is an exciting approach due to the history of using bone marrow cells in Gaucher disease treatment. In the 1980s, transplanting bone marrow from an unaffected person into patients with Gaucher disease reversed many symptoms of the disease. However, this was risky procedure with many complications related to bone marrow transplantation.  Today, new studies are showing lentiviral vector gene therapy using bone marrow holds great promise for several genetic diseases, including Gaucher disease.

While clinical trials for Gaucher disease in humans have not yet gotten underway, researchers report encouraging results from gene therapy in mice with Gaucher disease. Because lentiviral vectors actually replace the mutated genes that cause genetic diseases, this therapy could prove to be a promising future curative therapy for Gaucher disease.

• CRISPR-CAS

The CRISPR-CAS system is a new form of technology, called gene editing, that can permanently fix genetic defects by specifically targeting and correcting the defect in the gene. Currently, there are several academic researchers and biotechnology companies working toward bringing this technology to the clinic.

CRISPR-CAS works by permanently changing genetic mutations back to the normal sequence of genes. The enzyme system can enter cells and target specific genes in the genome. After locating the Gaucher gene in a patient’s DNA, CRISPR-CAS can identify where the genetic mutation is located in the gene, unlocking that part of the genome and removing the mutated sequence. The CRISPR-CAS enzyme system provides the necessary enzymes for the genome to reform the correct genetic sequence after the mutation is removed.

“In the 21^st century, we’re going to see some incredible breakthroughs in Gaucher disease. We already have multiple therapies and clinical trials for next generation treatments,” says Dr. Mistry. “I am optimistic there are going to be significant advances in gene therapy over the next 10 to 20 years. The big question is how much incremental benefit can patients get over the existing treatments? In order for gene therapy treatments to become standard of care, they not only have to be as effective as ERT, and superior in addressing some of our unmet needs, but also safe.”