[Interview] Professor Ari Zimran at Shaare-Zedek Medical Center in Israel

There are about 7,000 rare diseases found worldwide, but a fraction of them have any treatments. Fortunately, Gaucher’s disease, an illness caused by the lack of the enzyme, is one of the few that have found the treatment. Doctors still consider it a disease whose patients are hard to find, however, as the popular awareness of its remains low and its diagnosis quite tricky.

There are currently about 60 patients with the Gaucher’s disease in Korea, but one can hardly know how many more are out there, being left in the dead angle of healthcare services.

Korea Biomedical Review met with Professor Ari Zimran at Shaare-Zedek Medical Center in Israel to know about the diagnosis and treatment of the Gaucher’s disease. Professor Zimran is the world-renowned scholar of the Gaucher’s disease, and Shaare-Zedek is also the medical institution which treats the largest number of patients suffering from the disease.

Dr. Ari Zimran at Shaare-Zedek Medical Center in Israel talks about the diagnosis and treatment of the Gaucher’s disease in a recent interview with Korea Biomedical Review.

Question: What is the Gaucher’s disease?

Answer: The Gaucher’s disease is an inferior genetic disease caused by an autosome. So if people receive the genes of the disease from both parents, they come down with the disease, and if they get the genes from one of the parents, they become carriers. Because of these characteristics, the attack rate of Gaucher’s disease is higher in particular nations or races who get married within a family. Gaucher’s disease patients show symptoms, such as enlarged spleen and enlarged liver, and bones-related symptoms. Before the introduction of Enzyme Replacement Therapy (ERT), there wasn’t effective treatment to relieve the symptoms. Especially the common complications of the disease are joint problems, which causes patients to suffer from severe pains and troubles in daily life.

Q: Please explain the details about treatments, including ERT?

A: Since the 1990s, there has been a major turning point in the medical community in the diagnosis and treatment of the Gaucher’s disease. Firstly, doctors analyzed mutation through DNA analysis and knew the levels of severity by mutation.

There are three types of the disease according to the types of mutations and symptoms. The first type has slow progress and mostly occurs in Western countries, such as North America and Europe. The second type, aside from the hypertrophy of liver and spleen, accompanies shows acute neuropathic disease. The symptoms of this type are more severe, and infants can die between several months after birth and the age of two. Therefore, it is called Infantile Gaucher Disease. The third type reveals neuropathic disease related to the central nervous system and the symptoms aren’t severe. But before the introduction of ERT, people died during childhood. In this way, the Gaucher’s disease has various symptoms and different level of severity.

The second change is the introduction of RET to treat Gaucher’s disease. Since its introduction, doctors have come to be able to treat it without performing risky operations, including spleen removal surgery and artificial joint surgery, to relieve the symptoms. Gaucher’s disease patients of the first type with severe symptoms can enjoy normal life if they can receive ERT before irrecoverable damages occur.

Q: Is there any possibility doctors misdiagnose the disease by confusing it with other illnesses?

A: It’s difficult to diagnosis because of various symptoms. Gaucher’s disease is the disease that has flaws in the enzyme, glucocerebrosidase, or doesn’t have it sufficiently. The enzyme hydrolyzes sugar in a body, and if the enzyme is insufficient, sugar is accumulated in small amounts in the membranes of blood cells.

The problem is the symptoms such as bleeding, fatigue and enlarged spleen are common to other diseases. Because most doctors don’t have experiences of treating patients with the disease, they have trouble making a right diagnosis to patients who show these symptoms.

Even doctors in Israel where the attack rate of the Gaucher’s disease is high need several years to diagnose it.

Q: What is important in diagnosing the disease?

A: Making correct diagnoses at an early stage is essential. Doctors always have to suspect the possible outbreak of the Gaucher’s disease and conduct tests for the suspects.

A typical test for Gaucher’s disease is Dried Blood Spot(DBS). DBS can test with a small amount of blood to make three principal diagnoses; an enzyme activity test to know the lack of the enzyme, mutation check through DNA analysis, and biochemical analysis to know the level of biomarker related to the existence of Gaucher’s cells. The biomarker test can increase the accuracy of these tests for the Gaucher’s disease. For example, patients who don’t show Gaucher’s disease symptoms, but low enzyme activity can use the test for the diagnosis. If the level of the biomarker is high, patients who have no symptoms are caught with the Gaucher’s disease. The biomarker test can be used to monitor the treatment effect.

Q: Is there any difference among races?

A: Ashkenazy Jews have a high attack rate of the Gaucher’s disease, but often have many mutations with mild symptoms. Because the progress is very low, they are diagnosed in one’s late 20s, or even after the 30s and 40s.

On the other hand, people in Asia, such as Korea and Japan, have many mutations with severe symptoms. Because they show symptoms related to the Gaucher’s disease from childhood and the progress is so fast, early diagnosis and conducting ERT at an early stage are important. People can have a burden because of costs for tests and treatment and intravenous injection treatment for about one hour on a regular basis.

Q: You mentioned the introduction of ERT as a turning point in the treatment.

A: In 1991, Genzyme젠자임 developed the first ERT (compound: alglucerase) using placentin, and in 1994, it developed the treatment with imiglucerase compound. Imiglucerase is a mutated enzyme compared with the existing enzyme glucocerebrosidase. Imiglucerase worked for many Gaucher’s disease patients, and this had been the only ERT treatment to cure Gaucher’s disease until 2010.

In 2010, ‘Vpriv’(compound: velaglucerase alfa) appeared, produced from human cells.

Q: What is the basis of Vpriv’s effect?

A: In 2009, the Early Access Program (EAP) of Vpriv went into operation when the supply of the treatments ran short because of the pollution of Imiglucerase by a virus in its production processes. At that time it was possible to manufacture only 20 percent of the treatments needed worldwide with the remaining amount of Imiglucerase, the U.S. Food and Drug Administration (FDA), and European Medicine Agency(EMA) approved velaglucerase alfa(Vpriv) in its development stage.

However, the FDA asked the company to prove the symptom of patients who had received treatments with Imiglucerase for a long time did not aggravate after shifting to new therapies. The standards to prove it was the hemoglobin level did not fall more than 1g/dL, and the decrease of platelet levels should be less than 20 percent while liver and spleen did not enlarge by 15 percent or more.

As the result of treating the Gaucher’s disease patients who shifted to Vpriv through EAP with the same amount as Imiglucerase, pharmaceutical companies proved the treatment effects of Vpriv were safe and even found “booster-effect” to improve some symptoms that weren’t cured by Imiglucerase. Up to 40 percent patients who changed the treatment from Imiglucerase to Vpriv showed booster-effect

Q: Has Vpriv exerted influence on improving patients’ quality of life?

A: It shortened the time for intravenous injection. The center conducted Investigator Initiated Research and examined the possibility of reducing intravenous injection time for ERT. It monitored patients’ conditions whether it was safe if we gradually reduced the injection time from one hour to 10 minutes.

We are waiting for the final analysis results about antibody and PK profile related to the research, but the result was satisfactory. Patients didn’t show severe side effects when the injection time of Vpriv was reduced to 10 minutes, and the treatment effect also remained stable. We will share the result with the FDA after the outcome is available and ask for clinical trials to change the approval conditions for the injection time.

Besides, as Vpriv was produced from human cells, it is less likely to form an antibody or show an anaphylaxis reaction than Imiglucerase and taliglucerase alfa.

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