Gaucher disease occurs when people have mutations, or changes, in a gene called GBA. The GBA gene acts like a switch that controls the way your body breaks down a specific lipid (fat), glucocerebroside. The “switch” is faulty in people with Gaucher disease. That prevents cells from making functional glucocerebrosidase (GCase), the enzyme that breaks down glucocerebroside. As a result, glucocerebroside accumulates and causes damage.

For years, medical researchers have looked for ways to repair that GBA switch to relieve or cure Gaucher disease. But where does this work stand today?

On Feb. 25, the National Gaucher Foundation, in collaboration with the Gaucher Community Alliance, hosted an informative webinar about gene therapy. The webinar was sponsored by the Dawe Family Foundation in tribute to Susie Dawe Gervich.

Four clinical speakers addressed different perspectives on gene therapy, from exciting new opportunities to the ethics of gene revision. These speakers were:

• Chris Mason, MD, PhD, FRCS, FMedSci, Chief Scientific Officer, AVROBIO; Professor of Cell & Gene Therapy at University College London
• Asa Abeliovich, MD, PhD, CEO & Founder, Prevail Therapeutics
• Insoo Hyun, PhD, Senior Lecturer on Global Health and Social Medicine at Harvard Medical School Center for Bioethics; Professor of Bioethics and Philosophy at Case Western Reserve University School of Medicine; Fulbright Scholar and Hastings Center Fellow
• Neal Weinreb, MD, FACP, Voluntary Associate Professor of Human Genetics and Medicine (Hematology) at the University of Miami Miller School of Medicine

What Is Gene Therapy?

In a nutshell, gene therapy modifies mutated genes to “correct their behavior.” Successful gene therapy might provide a one-time, long-term treatment or potential cure of a genetic disorder. For Gaucher disease, the treatment would provide some cells with a healthy copy of the GBA gene.

Researchers are working on two techniques:

• Gene editing: A process that’s still in the early stages, gene editing works by removing specific sequences of DNA and replacing them with a corrected version. “Think of it as ‘cut and paste’ in Microsoft Word,” explained Dr. Mason.
• Gene augmentation: Also called gene addition, this process adds a functional copy of the gene. With the new gene, the cell can function as a healthy cell. The revised cell can produce the GCase enzyme your body needs to break down glucocerebroside. Researchers have used this process successfully for 30 years, Dr. Mason said. It’s the basis for several U.S. Food and Drug Administration (FDA)-approved .

How does gene therapy work?

Transferring the gene into the body requires a vehicle to deliver the gene cargo into the cell. The most common vehicle is a deactivated virus that has been changed so that, once it’s inside the cell, it cannot reproduce itself or cause illness. This carrier is called a vector.

Gene modifications can happen in two ways:

In vivo: Doctors use an injection or IV drip to put the vector in your blood or cerebrospinal fluid, where it can interact with the cells that need repair. The vector carries the therapeutic genetic material.

Ex vivo: Scientists collect hematopoietic stem cells (cells that can mature into all types of blood cells) from your blood or sometimes bone marrow. In the lab, the vector that carries copies of the normal gene is mixed with the cells, which then incorporate the healthy gene. The corrected stem cells are allowed to multiply. Doctors watch to be sure enough corrected blood stem cells develop to successfully establish a new home in your bone marrow. Then the corrected stem cells are infused back into your body.

• Before the infusion, you need to have a drug treatment that gets rid of unhealthy bone marrow cells. Eliminating those cells makes space in the bone marrow for the healthy stem cells that will take their place. These new cells then can start making new, healthy blood cells.
• Over time, the stem cells can develop into any kind of blood cell. Some can become different types of white blood cells, which leave the bloodstream and reach every organ in your body. They can deliver the working GCase enzyme to other tissue cells. In particular, the healthy stem cells that become macrophages (a type of immune cell) now can do their job and not turn into Gaucher cells.

Dr. Mason pointed out that since the beginning of 2019, ex-vivo therapy has been used to treat 350 patients who have several types of hereditary diseases. However, clinical trials of this method are only just beginning for patients with Gaucher disease.

AAV gene therapy and lentiviral gene therapy

Dr. Mason and AVROBIO use a type of ex-vivo gene therapy called lentiviral therapy. Lentiviral refers to the specific type of virus that this therapy uses as a vector to transfer the healthy gene.

Several lentiviral gene therapy techniques have received regulatory approval to treat different conditions. Approved treatments address transfusion-dependent β-thalassemia (TDT) in Europe and acute lymphoblastic leukemia (ALL) in the U.S., Europe, and Japan.

Prevail Therapeutics, founded by Dr. Abeliovich, uses in-vivo gene therapy with a different vector, adeno-associated virus (AAV). Prevail’s methods use a one-time injection of an AAV “army” with healthy GBA gene cargo that invades targeted body cells. The cells then start making the functioning GCase enzyme.

Dr. Abeliovich noted that other companies have developed similar approved AAV-based therapies. These treatments offer promise for spinal muscular atrophy and an inherited retinal disease. Another therapy is in development for Duchenne muscular dystrophy.

Gene Therapy Clinical Trials Process

Before a therapy receives FDA approval for widespread use, it must be tested through clinical trials. Dr. Hyun explained that the clinical trial process consists of four phases:

• Phase 1 assesses safety and dosage for human use. For many therapies, said Dr. Hyun, researchers would first try a drug with healthy volunteers. But a treatment for Gaucher disease wouldn’t be suited to people without the condition, so early studies will require Gaucher disease patients. In Phase 1 trials, every subject usually gets the treatment (there is no control or placebo).
• Phase 2 tests the therapy on more patients. At this phase, researchers may compare the treatment to another therapy. Safety and efficacy are now the main considerations.
• Phase 3 requires a larger number of subjects and could happen at multiple study locations. For rare diseases, these study centers may be at different U.S. sites or even international. A disease like GD—and the way patients respond to treatment—varies. Researchers need to test sufficient numbers of patients to understand the spectrum of response. Broad study can also detect rare and unexpected unwanted side effects. For Gaucher disease treatment studies, it may be a challenge to enroll the required number of patients, especially if several trials start at the same time. A special safety monitoring committee of experts oversees virtually all clinical trials. These experts are not participating investigators in the clinical trial. They can suggest modifying or even stopping a trial if they see a problem. After Phase 3, a therapy may receive FDA approval, or the FDA may require further study or issue an outright denial. Most of the time, FDA personnel work with the drug sponsor on trial design to make the approval process more efficient.
• Phase 4 is the post-launch market phase when a therapy is commercially available for use. Researchers and regulators continue to monitor its safety and effectiveness. Disease registries such as the ICCG Registry and Gaucher Outcome Survey (GOS) have proven to be exceptionally valuable for Phase 4 follow-up. So far, no FDA-licensed treatment for GD has been withdrawn from the market permanently due to safety concerns.

Dr. Hyun pointed out that efficacy is not the major focus in the preclinical phase—safety is. Obviously, a candidate drug must have known positive effects before a company will even consider the very expensive human trial process.

All clinical trials are, by definition, experimental. Patients may or may not see any improvement in their condition. And every trial does have certain risks, which patients should fully understand before agreeing to participate by signing the informed consent document. In any clinical study, a patient can withdraw consent at any time for any reason.

Gene Therapy Trials for Gaucher Disease Now Underway

Two of the webinar speakers described new clinical trials that are beginning to test gene therapy as a treatment for Gaucher disease.

AVROBIO Phase 1/2 trial for Type 1 Gaucher disease

Dr. Mason’s team at AVROBIO is currently enrolling patients in a Phase 1/2 trial called GuardOne for patients with Type I Gaucher disease. In this trial, the therapy is designed to genetically modify blood and bone marrow stem cells using lentiviruses. When these stem cells mature to produce macrophages, they express GCase, the enzyme that is deficient in Gaucher disease.

One patient has enrolled already, and the group is actively recruiting volunteers. As study sites come on board, NGF will help spread the word. The study will consist of:

• 8-16 patients between the ages of 18 and 35 with Gaucher type 1 in the U.S., Canada or Australia
• Patients who are either:
  • Receiving enzyme replacement therapy (ERT) and are currently stable
  • Have had no treatment with ERT or substrate reduction therapy (SRT) for the past 12 months
• 12 months of initial follow-up, followed by long-term follow-up for 14 years

Prevail Phase 1/2 trials for Gaucher disease patients and carriers

Prevail’s work focuses on the potential link between Parkinson’s disease and Gaucher disease. As people living with Type 1 Gaucher disease get older, Dr. Abeliovich noted, their risk of developing Parkinson’s disease increases. Similarly, parents, grandparents, and other close relatives of people with Gaucher disease who are themselves carriers of the GBA mutation have an elevated Parkinson’s risk.

Prevail’s efforts focus on three trials for different groups:

• PROPEL trial: People who have Parkinson’s disease with a GBA1 mutation (currently recruiting 16 patients)
• PROVIDE trial: Infants with Type 2 Gaucher disease (launching in 2020)
• PROGRESS trial: Children living with neuronopathic Type 3 Gaucher disease (launching in 2020)

Is Gene Therapy a “Super ERT”?

Dr. Weinreb, a Gaucher disease specialist and a member of the NGF Medical Advisory Board, closed out the webinar with a review of the common Gaucher disease symptoms.

He noted that current therapies can relieve or treat many of these symptoms. Effective treatments include ERT and SRT, although the long-term outcomes aren’t certain. “The main goal of therapy is to feel better,” Dr. Weinreb pointed out.

Dr. Weinreb asked the important question, “Is gene therapy really a ‘super ERT’?” He pointed out that gene therapy may provide some of the same benefits of ERT, but on a continuous basis. That continuity may resolve some of the issues with today’s ERT—for instance, that ERT doesn’t always stop osteopenia (bone loss) and osteoporosis.

“It certainly deserves serious consideration in that light,” Dr. Weinreb said. But he also noted that as gene therapy becomes better understood, researchers will study how fragments from repaired genes might affect the rest of the body.

Who Is a Candidate for Clinical Trials?

Dr. Weinreb suggested that older patients may not be the best candidates for clinical trials because existing therapy often treats their symptoms adequately. Similarly, very young patients aren’t ideal candidates because we don’t yet know the long-term outcomes. Most candidates will be midlife.

In addition, gene therapy is not a cure for the disease itself, meaning that people living with Gaucher disease could still pass on the GBA mutation to their children. “Treating the eggs and sperm is still considered to be unethical,” Dr. Weinreb said. “People who receive gene therapy need to know they still may have children who have Gaucher disease or who are carriers.”

Watch the Webinar

If you’re interested in learning more about the current state of gene therapy and Gaucher disease, you can view the webinar video recording: https://www.gaucherdisease.org/gene-therapy-webinar/