Krabbe Disease

What Causes Krabbe Disease?

Krabbe disease is caused by an abnormal change (mutation) in a gene called the GALC gene. This gene contains instructions for making an enzyme crucial in the process of creating and maintaining myelin. The mutation causes the enzyme to be incorrectly produced or not produced at all. As a result, the myelin coating surrounding nerve cells in the brain and elsewhere in the nervous system breaks down, impairing the nerve cells’ ability to send and receive signals from one another.

Is Krabbe Disease Hereditary?

Krabbe disease is inherited when parents pass the GALC gene mutation to their children. The condition is inherited in an autosomal recessive pattern, meaning that the child must inherit two copies of the mutated gene, one from each parent, to develop the disorder.

People with only one copy of the mutation usually don’t have symptoms of the disease, but they are carriers who may pass the mutation to their children. When two carriers have children, they have a 25 percent chance of having an affected child with each pregnancy. They have a fifty percent chance of having a child who is a carrier. Twenty-five percent of the time, their child will inherit two normal copies of the GALC gene and be entirely unaffected by the disorder.

How Is Krabbe Disease Detected?

The early symptoms of Krabbe disease are similar to those of many other disorders, so diagnosis may be delayed. Genetic testing of newborns may detect the disease, and in some places, these screening tests are routinely performed on all newborn infants. Because some therapies have shown effectiveness at slowing the progression of the disease when administered before symptoms emerge, early detection of KD is essential.

How Is Krabbe Disease Diagnosed?

A doctor may suspect Krabbe disease if a baby (or older child) shows symptoms characteristic of KD or other neurological disorders. The diagnostic process will include an evaluation of the baby’s medical history, along with physical and neurological exams. Further diagnostic steps may include:

• Blood tests to measure GALC enzyme levels
• Imaging exams such as magnetic resonance imaging (MRI) or computerized tomography (CT) to look for evidence of demyelination in the brain
• Nerve conduction test to measure nerve cells’ function
• Genetic testing to look for the GALC gene mutation

PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.

How Is Krabbe Disease Treated?

Krabbe disease has no cure, and no treatment will reverse symptoms once they appear. Stem cell therapy, in which healthy stem cells are transplanted into the baby’s bloodstream, may be effective if administered before symptoms emerge. Stem cell therapy sometimes slows the progression of symptoms and increases life expectancy. However, studies have not shown the treatment to be effective if it begins after the appearance of symptoms.

Other treatment options focus on lessening the severity of symptoms, preventing complications, and improving quality of life. Common treatments include:

• Anti-seizure medications
• Medications to reduce muscle stiffness
• Feeding assistance
• Physical therapy
• Occupational therapy

How Does Krabbe Disease Progress?

Krabbe disease is progressive, and symptoms worsen over time. Late-onset forms may have a slower progression and less severe symptoms, but everyone with KD has a shorter than average life expectancy.

Later symptoms of the disorder may include:

• Seizures
• Loss of developmental skills already acquired
• Increased muscle stiffness
• Vision loss
• Hearing loss
• Loss of mobility
• Loss of ability to swallow
• Breathing difficulties

How Is Krabbe Disease Prevented?

People with a family history of Krabbe disease should consult a genetic counselor to assess their risks before becoming pregnant. Parents who have had a child with KD should also seek genetic counseling before having more children. Prospective parents attempting to have children using in vitro fertilization may request that fertilized eggs be tested for KD before implantation.

Krabbe Disease Caregiver Tips

• Learn about the disease. A diagnosis of Krabbe disease can be overwhelming emotionally. You’ll be better able to cope if you know what is ahead for you and your child.
• Stay up-to-date on research developments. Research is ongoing in the search for new therapies and treatments for Krabbe disease. Keep abreast of the latest studies so you can be an informed part of your child’s medical team.
• Remember that there is a community of people who know what you’re going through, and they can help. The United Leukodystrophy Foundation maintains a directory of resources for families living with Krabbe disease, including links to education, medical referrals, and financial assistance programs.

Krabbe Disease Brain Science

The GALC gene carries instructions for producing the enzyme galactocerebrosidase. The enzyme’s function is to break down compounds called galactolipids, normal byproducts of processes in each cell. The galactolipid called galactosylceramide is part of the cycle of normal myelin production.

The GALC gene mutation that causes Krabbe disease limits the production of functional galactocerebrosidase. As a result, galactolipids are not broken down as they usually are, and they accumulate in cells. The galactolipid psychosine is a normal byproduct of the myelin production process, but it is toxic to nerve cells when it accumulates in the cell. In addition, the accumulation of galactosylceramide causes the formation of globoid cells, which also contribute to the process of demyelination.

As the myelin around nerve cells in the brain and elsewhere in the nervous system is lost, the cells cannot transmit signals effectively. The dysfunction worsens as demyelination progresses, leading to the symptoms of KD.

Krabbe Disease Research

Title:  Gene Transfer Clinical Trial for Krabbe Disease (RESKUE)

Stage: Recruiting

Principal investigator: Jessie Barnum, MD

UPMC Children’s Hospital of Pittsburgh

Pittsburgh, PA

This is a nonblinded, non-randomized dose-escalation study of intravenous AAVrh10 after hematopoietic stem cell transplantation (HSCT) in which subjects will receive standard of care hematopoietic cell transplantation for Krabbe disease, followed by a single infusion of an adeno-associated virus gene therapy product. Extensive natural history subjects will be compared as a control group.

Title: Study of Safety, Tolerability and Efficacy of PBKR03 in Pediatric Subjects With Early Infantile Krabbe Disease (GALax-C)

Stage: Recruiting

Principal investigator: Paul S. Kruszka, MD

National Institutes of Health Clinical Center

Bethesda, MD

PBKR03 is a gene therapy for Krabbe Disease (Globoid cell leukodystrophy) intended to deliver a functional copy of the GALC gene to the brain and peripheral tissues. This study will evaluate the safety, tolerability, and efficacy of this treatment by first evaluating two different doses in two different age groups, then confirming the optimal dose to be used for confirmation of safety and efficacy.

PBKR03 is an adeno-associated viral vector serotype Hu68 carrying the gene encoding for human galactosylceramidase, GALC, formulated as a solution for injection into the cisterna magna.

This is a global interventional, multicenter, single-arm, dose-escalation study of PBKR03 delivered as a one-time dose administered into the cisterna magna of subjects with early infantile Krabbe Disease.

The dose-ranging portion of the study will enroll independent dose-escalation cohorts in two age groups of subjects with early infantile Krabbe disease:

• Cohort 1: 3 subjects aged ≥4 to <9 months will receive the low dose (Dose I)
• Cohort 2: 3 subjects aged ≥4 to <9 months will receive the high dose (Dose II)
• Cohort 3: 3 subjects aged ≥1 to <4 months will receive the low dose (Dose I)
• Cohort 4: 3 subjects aged ≥1 to <4 months will receive the high dose (Dose II)

Part 1 of the study will enroll a total of four cohorts, enrolled sequentially with separate age-based dose-escalation cohorts. Enrollment will initiate in Cohort 1. Following completion of Cohort 1, simultaneous enrollment in Cohort 2 and Cohort 3 will occur. Cohort 4 will follow the completion of cohort 3.

The confirmatory cohort, Part 2, will enroll subjects with early infantile Krabbe Disease, aged >1 to <9 months. These subjects will receive a dose chosen based on the data obtained in part 1 of the study. This will be a 2-year study with a 3-year safety extension.

Title: UCB Transplant of Inherited Metabolic Diseases With Administration of Intrathecal UCB Derived Oligodendrocyte-Like Cells (DUOC-01)

Stage: Recruiting

Principal investigator: Joanne Kurtzberg, MD

Duke University Medical Center

Durham, NC

The primary objective of the study is to determine the safety and feasibility of intrathecal administration of DUOC-01 as an adjunctive therapy in patients with inborn errors of metabolism who have evidence of early demyelinating disease in the central nervous system (CNS) who are undergoing standard treatment with unrelated umbilical cord blood transplantation (UCBT). The secondary objective of the study is to describe the efficacy of UCBT with intrathecal administration of DUOC-01 in these patients.

The inherited metabolic disorders (IMD) are a heterogeneous group of genetic diseases, most of which involve a single gene mutation resulting in an enzyme defect. In most cases, the enzyme defect leads to the accumulation of substrates that are toxic and/or interfere with normal cellular function. Often, patients may appear normal at birth but during infancy begin to exhibit disease manifestations, frequently including progressive neurological deterioration due to absent or abnormal brain myelination. The ultimate result is death in later infancy or childhood.

Currently, the only effective therapy to halt the neurologic progression of the disease is allogeneic hematopoietic stem cell transplantation (HSCT), which serves as a source of permanent cellular ERT.3 However, one barrier to the success of this therapy is delayed engraftment of donor cells in the CNS when administered through the intravenous route, which is associated with ongoing disease progression over 2-4 months before stabilization. The engraftment of donor cells in a patient with an IMD provides a constant source of enzyme replacement, thereby slowing or halting the progression of the disease.

This study will evaluate the safety of a potential new treatment for patients with certain IMDs known to benefit from HSCT using allogeneic UCB donor cells. The new intervention, intrathecal administration of UCB-derived oligodendrocyte-like cells (DUOC-01) will serve as an adjunctive therapy to a standard UCB transplant. The goal of this therapy is to accelerate delivery of donor cells to the CNS, thereby bridging the gap between systemic transplant and engraftment of cells in the CNS and preventing disease progression. The DUOC-01 cells and cells used for HSCT will be derived from the same UCB donor unit.