What is Gaucher, anyway?
Gaucher disease is a rare, lysosomal disorder caused by a variation (or change) in the GBA gene. It is an autosomal recessive condition, meaning an individual with Gaucher disease has received a copy of the genetic variation from both parents.1
Because of this genetic variation, the body doesn’t make enough of an enzyme called glucocerebrosidase (GCase). As a result, the body cannot break down a lipid called glucocerebroside. This results in a build-up of fatty substances within lysosomes in certain parts of the body, resulting in the symptoms of Gaucher disease.2
What do lysosomes do?
Lysosomes are compartments within cells that help recycle materials.3,4 They break down cellular waste products such as fats, carbohydrates, and proteins into simple compounds, which are then used as new cell-building materials.5
There are three types of Gaucher disease, with type 1 being the most common.6 Symptoms of Gaucher disease type 1 include fatigue,7 easy bruising and bleeding (caused by low platelet and haemoglobin counts), bone pain and an enlarged liver and spleen. People with Gaucher disease may also have an increased risk of developing Parkinson’s disease.6
Did you know?
Bones are made up of calcium, phosphorus, sodium, and other minerals, as well as the protein collagen.8
You can feel it in your bones: Bone complications and Gaucher disease
It is estimated that 62% of people with Gaucher disease have bone issues.9 Some of the most common bone-related symptoms include joint pain, arthritis, joint damage, spontaneous fractures, and bone pain and bone crises.9 Many people with Gaucher disease will require surgeries, including joint replacements, during their lifetime.10
Bones are living tissues and are continuously remodelled. Specialised cells, called osteoblasts and osteoclasts, help maintain our bones. Osteoblasts help the body build up bones, while osteoclasts work to break down and remove old bone tissue.9
Did you know?
There are 206 bones in the human body. That’s a lot of work for those osteoblasts and osteoclasts!8
Though not completely understood, researchers and doctors believe that Gaucher disease makes it hard for osteoblasts to create new bone tissue and makes osteoclasts overactive. In other words, the body destroys bone cells faster than it can make new ones. This can cause bones to lose density, a condition called osteopenia. Bones can also lose their strength, a condition called osteoporosis, which can lead to fractures.9 These conditions can occur very early in life in people with Gaucher disease.11
A more severe bone issue in Gaucher disease is caused by reduced blood flow to the bones, robbing them of oxygen, which can cause part of the bone to die. This is called avascular necrosis, or bone death.6
Patients typically describe bone pain as chronic, daily pain that occurs with activity and goes away quickly and bone crises as less frequent but more debilitating occurrences. It can take weeks or even months for a bone crisis to go away.12 Bone crises can be so severe that they prevent people from everyday activities like going to work, spending time with family, or even walking.
No bones about it: Bone complications still occur in Gaucher disease despite available treatments
Enzyme replacement therapy (ERT) is widely used to treat people with Gaucher disease type 1. It works by replacing the non-functioning GCase enzyme, which allows the body to break down glucocerebroside. This reduces the build-up of fatty substances in various organs.2
ERT dramatically improves some of the symptoms of Gaucher disease, but bone disease remains an often-overlooked complication in some people,6 and ERT does not eliminate fracture risk.13 Additionally, ERT treatment requires infusions every other week for the duration of someone’s life. Each infusion takes one to two hours, which means time away from work and family.2,14,15 During an advisory board hosted by AVROBIO that convened nine individuals with Gaucher disease type 1, participants indicated that ERT every other week makes planning for future events, including travel, vacation, and social events difficult.12
Another treatment option for Gaucher disease is substrate reduction therapy (SRT). SRT is administered as a pill that must be taken once or twice every day.2 Like ERT, SRT helps reduce symptoms of Gaucher disease, and while it helps with bone complications more that ERT, it is not suitable for all patients with Gaucher disease type 1 and does not fully address all bone issues.16
Bone up on your options: Potential new treatments for Gaucher
There is a need for new treatments that better address all symptoms of Gaucher disease, including: addressing bone complications, reducing pain and fatigue, and slowing or halting disease progression. New treatments must also take into consideration the impact on daily life and quality of life, offering solutions that give patients back time that’s currently lost to pain, fatigue, and sick days.
Did you know?
The human skeleton completely regenerates every 10 years.17
Researchers continue to study potential new treatments, including gene therapy, for Gaucher disease in hopes of making progress toward these goals. Gene therapy is a technique that uses genetic material for the long-term treatment or potential cure of genetic disorders.
For a gene therapy to work, a new therapeutic gene must be introduced into cells so that the usual cellular mechanisms can produce proteins such as enzymes.18,19 This is done using a vector, which is a delivery system used to introduce genetic material into the nucleus of a cell.20,21
There are currently two types of vectors being studied in Gaucher disease: lentiviral (LV) vectors and adeno-associated viral (AAV) vectors.22 LV vectors are delivered to a person’s stem cells outside the body in a process known as ex vivo gene therapy. This involves collecting stem cells from the person, using the LV vector to introduce the therapeutic gene into the stem cells, and then delivering the cells back to the person through intravenous infusion.18,19 AAV vectors are delivered directly to the person’s body by intravenous or direct injection to the organs or tissue being targeted in a process called in vivo gene therapy.18,19
AAV and LV gene therapies are investigational and are currently being studied in clinical trials. As studies evaluating these investigational approaches progress, more information about their safety and efficacy, as well as potential risks and benefits, will become available. To date, no gene therapy for Gaucher disease has been approved by the FDA or any other regulatory agency, and their safety and efficacy have not been determined.
To continue learning about Gaucher disease and patient support you can read the following articles in this Digital Spotlight here:
1. Futerman AH, Platt FM. The metabolism of glucocerebrosides — from 1965 to the present Mol Genet Metab. 2017;120:22-26.
2. Van Rossum A, Holsopple M. Enzyme replacement or substrate reduction? A review of
Gaucher disease treatment options. Hosp Pharm. 2016;51:553-563.
3. MedicineNet. MedTerms medical dictionary A-Z list. www.medicinenet.com/medterms-medical-dictionary/article.htm. Accessed October 7, 2020.
4. U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute. NCI Dictionary of Cancer Terms. https://www.cancer.gov/publications/dictionaries/cancer-terms/. Accessed March 25, 2020.
5. Florida State University Molecular Cell Expressions. Lysosomes. https://micro.magnet.fsu.edu/cells/lysosomes/lysosomes.html#:~:text=In%20this%20regard%2C%20the%20lysosomes,as%20new%20cell%2Dbuilding%20materials. Accessed April 14, 2021.
6. Pastores GM, Hughes, D. Gaucher Disease. GeneReviews (online). https://www.ncbi.nlm.nih.gov/books/NBK1269/. Accessed April 15, 2021.7. Kaplan P, et al. The Clinical and Demographic Characteristics of Nonneuronopathic Gaucher Disease in 887 Children at Diagnosis. Arch Pediatr Adolesc Med. 2006;160:603-608.
8. Beth Israel Lahey Health. Fun facts about bones and joints. https://www.bidmc.org/about-bidmc/wellness-insights/bones-and-joints/2018/08/fun-facts-about-bones-and-joints. Accessed March 31, 2021.
9. National Gaucher Foundation. Bone disease: an often-overlooked complication of Gaucher disease. https://www.gaucherdisease.org/blog/bone-disease-an-often-overlooked-complication-of-gaucher-disease. Accessed: March 31, 2021.
10. Cohen D, Kogan D, Rubin A, et al. Longevity of total hip arthroplasty implants in patients with Gaucher disease. Hip Int. 2020;30(2):147-151.
11. Ozlem Goker-Alpan. Therapeutic approaches to bone pathology in Gaucher disease: Past, present and future. Mol Genet Metab. 2011;104,(4):438-447.
12. Copeland FD, Correia LA, White ML. Uncovering the burden of gaucher disease type 1: patient perspectives on unaddressed symptoms, impact of disease, and the future of treatment. Poster presented at: 17th Annual WORLDSymosium 2021; February 8-12, 2021.
13. Deegan P, Khan A, Camelo JS Jr, et al. The International Collaborative Gaucher Group GRAF (Gaucher Risk Assessment for Fracture) score: a composite risk score for assessing adult fracture risk in imiglucerase-treated Gaucher disease type 1 patients. Orphanet J Rare Dis. 2021;16(1):92.
14. Wraith, JE. Limitations of enzyme replacement therapy: current and future. J Inherit Metab Dis. 2006;29: 442-447.
15. Smid BE, et al. Biochemical response to substrate reduction therapy versus enzyme replacement therapy in Gaucher disease type 1 patients. Orphanet J Rare Dis. 2016;11:28.
16. Limgala RP, Goker-Alpan O. Effect of substrate reduction therapy in comparison to enzyme replacement therapy on immune aspects and bone involvement in gaucher disease. Biomolecules. 2020;10:1-12.
17. Ortho Info. Bone health basics. https://orthoinfo.aaos.org/en/staying-healthy/bone-health-basics/#:~:text=The%20body's%20skeleton%20forms%20and,with%20new%2C%20fresh%20bone%20tissue. Accessed April 5, 2021.
18. NIH, US National Library of Medicine. Medline Plus. How Does Gene Therapy Work? https://medlineplus.gov/genetics/understanding/therapy/procedures/. Accessed October 28, 2020.
19. FDA. What is gene therapy? How does it work? https://www.fda.gov/consumers/consumer-updates/what-gene-therapy-how-does-it-work. Accessed March 31, 2021.
20. RegMedNet, Regenerative Medicine: The Journal. The Glossary for Cell & Gene Therapy and Regenerative Medicine 2018. https://www.regmednet.com/the-glossary-for-cell-gene-therapy-and-regenerative-medicine-2018/. Accessed March 25, 2020.
21. European Society of Gene & Cell Therapy. What is gene and cell therapy? Available at: www.esgct.eu/PublicPatients/Gene-and-cell-therapy-glossary.aspx. Accessed October 7, 2020.
22. National Gaucher Foundation. Gene therapy for Gaucher disease: AAV, lentivirus, & more.
Accessed March 31, 2021.
Rare Revolution Editor