Creutzfeldt-Jakob disease (CJD) is an uncommon and progressive neurodegenerative disorder that damages the brain. It is caused by abnormally folded proteins called prions, which accumulate in the brain and lead to the destruction of nerve cells. This process causes a rapid decline in mental and physical function. CJD is a fatal condition, and there is currently no treatment that can cure the disease or slow its progression.
Most cases of CJD occur spontaneously, while a smaller number are inherited or acquired through exposure to infected tissue. The disease progresses quickly, with most individuals passing away within a year of symptom onset. While a definitive diagnosis is only confirmed by a brain autopsy, tests like MRI scans and cerebrospinal fluid analysis can help make a probable diagnosis. The focus of care is providing comfort and managing symptoms.
The Challenge of Treating Prion Diseases
The difficulty in treating CJD lies in the nature of prions. Unlike bacteria or viruses, prions are not foreign invaders but are misfolded versions of a protein naturally present in the human body. These abnormal prions act as a template, causing healthy proteins to change shape and become infectious in a chain reaction. This makes it challenging to develop a drug that can target the harmful prions without affecting the normal proteins.
An effective treatment must be able to distinguish between the healthy protein and its misfolded, disease-causing counterpart. The body’s immune system does not recognize these prions as a threat, which allows the disease to advance without a natural defense. This lack of an immune response means that therapies cannot rely on stimulating the body’s defenses to fight the disease.
A physical obstacle to treatment is the blood-brain barrier. This is a protective, semi-permeable membrane that lines the blood vessels in the brain and regulates the passage of substances from the blood into the neural tissue. While this barrier is effective at keeping out toxins and pathogens, it also prevents most potential drug molecules from reaching the brain. Overcoming this barrier to deliver therapeutic agents to the central nervous system is a hurdle in developing treatments for CJD.
Current Symptomatic and Supportive Care
With no cure available, the current approach to managing CJD is centered on palliative care, which aims to relieve symptoms and improve the patient’s quality of life. This involves a strategy to address the physical and psychological issues that arise as the disease progresses. Care is highly individualized, focusing on the specific symptoms a person is experiencing.
A prominent physical symptom is myoclonus, characterized by sudden, involuntary muscle jerks and spasms. To manage these movements, physicians may prescribe medications such as clonazepam and sodium valproate. These drugs can help reduce the severity and frequency of the jerks, but their effectiveness can be limited and they may cause side effects like drowsiness.
The psychological and behavioral symptoms of CJD can be equally challenging. These can include severe anxiety, agitation, depression, hallucinations, and psychosis. Antidepressants, like selective serotonin reuptake inhibitors (SSRIs), may be used to address depression. For agitation and psychosis, antipsychotic medications like quetiapine are sometimes prescribed. Benzodiazepines can also be used to help calm anxiety and manage aggression.
As CJD advances, it affects mobility, coordination, and the ability to perform daily activities. A multidisciplinary care team becomes necessary to provide support. Physical therapists can assist with exercises to maintain mobility and prevent joint stiffness. Speech-language pathologists address difficulties with speech and swallowing (dysphagia), which can lead to choking and pneumonia.
Nutritional support is another facet of care, as swallowing problems and cognitive decline can make it difficult for patients to eat and drink adequately. A dietitian can recommend modified food textures and high-calorie supplements to prevent malnutrition and dehydration. In the later stages, when oral intake is no longer safe or possible, a feeding tube may be considered to provide nutrition and fluids.
Investigational and Experimental Therapies
Research into treatments that target the underlying cause of CJD is ongoing, with several strategies being explored in laboratory and clinical settings. These therapies are investigational and are not yet available as a standard of care. A goal of this research is to reduce the amount of the normal prion protein (PrP) in the brain, limiting the fuel the disease uses to propagate.
One developed approach involves antisense oligonucleotides (ASOs). ASOs are synthetic chains of nucleic acids designed to be the reverse complement of a specific segment of messenger RNA (mRNA). An ASO is designed to bind to the mRNA that carries the instructions for making the normal PrP protein. This binding signals the cell to break down the mRNA, which reduces the production of the PrP protein and has been shown to extend survival in animal models.
Another avenue of investigation is antibody-based therapy. This strategy uses laboratory-produced antibodies designed to recognize and bind to the normal PrP protein. The goal is to stabilize the protein and prevent it from being converted into the misfolded, infectious form. A humanized monoclonal antibody known as PRN100 was administered to a small number of CJD patients in a preliminary treatment program, showing it was well-tolerated and could reach the brain.
Other existing drugs have been studied for their potential to treat CJD, though with limited success. The antimalarial drug quinacrine and the antibiotic doxycycline were identified in cell culture experiments as having anti-prion properties and were tested in human clinical trials. These trials did not demonstrate a significant benefit in slowing disease progression or improving survival compared to a placebo, shifting the research focus toward developing new molecules.
Clinical Trials and Future Research Directions
For patients and families seeking access to emerging treatments, clinical trials are the pathway. A clinical trial is a research study involving human participants that is designed to evaluate the safety and effectiveness of a new medical intervention. Participating in a trial can provide access to investigational therapies while contributing to the scientific understanding of the disease. Information on clinical trials for CJD can be found through online databases like ClinicalTrials.gov, and patient advocacy groups like the CJD Foundation are also resources.
Future research in CJD treatment is focused on two main goals. The first is the development of methods for earlier diagnosis. By the time clear symptoms of CJD appear, significant and irreversible brain damage has already occurred, which limits the potential effectiveness of any treatment. Scientists are working to identify biomarkers that could signal the presence of the disease before the onset of clinical signs. Advanced imaging techniques are also being refined to detect the earliest brain changes.
The second research direction is the development of preventative treatments for individuals at a high genetic risk of developing prion disease. This includes people who carry a mutation in the prion protein gene. Therapies like the ASOs that lower prion protein levels could potentially be used prophylactically in these individuals, delaying or even preventing the onset of the illness. This preventative approach represents a goal for the field.