NWPF

On the Horizon

Medication piepline
j0400870Medications showing great promise or soon to be available.

Droxidopa- FDA (Feb 2104) has recently approved this medicine as a treatment for orhtostatic hypotension. This problem assoiated with llow blood pressure when standing, can be a disabling problem causing dizziness, lightheadedness, fainting and walking problems.

Pimavanserin- Novel medication for treatment of PD psychosis. Primavanserin works by blocking serotonin receptors in the brain cortex (5HT-2a), associated with language, sensory perceptions  and thought interpretation. This placebo controlled phase 3 trial tested 199 people with PD and psychosis and showed improvement in psychosis. Further study is needed before this drug is released for market by the FDA. Why is this study important:

  • Focus on troubling non-motor symptoms
  • Hallucinations are a leading cause of caregiver burden, reduced QOL and nursing home placement
  • Drug does not act by blocking dopamine receptor
  • No  worsening motor symptoms such as tremor as can be seen with existing antipsychotics, clozapine and quetiapine.
  • Added benefits- Improved sleep, daytime wakefulness and caregiver burden

IPX 066, New carbidopa/levodopa extended release (IPX066). A novel bead pill formulation allowing intestinal absorption at different rates. In a study of 393 people with PD experience off time. Overall study participants took less doses daily (3.6 v. 5 doses) due to extended on time between pills. This new form of carbidopa/levodopa will soon be available and can help by:

  • Increase medication 'on effect'
  • Reduce medicine 'wearing off effect'
  • Effect of increased levodopa exposure on dyskinesia is not yet certain.
Biomarkers

datscanA biomarker is a ‘substance, process or characteristic of the body that correlates with a person’s risk of developing a disease, the diagnosis of the disease or changes along with the disease. For example, a measure of blood pressure is a simple maker of heart and blood vessel function. 

Why are biomarkers important?

A biomarker allows researchers to accurately diagnose disease. It also serves as a way to measure true changes in disease over time or in response to treatment. With biomarkers, researchers will have tools to measure whether a therapy is neuroprotective or modifies the course of Parkinson’s over time helping to bring neuroprotective therapies to market.

What are some of the potential biomarkers in Parkinson’s?

Pre-motor Symptoms  Non-movement problems can predate motor symptoms and collectively may identify people at risk for displaying future Parkinson’s motor symptoms. Pre-motor symptoms include:

  • Loss of Smell
  • Depression
  • Constipation
  • REM Behavior Disorder

Imaging

  • DAT Scan In 2011 the FDA has approved the use of a nuclear medicine brain imaging technique called SPECT imaging. The DAT Scan that can indirectly measure the levels of dopamine nerve cells in the brain. It is important to note that this test can be used to differentiate essential tremor from Parkinson’s tremor but cannot accurately state whether someone has Parkinson’s disease or other type of atypical parkinsonism.
  •  Transcranial ultrasound  Parkinson’s is associated with an increase in substantia nigral (area of the brain with dopamine nerve cell loss) echogenicity or ultrasound signal. This finding is also seen in elderly people. It is not yet known whether this will become a clinically useful tool for diagnosis or early detection, however, the relatively low risk and cost of this procedure adds to its promise.
  • Cardiac metaiodabenzylguanidine (MIBG)  Clinicians have long known that Parkinson’s affects our autonomic nervous system. A research test nuclear medicine test shows reduced heart uptake of this compound (similar to the autonomic nervous system neurotransmitter, norepinephrine) in the heart. Unfortunately these findings are not specific to Parkinson’s since many other disease can also show this finding.

Genetics  

Multiple candidate genes thought to play a role in Parkinson’s. 23 and Me, a genetic and ancestry analysis company, launched a major research initiative with the Parkinson’s Institute to measure gene abnormalities associated with Parkinson’s.  

  • Log on to 23 and Me for more information on this project.
Other Tissue Biomarkers

The following lab tests measuring changes in certain blood and/or cerebrospinal fluid compounds show promise but are not yet proven for clinical use

    • Blood platelet mitochondrial function
    • Phosphorylated Alpha synuclein- found to be higher in blood samples of a small group with Parkinson’s
Gene Therapy

Gene therapy involves inserting a specific gene into a cell so the recipientcell can use that gene to produce the gene product, something otherwise missing in this cell.

dna1This therapy is especially important to conditions like Parkinson’s disease since dopamine nerve cell lost is a known problem in this condition. Gene therapy can alter the course of Parkinson’s diseases if the gene can be turned on or ‘expressed’ in brain cells to produce more dopamine or promote healthier cells less likely to die.

How is gene therapy performed? Once a potentially helpful gene is identified, scientists need to find ways to incorporate that gene into a nerve cell. One technique is to use viruses that do not cause human disease but do get into or ‘infect’ cells. Once such virus is the adenovirus. The desired gene is incorporated into the DNA of the adenovirus. This virus is surgically placed into the target area of the brain where it gains entry to the nerve cell is loans its DNA to that cell.

Are gene therapies available for Parkinson’s disease? Gene therapy is in the research phase although results are promising. The following studies showed initial promise with improvement in Parkinson’s movement symptoms in open label studies tested on a small number of patients. Two promising gene therapy studies are highlighted below:

  • Nerve Growth Factor
    • Cere-120. This gene produces neurturin a growth factor similar to GDNF designed to promote cell sprouting and cell health. The hope is that this action will reduce the number of dopamine nerve cells that degenerate or die over time. A phase 2 research trial with a sham surgery arm (patients that received the Ceregene 120 product were compared to patients that underwent surgery without the treatment to control for the placebo effect) did not show a statistically significant difference in movement symptoms after one year. However, a closer look at the results did show some benefit if the patient had milder disease and when patients were followed over 2 years rather than one year.
    • Another study is underway using different doses and brain placement, and a longer follow-up period.
  • Genes that Change Enzymes
    • Glutamic acid decarboxylase (GAD). This enzyme increases the breakdown of glutamate to a chemical called GABA. Glutamate is present in excess in the subthalamic nucleus (STN). Reducing this neurotransmitter appears to cause similar effects as STN DBS surgery. A sham controlled study in moderately advanced PD showed some improvement in motor control in the gene therapy group compared with placebo. Effects were not as large as current treatment with DBS and effect was measured after 6 months so longer term results will be needed.
  • Unanswered Questions
    • More work will need to be done before gene therapy is proven safe and effective. To date, positive results have not been associated with dramatic motor improvement and the effects over a longer period of time will be needed.
    • Additional concerns are whether this therapy can lead to unanticipated gene mutations and immune responses that would not be reversible. 
Stem Cell

stemcellsStem cells are immature cells in the body that have the potential to turn into many different cell types. Cells like this are important to the growth and development of a fetus. They also help the body repair and rejuvenate cells that are damaged. Stem cells come from different sources. 

  • Embryonic and Fetal. Cells from embryos just a few days old and fetal tissue are the most immature stem cells and are pluripotent or have the ability to grow into any cell type in our body. Ethical and political tensions have limited the use and research with these types of cells, causing researchers to look for other sources.
  • Adult stem cells are an alternative to embryonic cells. These cells are found in very small quantity in certain tissues. In 2007 scientists made a major breakthrough when they found ways to induce or reprogram these cells to turn into other cells. These cells are multipotent as they can only turn into certain types of cells and are more limited in their ability to proliferate.
  • Umbilical cord stem cells are derived from the umbilical cord of a newborn baby. No blood or tissue is taken from the baby so it has no impact on the pregnancy, delivery or safety of the infant. Some people are donating cord blood from related children at birth for private storage or public storage bank donation. It must be stressed that this is not a current treatment for Parkinson’s disease. See the National Marrow Donor Program for more information

What problems stand in the way?

  • Ethical arguments continue to cloud stem cell research despite the tremendous promise and potential effect on human suffering. 
  • Stem cells especially more immature pluripotent cells divide easily and scientist need to understand how to turn this growth off. This is like designing a care with a gas pedal and no break. Uncontrolled growth could cause unwanted tumor growth. 
  • Stem cells could potentially be rejected by the body’s immune system so immune suppressant treatment may be needed to protect some cell lines in the body.
  • More mature adult stem cells can contain genetic abnormalities that occur naturally with aging and exposure to toxins or even sunlight.

These studies are investigating how to make stem cells in the laboratory and include stem cell sources taken during brain surgery. One important part of research is the search for non-embryonic sources of cells.   Researchers have turned to bone marrow, fibroblasts, and testes, as a source of cells to produce stem cells.

Some positive results from animal studies

  • Parkinsonian monkeys injected with human neural stem cells showed improved movement and no toxic effects. A small number of stem cells turned into dopamine producing nerve cells.   Researchers were from UCO, Yale and Harvard 2007
  • Mice treated with stem cells form their clones of their own skin showed improved movement. Research was performed at Sloan-Kettering

 Research in people with Parkinson’s

International research studies that include PWP are using stem cell sources from bone marrow, fat cells, fibroblasts (type of skin cell) are underway.

  • Researchers from Los Angeles are planning a phase 2 trial investigating safety and effect of neural derived cells taken from the patient, turned into mature cells and surgically introduced into the brain. Both measures of movement symptoms and PET imaging of dopamine nerve cells will be used to test the effect. This study is currently on hold. Results from an initial phase 1 study of neural stem cells showed significant improvement in movement symptoms. 

Some positive results from animal studies

  • Parkinsonian monkeys injected with human neural stem cells showed improved movement and no toxic effects. A small number of stem cells turned into dopamine producing nerve cells.   Researchers were from UCO, Yale and Harvard 2007
  • Mice treated with stem cells form their clones of their own skin showed improved movement. Research was performed at Sloan-Kettering

Questions remain

  • Researchers from South Korea and UC San Diego showed that abnormal protein accumulations seen in Parkinson’s nerve cells can be passed from one cell to the other. An autopsy done on a person that had fetal cell transplant many years ago showed these proteins moved from the person’s cells to the transplanted fetal cells. How this would affect stem cells is not known. It does give significant clues as to how cells are changed in Parkinson’s.

A word of caution

  • These are early phase 1 and 2 trials and to show safety and effect and not yet ready for widespread study. 
  • Many claims exist from stem cell clinic claiming to cure Parkinson’s or reverse symptoms. These claims have not been proven, safety has been shown, and they are extremely expensive. Remember anecdotal reports and stories of improvement do not mean the treatment work, remember the placebo effect?

More information on the placebo effect, clinical research trials and new research updates are available in the Ask the Expert Blog section of this site. 

Find out more about clinical trials and research for PD on the followig websites

Monique L. Giroux, MDMonique L. Giroux, MD
Medical Director, Northwest Parkinson's Foundation