SCIENCE AND RESEARCH: IT’S IN OUR DNA
CND Life Sciences is built on a decade of scientific discovery with a goal of improving health outcomes by developing novel, easily accessible testing for neurodegenerative diseases. CND’s technology uses small skin biopsies and a combination of advanced laboratory techniques and neuroimaging to detect abnormal proteins within cutaneous nerve fibers.
The Science of Synucleinopathies
Neurodegenerative diseases are a group of progressive conditions that damage the nervous system and are one of the leading sources of disability. Most neurodegenerative disorders are linked to some form of protein misfolding, resulting in accumulation of the protein, neuronal dysfunction, and eventually cell death.
Common protein misfolding disorders include:
- Parkinson’s disease, with the misfolded alpha-synuclein (A)
- Alzheimer’s disease, with the misfolded tau protein (B)
There are 5 distinct disorders characterized by the deposition of phosphorylated alpha-synuclein:
- Parkinson’s disease (PD)
- Dementia with Lewy bodies (DLB)
- Multiple system atrophy (MSA)
- Pure autonomic failure (PAF)
- REM sleep behavior disorder (RBD)
All synucleinopathies are characterized by the deposition of the pathological protein— phosphorylated α-synuclein—in the central and/or peripheral nervous systems, resulting in progressive neurological degeneration. The specific location where the phosphorylated alpha-synuclein is deposited determines the clinical presentation of the disorder. The prevalence of these disorders is increasing as our population ages.
Figure 1: In 1A, the presence of phosphorylated alpha-synuclein is seen within a neuron in a patient with Parkinson’s disease. The dark brown inclusions marked with blue arrows are Lewy bodies that are made up of phosphorylated alpha-synuclein. In Figure 1B, the presence of hyperphosphorylated tau protein is seen as a neurofibrillary tangles (red arrow), neuritic plaques (yellow arrow), and neuropil threads (orange arrow) in a patient with Alzheimer’s disease.
- There are over 2 million people in the United States who have been diagnosed with a synucleinopathy, with 100,000 new diagnoses each year
- The synucleinopathies belong to a group of diseases that are labelled as neurodegenerative. This term implies that they are associated with progressive disability and increasing symptoms over time
- The progressive disability and high mortality associated with synucleinopathies make these diseases difficult for patients and their loved ones
- In addition, the annual healthcare costs in the US attributable to synucleinopathies alone are estimated in the tens of billions of dollars
Current and Future Innovation: The CNDx™ Testing Platform
CND Life Sciences utilizes multiplex immunofluorescent imaging to detect the presence of misfolded disease-related proteins within nerve fibers in the skin. Our CNDx” testing platform highlights the presence of a specific type of misfolded protein, and therefore identifies the disease of interest in an individual. These proteins are difficult to detect, and our technology highlights the protein in such a way that abnormal proteins within a single nerve fiber out of thousands can be visualized.
Mastering what’s beneath the skin
The founders of CND have spent the past decade developing a unique and highly specialized process that enables visualization of phosphorylated α-synuclein on the same easily obtained skin biopsy samples that neurologists are already accustomed to performing. We call this test the Syn-One Test™ and this includes immunofluorescent analysis of protein gene product 9.5 (PGP 9.5) and phosphorylated alpha-synuclein. Phosphorylated α-synuclein has only been detected in individuals with a diagnosis of synucleinopathy and is not present in hundreds of healthy and non-synucleinopathy disease control patients. Our study results, and the data of many other groups, has demonstrated a very high specificity and sensitivity for diagnosing the synucleinopathies. However, these robust scientific advances were not commercially available to patients or physicians until now. CND brings this ground-breaking technology into the hands of every neurologist and physician in the US that treats patients with synucleinopathies.
Our understanding of neurodegenerative disorders has been greatly enhanced through our ability to detect the presence of phosphorylated alpha-synuclein within nerve fibers in the skin. Our flagship technology quantitates the presence of this pathological alpha-synuclein from simple punch skin biopsies to aid clinicians in making a diagnosis of synucleinopathy. This technology makes us the first, and only, company to make an in-vivo diagnosis of synucleinopathy. The CNDx platform can be applied to many other neurodegenerative conditions by investigating a host of pathological proteins. These novel protein detection programs are part of our active pipeline of novel testing platforms.
CND Research Programs
Beyond the flagship Syn-One Test, CND Life Sciences continues to expand its diagnostic testing capabilities in new directions through research programs and collaborations with biopharma and other organizations. From enhancing current Syn-One capabilities, to exploring new protein detection to examining novel image analysis technology, CND is committed to advancing innovation.
Here’s a highlight of one current research program:
Over the past decade, it has become clear that one of the common findings in ALS (also known as Lou Gehrig’s disease) is the misfolding of certain neural proteins, specifically TDP-43. This protein has been identified in the cortex and motor neurons of patients with both sporadic ALS and has also been linked to patients with fronto-temporal type dementia.
Based on our experience with cutaneous intra-axonal protein detection, CND has launched an investigator-initiated trial with support from Mitsubishi Tanabe Pharma to study the role of TDP-43 deposition within cutaneous nerve fibers of individuals with ALS. To date, ALS has no specific early test for diagnosis, only a combination of clinical examination findings and nerve/muscle studies that support a diagnosis after the disease has been present for an extended time. There is a critical need to develop an early diagnosis, an even more importantly, there is a need to track disease progression over time. The development of novel therapeutic agents by pharmaceutical companies will require biomarkers of efficacy to succeed, and changes in intra-axonal protein deposition would serve in that capacity.
Taken together, these data suggest that identification and quantification of TDP-43 within the dermal nerves can serve as a diagnostic biomarker for the disease, a prognostic biomarker, and a therapeutic biomarker of disease severity and target engagement. We are excited about the successful initiation of this key milestone project.
Scientific Publications of Interest
1. Kim JY, Illigens BM, McCormick MP, Wang N, Gibbons CH. Alpha-Synuclein in Skin Nerve Fibers as a Biomarker for Alpha-Synucleinopathies. J Clin Neurol. 2019;15(2):135-42. Epub 2019/04/03. doi: 10.3988/jcn.2019.15.2.135. PubMed PMID: 30938106; PubMed Central PMCID: PMCPMC6444158.
2. Donadio V, Doppler K, Incensi A, Kuzkina A, Janzen A, Mayer G, et al. Abnormal alpha-synuclein deposits in skin nerves: intra- and inter-laboratory reproducibility. European journal of neurology : the official journal of the European Federation of Neurological Societies. 2019. Epub 2019/02/17. doi: 10.1111/ene.13939. PubMed PMID: 30770596.
3. Donadio V. Skin nerve alpha-synuclein deposits in Parkinson’s disease and other synucleinopathies: a review. Clinical autonomic research : official journal of the Clinical Autonomic Research Society. 2018. Epub 2018/12/07. doi: 10.1007/s10286-018-0581-4. PubMed PMID: 30506233.
4. Donadio V, Incensi A, El-Agnaf O, Rizzo G, Vaikath N, Del Sorbo F, et al. Skin alpha-synuclein deposits differ in clinical variants of synucleinopathy: an in vivo study. Sci Rep. 2018;8(1):14246. Epub 2018/09/27. doi: 10.1038/s41598-018-32588-8. PubMed PMID: 30250046; PubMed Central PMCID: PMCPMC6155202.
5. Gibbons CH, Wang N, Freeman R. Cutaneous Alpha-Synuclein From Paraffin Embedded Autopsy Specimens in Parkinson’s Disease. Journal of Parkinson’s disease. 2017;7(3):503-9. doi: 10.3233/JPD-171088. PubMed PMID: 28582870.
6. Donadio V, Incensi A, Rizzo G, Capellari S, Pantieri R, Stanzani Maserati M, et al. A new potential biomarker for dementia with Lewy bodies: Skin nerve alpha-synuclein deposits. Neurology. 2017;89(4):318-26. Epub 2017/07/02. doi: 10.1212/WNL.0000000000004146. PubMed PMID: 28667178.
7. Antelmi E, Donadio V, Incensi A, Plazzi G, Liguori R. Skin nerve phosphorylated alpha-synuclein deposits in idiopathic REM sleep behavior disorder. Neurology. 2017;88(22):2128-31. Epub 2017/05/05. doi: 10.1212/WNL.0000000000003989. PubMed PMID: 28468843.
8. Gibbons CH, Garcia J, Wang N, Shih LC, Freeman R. The diagnostic discrimination of cutaneous alpha-synuclein deposition in Parkinson disease. Neurology. 2016;87(5):505-12. Epub 2016/07/08. doi: 10.1212/WNL.0000000000002919. PubMed PMID: 27385742; PubMed Central PMCID: PMC4970658.
9. Donadio V, Incensi A, Piccinini C, Cortelli P, Giannoccaro MP, Baruzzi A, et al. Skin nerve misfolded alpha-synuclein in pure autonomic failure and Parkinson disease. Annals of neurology. 2016;79(2):306-16. Epub 2015/11/26. doi: 10.1002/ana.24567. PubMed PMID: 26606657.
10. Wang N, Gibbons CH, Lafo J, Freeman R. alpha-Synuclein in cutaneous autonomic nerves. Neurology. 2013;81(18):1604-10. Epub 2013/10/04. doi: 10.1212/WNL.0b013e3182a9f449. PubMed PMID: 24089386; PubMed Central PMCID: PMC3806913.
Parkinson’s disease was described over 200 years ago in 1817 by James Parkinson and is the most well-known of the synucleinopathies. Parkinson’s disease is characterized by the accumulation of phosphorylated alpha-synuclein within the neurons in the region of the brain known as the substantia nigra, resulting in some of the characteristic features of slowness, tremor and masked facies. It was almost 150 years later that levodopa was introduced as a treatment for some of these clinical manifestations of Parkinson’s disease. However, we now know that phosphorylated alpha-synuclein accumulates throughout the rest of the nervous system to a varying degree, causing many of the other ‘non-motor’ manifestations. The alpha-synuclein is seen throughout the brain, spinal cord and the peripheral nervous system.
Figure 2: The Braak hypothesis of phosphorylated alpha-synuclein spread throughout the nervous system. In the earlies stages (1&2), the phosphorylated alpha-synuclein is predominantly within the lower brainstem. These stages are characterized by anosmia (loss of smell), and autonomic disturbances such as constipation. In stages 3&4, synuclein spreads to throughout the brainstem and into the cortical regions. These stages are characterized by sleep disorders and the onset of motor dysfunction. In stage 5&6 there is widespread phosphorylated alpha-synuclein deposition throughout the cortex causing cognitive changes and emotional disturbances.
Although Parkinson’s disease is the most well-known of the synucleinopathies, dementia with Lewy bodies is more prevalent, causing a cognitive impairment that is often confused with Alzheimer’s disease. However, we now know that these conditions are very different, and require caution in use of medications for treatment.
Multiple system atrophy is the most rapidly progressive of the synucleinopathies, resulting in progressive autonomic failure, parkinsonism or ataxia. Multiple system atrophy can present with a host of different clinical features creating challenges to diagnosis. In contrast, pure autonomic failure is the synucleinopathy with the slowest progression. Pure autonomic failure typically presents with drops in blood pressure while standing (orthostatic hypotension), constipation and loss of bladder control. Although pure autonomic failure is considered the most benign of the synucleinopathies, it often does convert over time into one of the more aggressive synucleinopathies.