NEW YORK ─ San Francisco-based Amprion is launching a diagnostic test that detects misfolded synuclein in cerebrospinal fluid as an aid to clinicians trying to diagnose Parkinson's disease and Lewy body dementia in patients presenting with confusing symptoms.
Following College of American Pathologist (CAP) accreditation last year, the firm has launched its misfolded alpha-synuclein test, called SynTap, from its CLIA-registered lab in San Diego.
Amprion obtained US Food and Drug Administration breakthrough device designation in 2019 for use of its protein misfolding cyclic amplification (PMCA) technology and an assay to aid in the diagnosis of Parkinson's.
The firm has "subsequently shown that the same technology can detect misfolded synuclein in patients with Lewy body dementia, multiple system atrophy, and the Lewy Body variant of Alzheimer's disease," Russ Lebovitz, Amprion's cofounder and CEO, said in an interview.
People suspected of having different neurodegenerative conditions often present with similar symptoms, making a diagnosis especially challenging. The SynTap test adds clinical utility by providing an objective criteria for a clinician's evaluation, Lebovitz said. In some cases, its assay detected misfolded synuclein aggregates in CSF more than 10 years before the aggregates were detected during an autopsy, he said.
In a 2020 paper published in Nature, Amprion cofounder Claudio Soto along with researchers at the University of Texas Medical School in Houston and other organizations reported using Amprion's technology to discriminate between patients diagnosed with Parkinson’s disease and patients with multiple system atrophy. The assay demonstrated an overall sensitivity of 95.4 percent, the researchers wrote.
Last November, Soto and his colleagues used Amprion's assays to test 140 CSF samples in three independent laboratories. The results, published in Acta Neuropathologica Communications, were similar across laboratories, reflecting a sensitivity ranging from 86 percent to 96 percent and specificity from 93 percent to 100 percent.
The firm recently announced the results of a joint study with the Oregon Health & Science University in which its SynTap test detected the presence of Lewy bodies in CSF samples of 43 patients diagnosed with Alzheimer's disease. The study, whose results were confirmed at autopsy, included samples from 12 patients with neurodegenerative diseases unrelated to misfolded synuclein, and four healthy control subjects.
Amprion's PMCA technology, the centerpiece of all the studies, relies on the conversion of normal proteins into misfolded proteins, including alpha-synuclein. It takes a small number of misfolded aggregates to induce progressive misfolding of the normal proteins, and Amprion uses this by adding normal proteins to patient samples in its test.
That triggers the amplification and progressive misfolding of the normal proteins, producing protein aggregates in the sample that are broken into pieces and amplified again by adding normal proteins.
"After several hundred such cycles, we've amplified the initial small number of misfolded protein aggregates around a billionfold, making them detectable by numerous, standard testing technologies," Lebovitz said, adding that Amprion uses a fluorescence assay to detect specific dyes that bind to the misfolded protein aggregates.
Until now, clinicians have had to rely mainly on symptoms and clinical exams to decide whether their patients had Parkinson's or Lewy body dementia, and they only knew the results for sure when they were confirmed during an autopsy, said Kathleen Poston, chief of the movement disorders division in the department of neurology and neurological sciences at Stanford University.
Particularly in the early stages of the disease, many patients present with symptoms that can "easily be mistaken for a number of neurodegenerative diseases," said Poston who is not affiliated with Amprion but uses results of its test in the clinic and for neuroscience research at Stanford.
Though CSF is used for the diagnosis of diseases such as multiple sclerosis and Alzheimer's disease, "we’ve never had a CSF test to detect Parkinson's disease or Lewy body dementia," Poston said, adding, "The ability to do a lumbar puncture and directly detect abnormal alpha synuclein is the closest we can get to a biological diagnosis."
That has an impact on how patients are treated, she noted. Though there are no medicines that can cure or slow the progression of Lewy body dementia or Parkinson's, medications are frequently prescribed to treat disease symptoms.
For example, patients with mild cognitive impairment that are found to have Lewy bodies should show improvement by taking dopamine replacement medication, she said, adding that on the other hand, Alzheimer's disease patients who do not have Lewy bodies as a coexisting pathology should not be treated with a dopamine replacement.
Apart from Amprion's assay, there are few IVD tests to detect Parkinson's and Lewy body dementia. However, CND Life Sciences is offering a test that detects folded phosphorylated alpha-synucleins in dermal layers of the skin, and Norwegian startup Pre Diagnostics is developing an assay which uses alpha-synuclein peptides to differentiate patients with Parkinson's disease from those with Alzheimer's.
Lebovitz noted that there is an increasing focus in the neurodegenerative disease space on the development of immunoassays for the detection of Alzheimer's using amyloid beta or tau markers.
Amprion is also developing assays to detect amyloid beta, tau, and other misfolded proteins linked to neurodegenerative diseases, he said.
The firm was founded in 2007 to commercialize technology that detects prion proteins that can transmit their misfolded shapes to normal variants of the same protein, triggering Creutzfeldt–Jakob Disease (CJD). The company licenses its CJD testing technology to select university and government laboratories but does not conduct the test in its own clinical or research laboratories.
Through the years, Lebovitz said, the firm has obtained funding from the Michael J. Fox Foundation for Parkinson’s Research, the National Institutes of Health, and the McGovern Medical School at the University of Texas Health Science Center at Houston.
By now, Amprion has conducted up to 10,000 SynTap tests that have been used for research, including for the development of treatments for neurodegenerative diseases. It is collaborating with "almost all the major" companies developing medicines for synucleinopathies, Lebovitz said.
If new treatments are approved, the firm will seek regulatory approval for its test as a companion diagnostic to identify suitable patients for the new medications. By the first quarter of 2023, Amprion expects to file an application for 510(k) clearance for its SynTap test.
Regulatory approval would help generate greater test awareness and support Amprion's efforts to obtain reimbursement from private payors and Medicare, Lebovitz said, noting that Medicare covers a high percentage of patients taking its test. As it awaits coverage, the firm plans to charge about $1,500 per test, he said.
In the near-term, many of Amprion's initiatives to obtain adoption are centered around improving the awareness of the test's clinical utility among key opinion leaders working in the neurodegenerative disease space, Lebovitz said. The firm is planning an official launch of SynTap in parallel with the annual American Academy of Neurology 2022 annual meeting in April.