Clinical trial NCT04760171: Amyloid Proteins From Medullary Thyroid Cancer and Laryngeal Amyloidosis
Official title: An ex Vivo Study to Purify Amyloid Fibrils and Solve Their 3D Structures Using Amyloid Proteins From Medullary Thyroid Cancer and Laryngeal Amyloidosis
Study type: OBSERVATIONAL
Overall status: NOT_YET_RECRUITING
Conditions: Amyloid
Medullary Thyroid Cancer
Alzheimer Disease
Dementia
Lead sponsor: The Leeds Teaching Hospitals NHS Trust
Sponsor class: OTHER
Collaborators: name: University of Leeds
First posted: 2021-02-18
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients with MTC, who have been recommended via the Thyroid Multi-Disciplinary team meeting, to undergo hemi or total thyroidectomy surgery.

Patients with LA, who agree with their surgeon, to undergo surgical treatment of that condition

Brief summary: Using excess tumour samples that contain amyoid, from patients with Medullary Thyroid Cancer, we aim to determine the structures of ex vivo amyloid fibrils from human tumour tissue samples and compare them with that of existing stock of in vitro formed amyloid fibrils. This will permit the analysis of the effects of gene mutation and post-translational modification on the development of amyloid from a disease state.

Amyloid is known to accumulate in the brain tissue of patients with neuro-degenerative conditions such as Alzheimer's disease and Dementia. Therefore solving the structure of amyloid fibrils may aid the development of future treatments for these conditions.

Detailed description: This is an anonymous, voluntary inclusion, laboratory based, basic science research study. Appropriate patients who meet the inclusion criteria and complete the consent process will be asked to donate a small sample of excess tumour tissue after the completion of their surgical procedure. This tissue will be transferred to the research laboratory in Leeds University for analysis and subject to a variety of investigations and scientific procedures to achieve the study objectives.

These include:

1. - amyloid extraction by tissue homogenization and centrifugation as already documented in the literature.
2. - mass spectrometry analysis to identify and characterize the most prominent proteins present in the amyloid deposits and their possible post-translational modifications.
3. - Transmission Electron Microscopy to characterize at the gross features of the extracted amyloid fibrils at low resolution (\>20Å). This relatively simple procedure allows for quick characterization of the samples in order to optimize them for Atomic Force Microscopy (AFM) and Cryo-Electron Microscopy (Cryo-EM).
4. - Atomic Force microscopy to characterize helical parameters of the amyloid fibrils needed to calculate the structure from Cryo-EM data.
5. - Cryo-Electron Microscopy to elucidate the structure of the amyloids extracted from tissue affected in each disease

Eligibility criteria: Inclusion Criteria:

* Diagnosed with known or suspected MTC or LA
* Age \>= 18 years, no upper age limit
* Able to provide informed consent for both surgical treatment and inclusion into this study
* For MTC patients, treatment recommendation from the Thyroid MDT is for either hemithyroidectomy or total thyroidectomy
* for LA patients, agreement with their attending clinician to undergo surgical debulking of disease under general anaesthetic. The procedure is called 'microlaryngoscopy and biopsy/debulking'

Exclusion Criteria:

* No known or suspected diagnosis of MTC or LA
* Age \<18 years

  * Unable to provide informed consent
  * Treatment recommendation from Thyroid MDT is for any treatment excluding primary surgery (ie palliation, best supportive care, chemotherapy, radiotherapy etc)
  * For LA patients, no agreement between patient and attending clinician to proceed with surgery as primary treatment.

Primary outcomes:
measure: Amyloid extraction by tissue homogenization and centrifugation
timeFrame: 12-24 months
measure: Transmission electron microscopy
timeFrame: 12-24 months
measure: Atomic force microscopy
timeFrame: 12-24 months
measure: Cryo-electron microscopy (Cryo-EM)
timeFrame: 12-24 months
measure: Mass spectrometry
timeFrame: 12-24 months
Secondary outcomes:
Other outcomes:
Locations:
Study officials:
affiliation: Leeds Teaching Hospitals NHS Trust
name: James Moor, FRCS
role: PRINCIPAL_INVESTIGATOR
References:
citation: GBD 2016 Neurology Collaborators. Global, regional, and national burden of neurological disorders, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019 May;18(5):459-480. doi: 10.1016/S1474-4422(18)30499-X. Epub 2019 Mar 14.
citation: Knowles TP, Vendruscolo M, Dobson CM. The amyloid state and its association with protein misfolding diseases. Nat Rev Mol Cell Biol. 2014 Jun;15(6):384-96. doi: 10.1038/nrm3810.
citation: Gallardo R, Iadanza MG, Xu Y, Heath GR, Foster R, Radford SE, Ranson NA. Fibril structures of diabetes-related amylin variants reveal a basis for surface-templated assembly. Nat Struct Mol Biol. 2020 Nov;27(11):1048-1056. doi: 10.1038/s41594-020-0496-3. Epub 2020 Sep 14.
citation: Gallardo R, Ranson NA, Radford SE. Amyloid structures: much more than just a cross-beta fold. Curr Opin Struct Biol. 2020 Feb;60:7-16. doi: 10.1016/j.sbi.2019.09.001. Epub 2019 Nov 1.