Amyloid Proteins From Medullary Thyroid Cancer and Laryngeal Amyloidosis

Alzheimer Disease Clinical Trial

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04760171
• Other study ID #: EN21/138414
• Status: Not yet recruiting
• Start date: February 2021
• Est. completion date: February 2026

Study information

• Verified date: February 2021
• Source: The Leeds Teaching Hospitals NHS Trust
• Contact: Anne Gowing
• Phone: +441132060469
• Email: anne.gowing[@]nhs.net
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 10
• Est. completion date: February 2026
• Est. primary completion date: February 2023
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Alzheimer Disease
• Amyloid
• Amyloidosis
• Carcinoma, Neuroendocrine
• Dementia
• Medullary Thyroid Cancer
• Thyroid Diseases
• Thyroid Neoplasms

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
The Leeds Teaching Hospitals NHS Trust	University of Leeds

References & Publications (4)

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. Erratum in: Nat Struct Mol Biol. 2020 Oct 9;:. — View Citation

Gallardo R, Ranson NA, Radford SE. Amyloid structures: much more than just a cross-ß fold. Curr Opin Struct Biol. 2020 Feb;60:7-16. doi: 10.1016/j.sbi.2019.09.001. Epub 2019 Nov 1. Review. — View 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. — View 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. Review. Erratum in: Nat Rev Mol Cell Biol. 2014 Jul;15(7):496. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Amyloid extraction by tissue homogenization and centrifugation	A standard laboratory technique for subsequent analysis	12-24 months
Primary	Transmission electron microscopy	To characterize 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).	12-24 months
Primary	Atomic force microscopy	To characterize helical parameters of the amyloid fibrils needed to calculate the structure from Cryo-EM data.	12-24 months
Primary	Cryo-electron microscopy (Cryo-EM)	To elucidate the structure of the amyloids extracted from tissue affected in each disease	12-24 months
Primary	Mass spectrometry	Analysis to identify and characterize the most prominent proteins present in the amyloid deposits and their possible post-translational modifications.	12-24 months

External Links

•   British Thyroid Association guidlines for management of thyroid cancer