Proteasomal Inhibition for Patients With Mis-sense Mutated Dysferlin

Dysferlinopathy Clinical Trial

— Dysferlin  

Official title:

Proteasomal Inhibition for Patients With Mis-sense Mutated Dysferlin

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01863004
• Other study ID #: DYSF001A1
• Secondary ID: 2011DR1148
• Status: Terminated
• Phase: Phase 1
• First received: April 29, 2013
• Last updated: September 20, 2017
• Start date: December 2012
• Est. completion date: September 15, 2017

Study information

• Verified date: September 2017
• Source: University Hospital, Basel, Switzerland
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Dysferlin is a protein with an important role in the repair of muscle surface membranes. Mutations in dysferlin cause different forms of muscular dystrophies. Dysferlinopathies are inherited in an autosomal recessive manner, and many patients with this disease harbor mis-sense mutations in at least one of their two pathogenic DYSF alleles. These patients have significantly reduced or absent dysferlin levels in skeletal muscle, suggesting that dysferlin encoded by mis-sense alleles is rapidly degraded by the cell's quality-control system. In a series of in-vitro experiments we showed that mis-sense mutated dysferlin can be salvaged from degradation by proteasomal inhibition. This resulted in an increase of functional dysferlin protein and a subsequent repair of plasma membranes of cultured patient-derived muscle cells. In this proof-of-concept study we would like to test wether proteasomal inhibition can salvage mis-sense mutated dysferlin in patients harboring certain dysferlin mis-sense mutations.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 3
• Est. completion date: September 15, 2017
• Est. primary completion date: September 15, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• must carry at least one allele of a salvageable mis-sense mutation of dysferlin

• Age = 18 years

• Written informed consent

Exclusion Criteria:

• Bleeding disorder

• Acute or chronic kidney failure (CCL <50 ml/min)

• Advanced liver disease or active hepatitis

• Congestive heart failure NYHA III and IV

• Pregnancy or nursing

• Immunosuppression (prednisolone doses below 20 mg/d are allowed)

• Therapy with strong inhibitors of cytochrome P450 3A4

• HCV or HIV infection

• Regular alcohol consumption (>14 drinks a week)

• Drug addiction

Related Conditions & MeSH terms

• Dysferlinopathy

Intervention

Drug:
• Bortezomib

Locations

Country	Name	City	State
Switzerland	Neuromuskuläres Zentrum, Universitätsspital Basel	Basel

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Basel, Switzerland

Country where clinical trial is conducted

Switzerland, 

References & Publications (3)

Azakir BA, Di Fulvio S, Kinter J, Sinnreich M. Proteasomal inhibition restores biological function of mis-sense mutated dysferlin in patient-derived muscle cells. J Biol Chem. 2012 Mar 23;287(13):10344-54. doi: 10.1074/jbc.M111.329078. Epub 2012 Feb 8. Re — View Citation

Azakir BA, Di Fulvio S, Salomon S, Brockhoff M, Therrien C, Sinnreich M. Modular dispensability of dysferlin C2 domains reveals rational design for mini-dysferlin molecules. J Biol Chem. 2012 Aug 10;287(33):27629-36. doi: 10.1074/jbc.M112.391722. Epub 201 — View Citation

Di Fulvio S, Azakir BA, Therrien C, Sinnreich M. Dysferlin interacts with histone deacetylase 6 and increases alpha-tubulin acetylation. PLoS One. 2011;6(12):e28563. doi: 10.1371/journal.pone.0028563. Epub 2011 Dec 8. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Dysferlin protein expression levels change from baseline over 5 days assessed by repeated biopsies and blood draws in skeletal muscle and in blood monocytes following administration of a single dose of Bortezomib.	Repeated needle muscle biopsies and blood draws will be performed after administration of a single dose of Bortezomib (Velcade) to assess dysferlin protein expression in skeletal muscle and in blood monocytes over a five day period.	repeated needle muscle biopsies over a five day period