Clinical trial NCT01863004: Proteasomal Inhibition for Patients With Mis-sense Mutated Dysferlin
Official title: Proteasomal Inhibition for Patients With Mis-sense Mutated Dysferlin
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Dysferlinopathy
Lead sponsor: University Hospital, Basel, Switzerland
Sponsor class: OTHER
First posted: 2013-05-27
Enrollment: 3
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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

Primary outcomes:
measure: 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.
timeFrame: repeated needle muscle biopsies over a five day period
Secondary outcomes:
Other outcomes:
Locations:
city: Basel
country: Switzerland
facility: Neuromuskuläres Zentrum, Universitätsspital Basel
Study officials:
affiliation: Sponsor-Investigator, Neuromuscular Center, Neurology Clinic, University Hospital Basel, Switzerland
name: Michael Sinnreich, Prof. Dr. MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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):10344-10354. doi: 10.1074/jbc.M111.329078. Epub 2012 Feb 8.
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.
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 2012 Jun 26.