Bethlem Myopathy, Ullrich Congenital Muscular Dystrophy
Conditions
Keywords
Bethlem myopathy, Ullrich congenital muscular dystrophy, Low protein diet, Autophagy, Pilot clinical trial
Brief summary
* This is a 2 stage exploratory study with a 3-month observational phase on the natural course, followed by a 12-month, open-label, non-comparative, single-arm, phase II pilot study on the efficacy, safety and tolerability of a low-protein diet (LPD) in 8 adult patients with Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD). * Objective of this trial is to test the effect of a normocaloric LPD to reactivate autophagy in BM/UCMD patients. The primary end point of the study will be the change in muscle biopsy of Beclin 1, a marker of autophagy, at 1 year of LPD treatment when compared to baseline. * The rationale rests on our discoveries that (i) mitochondrial dysfunction mediated by inappropriate opening of the PTP plays a key role in collagen VI myopathies; (ii) defective autophagy with impaired removal of defective mitochondria amplifies the defect; and (iii) reactivation of autophagy with a low-protein diet or treatment with cyclosporine A, the mitochondrial PTP inhibitor, cured Co6a1-/- mice, hinting at a common target among all beneficial treatments - namely autophagy. * Specific aims of this project are to (i) study the modifications of clinical, nutritional and laboratory parameters in a cohort of patients with BM/UCMD during a 3-month observational period before starting the LPD treatment; (ii) assess the effect of a normocaloric LPD in correcting defective autophagy in muscle of patients; (iii) test if new non-invasive biomarkers of activation of autophagy examined in the blood are mirroring the effect of LPD in the muscle biopsy; (iv) assess the clinical efficacy and safety of the LPD with an innovative combination of complementary measures of the nutritional status in patients. * The anticipated output is defining and validating a therapeutic nutritional approach in autophagy upregulation for BM/UCMD.
Interventions
OTHERLow protein diet
Patients will receive a diet with 0.6-0.8 grams of protein/kilogram body weight/day for one year. Bread, biscuits and pasta will be in part substituted with aproteic food.
Sponsors
Istituto Ortopedico Rizzoli
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Males or females aged ≥18 years. * Women of childbearing age must have a negative pregnancy test and must use adequate contraception during the study. * Clinical and molecular diagnosis of Bethlem myopathy or Ullrich congenital muscular dystrophy. * No previous treatment with CsA within 6 months prior to the start of the study. * Willing and able to adhere to the study visit schedule and other protocol requirements. * Written informed consent signed.
Exclusion criteria
* Current or history of liver or renal disease. * Pregnant or breast-feeding women. * Any serious internal medicine condition interfering with the study.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Reactivation of autophagy measured as a change in Beclin 1 as a marker of autophagy in muscle biopsy from baseline (Day 1) to Day 365 | one year |
Secondary
| Measure | Time frame |
|---|---|
| Assess the safety of a LPD in patients with BM/UCMD . Nutritional parameters . Muscle mass . Muscle strength | one year |
Countries
Italy
Outcome results
None listed