Are Peripheral Blood Mononuclear Cells Derived from Patients with Certain Myopathies Suitable for Personalized Drug Screening?

Background: Limb girdle muscular dystrophies (LGMDs) and several other disorders which share their specific phenotype are rare, predominantly hereditary conditions with no curative treatment. Differential diagnosis of these myopathies is quite challenging and expensive in many cases. Therefore, a significant proportion of patients remains undiagnosed and untreated for a long time. At the same time there is a huge amount of drugs and supplements potentially able to modify the course of some of these muscular dystrophies. That is why a simple empirical approach able to define a patient’s reaction to a specific compound seems rational. Because most common basic pathogenetic mechanisms for these quite different disorders increase the vulnerability of muscle cells (or decrease ability for reparation) during mechanical stress, we propose a simple, noninvasive and inexpensive approach for individualized drug screening based on the drug’s influence on the mechanical vulnerability of peripheral blood mononuclear cells (PBMC).

Methods: PBMC derived from 8 patients with Duchenne muscular dystrophy (DMD), 2 patients with LGMD2A, 1 patient with LGMD2B, 1 with MERRF syndrome, 1 with facioscapulohumeral muscular dystrophy (FSHD) and 13 matched control subjects were irradiated by ultrasound in the presence of several compounds (lisinopril, vitamin D3, prednisolon, tocopherol, topiramate, glutargin, α-lipoic acid, essentialeÒ, and physiological solution). Then viability indexes of the samples were detected by citotoxic assays based on vital dye (neutral red and resazurin) metabolism.

Results: In cytotoxicity tests with active transport of neutral red into PBMC derived from DMD patients, the cells showed signs of destruction at 1.06±0.52 minutes of ultrasounding compared to 1.75±0.6 minutes in control. PBMCs from patients with other myopathies have either normal or decreased resistance to ultrasound. The addition of tocopherol significantly changes the PBMC time-destruction curves; however, these changes as well as changes caused by other compounds were inconclusive concerning their protective effects. In resazurin cytotoxicity tests, PBMC metabolic activity normalized to 0.9% NaCl in the presence of tested compounds differed significantly in experiments with and without ultrasounding. Also, profiles of the compounds’ protective effects were very dissimilar in patients with different myopathies.

Conclusion: We believe that peculiarities of PBCM behavior after US stress in the presence of different compounds are reliable patient-specific phenomena, which warrant further investigation and a proposed approach worth further improvement.