Assessment of Motor Unit Potentials Duration as the Biomarker of DT-DEC01 Cell Therapy Efficacy in Duchenne Muscular Dystrophy Patients up to 12 Months After Systemic–Intraosseous Administration

Abstract

Duchenne muscular dystrophy (DMD) is a lethal X-linked disease caused by mutations in the dystrophin gene, leading to muscle degeneration and wasting. Electromyography (EMG) is an objective electrophysiological biomarker of muscle fiber function in muscular dystrophies. A novel, DT-DEC01 therapy, consisting of Dystrophin Expressing Chimeric (DEC) cells created by fusing allogeneic myoblasts from normal donors with autologous myoblasts from DMD-affected patients, was assessed for safety and preliminary efficacy in boys of age 6–15 years old (n = 3). Assessments included EMG testing of selected muscles of upper (deltoideus, biceps brachii) and lower (rectus femoris and gastrocnemius) extremities at the screening visit and at 3, 6, and 12 months following systemic–intraosseous administration of a single low dose of DT-DEC01 therapy (Bioethics Committee approval no. 46/2019). No immunosuppression was administered. Safety of DT-DEC01 was confirmed by the lack of therapy-related Adverse Events or Serious Adverse Events up to 22 months following DT-DEC01 administration. EMG of selected muscles of both, ambulatory and non-ambulatory patients confirmed preliminary efficacy of DT-DEC01 therapy by an increase in motor unit potentials (MUP) duration, amplitudes, and polyphasic MUPs at 12 months. This study confirmed EMG as a reliable and objective biomarker of functional assessment in DMD patients after intraosseous administration of the novel DT-DEC01 therapy.

Chimeric Cell Therapies as a Novel Approach for Duchenne Muscular Dystrophy (DMD) and Muscle Regeneration

“…The most essential quality of DEC therapy is that DEC cell creation does not require cellular reprogramming, genome-editing, or viral vector-induced engineering, and has proven to be safe. Consequently, these encouraging results of the preclinical phase of DEC therapy development support the first in-human study [98][99][100].…”

“…The primary goal of the first in-human study, initiated in 2021, was to assess the safety and efficacy of a single dose of DT-DEC01 therapy, administered to 6-15 years old boys with genetically confirmed DMD. The study was designed as a single-site, open-label pilot study for the enrollment of ten DMD patients, regardless of the gene mutation and the ambulatory status [98][99][100]. Study participants received a single dose of (2 × 10 6 /kg body weight) DT-DEC01 cells via direct intraosseous administration to the bone marrow cavity of the iliac crests.…”

“…Study participants received a single dose of (2 × 10 6 /kg body weight) DT-DEC01 cells via direct intraosseous administration to the bone marrow cavity of the iliac crests. Following administration, the participants were subjected to a 6-month active follow-up period, and 18 months of passive follow-up [98][99][100]. With this consideration, as the next step in the development of DEC cell technology for DMD and muscle regeneration, the systemic-intraosseous administration of human DEC cells derived from normal and DMD-affected donors following delivery to the mdx/scid mouse model of DMD was tested [92,93,96,97].…”

“…Study participants received a single dose of (2 × 10 6 /kg body weight) DT-DEC01 cells via direct intraosseous administration to the bone marrow cavity of the iliac crests. Following administration, the participants were subjected to a 6-month active follow-up period, and 18 months of passive follow-up [98][99][100].…”

Amelioration of Morphological Pathology in Cardiac, Respiratory, and Skeletal Muscles Following Intraosseous Administration of Human Dystrophin Expressing Chimeric (DEC) Cells in Duchenne Muscular Dystrophy Model

“…We have confirmed the efficacy and protective multi-organ effect of systemic-intraosseous DEC therapy by performing histological, morphological, and immunofluorescent evaluations in the muscles essential for DMD patients’ survival. Furthermore, we assessed the long-term safety and biodistribution of DEC therapy by confirming local and systemic safety at 180 days after intraosseous administration, which led to the first in-human study [ 51 ].…”