At times in past decades, pharmaceutical companies considered CNS sequelae of disease to be difficult, potentially untractable, targets. Even in areas where both the burden of disease and socioeconomic costs have been high, say, in Alzheimer’s Disease, drug discovery and development pipelines are littered with failures. There are a variety of explanations for failure to demonstrate efficacy in CNS indications—including the slowly progressive nature of some diseases, lack of meaningful animal models, low drug bioavailability at target, difficulties of biomarker discovery and validation, and the clarity provided by available outcome measures.
The burden of CNS symptoms is considerable, as evidenced by patient and caregiver information such as that from Myotonic’s Voice of the Patient report. Publications and workshops have addressed the question, do we treat DM as a brain disease? The answer lies in the criticality of CNS symptoms for many living with DM1, yet is the CNS becoming tractable in these patients?
Generally, CNS targets now appear more tractable, with recent approvals of drugs/biologics for multiple sclerosis, cystic fibrosis, seizures, and spinal muscular atrophy, and the robustness of pharma/biotech pipelines suggests more approvals are on the horizon.
But Do We Have Sufficient Knowledge to Target the DM1 CNS?
There is increasing focus on the CNS in DM1 that is evident from PubMed searches or conference agendas, although many studies to date have not been sufficiently powered to gain broad insight into a heterogeneous disease. This is a gap that must be addressed to help justify the growing interest in drug development for DM1.
Dr. Peggy Nopoulos and colleagues at the University of Iowa are in the process of conducting longitudinal assessments of brain structure and function in DM. The broad goal of these studies is to investigate the use of MRI measures of white matter health as biomarkers of CNS disease in DM1.
As part of their overall biomarker effort, the Iowa group has now published data on muscle properties, spinal reflexes, and transcortical long-latency reflexes in a cohort of 24 subjects with clinically mild/moderate DM1 in comparison with 25 matched controls (Shields et al., 2019). These data support the potential to expand the repertoire of neurologic instruments, beyond currently available behavioral tools, to both track the progression of DM1 and to provide clinical trial assessment tools.
In this study, DM1 subjects showed decreased tibial nerve H-reflex depression compared to controls, although this alteration did not correlate with either MIRS score or CTG repeat length. Following supra-maximal tibial nerve stimulation, single twitch and doublet forces generated in the soleus were lower than control in DM1. In contrast to controls, repetitive stimulation did not result in force potentiation in affected subjects.
DM1 subjects tested in the single-limb squat visual-motor task showed higher overall absolute error in both perturbation and non-perturbation trials. Finally, the team established a relationship between transcortical long-latency reflexes magnitude (when normalized to nonperturbed trials) and the magnitude of H-reflex depression in DM1 subjects—those subjects with the least robust long-latency reflexes exhibited the greatest loss of spinal H-reflex depression.
Implications for Understanding CNS Involvement in DM1
Because of the multi-organ system involvement in DM1, it is important to understand the etiology of functional deficits. Here, the team has established the operation of homosynaptic depression of spinal reflexes and spinal trans-cortical reflexes. Many of these differences are viewed as neural circuitry and contractile apparatus adaptations that, in turn, may undermine lower extremity dysfunction in the DM1 patient.
Taken together, the team presents a cogent picture of how DM1-altered excitation-contraction coupling and diminished spinal reflex and transcortical reflex functioning collectively contribute to the motor phenotype of DM1. If validated in larger cohorts, the measures used here have the potential for following disease progression and evaluating therapeutic efficacy in interventional trials.
Myotonic dystrophy type 1 alters muscle twitch properties, spinal reflexes, and perturbation-induced trans-cortical reflexes.
Shields RK, Lee J, Buelow A, Petrie M, Dudley-Javoroski S, Cross S, Gutmann L, Nopoulos PC.
Muscle Nerve. 2019 Nov 26. doi: 10.1002/mus.26767. [Epub ahead of print]