The article reported here discusses gene therapy for ALS by intervention in the peripheral nervous system. Although this has already been done with good results, including in the central nervous system, this type of intervention has been very rarely experienced.
In sporadic as in familial ALS, the loss of motor neurons leads to muscle atrophy, accompanied by fasciculations and spasticity.
The mechanisms underlying the development of ALS in motor neurons are probably multifactorial and neighboring cells, such as microglia, astrocytes and interneurons, can contribute to the disease.
There is a controversy about the onset of ALS which going on since decades. Most scientists believe that it begins in the brain, precisely in the primary motor cortex, in the body of the higher motor neurons. This assumption is called "dying forward". However, other scientists believe that ALS begins at the other end of the motor pathway, possibly in the neuromuscular junction, or even in the muscles. This assumption is called "dying backward".
Although these two hypotheses seem contradictory, each has strong experimental support and neither has been conclusively refuted. Perhaps these two hypotheses represent different subtypes of ALS. The article discussed here supposes that the hypothesis of "dying back" is true so the authors present an intervention in the PNS.
The authors use a classical mouse model of ALS: SOD1G93A. This model animal exhibits the most common clinical and pathological features of ALS as well as rapid and severe progression of the disease.
As has been recently reported on Padirac Innovation, gene therapy has become very important in the context of ALS.
Furthermore, a currently promising therapy consists of in vitro modification and reimplantation of cells generating growth factors (Nurown).
Neuregulins or neuroregulins are a family of four structurally related proteins that are part of the EGF protein family. These are growth factor proteins. They have various functions in the development of the nervous system and play multiple essential roles in the embryogenesis of vertebrates, in particular: cardiac development, differentiation of Schwann cells and oligodendrocytes, certain aspects of neuronal development, as well as the formation of synapses neuromuscular.
Neurotrophic factors derived from spliced forms of neuregulin 1 (NRG1) have been shown to be essential for the survival of motor neurons, supporting axonal and neuromuscular development and maintenance. However, the exact role of NRG1-I is not fully understood.
It has been reported (Mancuso et al., 2016) that the expression of NRG1-I by Schwann cells is essential for promoting axonal regeneration and remyelination. Indeed, the overexpression of NRG1-I by means of an AAV vector, injected locally into the gastrocnemius muscle produced a functional improvement by improving the collateral germination of the motor axons in SOD1G93A mice.
Given these recent discoveries, the authors aim here to overexpress humanized NRG1-I in all skeletal muscles by using gene therapy vectors to maintain motor innervation in SOD1G93A mice.
Interestingly, they found that overexpression of NRG1-I in muscles activates cell survival pathways via PI3K / AKT not only in this tissue, but also in the spinal cord, promoting better motor neuron survival and attenuation of reactivity of astrocytes and microglia.
Overexpression of NRG1-I increased ErbB receptors in skeletal muscles and their downstream pro-survival signaling. Signaling from the ErbB family of proteins is important during development. For example, the lack of maturation of Schwann cells leads to a degeneration of motor and sensory neurons. Excessive ErbB signaling is, however, associated with the development of a wide variety of solid tumor types.
Consequently, while NRG1-I could have a deleterious role during an upregulation in the spinal cord of SOD1G93A mice (Song et al., 2012), overexpression of NRG1-I improved the maintenance of neuromuscular function and innervation in SOD1G93A transgenic mice.
Since the pathogenesis of ALS is considered in the framework of the "dying backward" hypothesis, to develop in a process where the nerve endings and neuromuscular junctions are partially degraded while the cellular bodies (motor neurons, interneurons and glial cells) of the spinal cord are still intact, NRG1-I virally mediated therapy may be an appropriate approach to counter this initial degenerative process in motor neuron diseases.
However, further experiments are needed to elucidate the pathways modulated by overexpression of NRG1-I in skeletal muscle.
The mice were euthanized at 16 weeks, which is far too soon to draw conclusions about the long-term course of the therapy. Although it is clear that the treated mice experienced a much slower development of their disease, there was no remission.
There is also might be concern about the effects of excessive ErbB signaling on the risk of developing cancer.
This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.