Introduction
Tetanus neurotoxin (TeNT) is the only known molecule that can
sustainably increase the neurological tone of skeletal muscle localised
to the point of injection. It is one of a family of Clostridial
neurotoxins that can modulate muscle function. The therapeutic potential
of Botulinum neurotoxin (BoNT; available commercially as
BotoxTM, DysportTM,
XeominTM or MyoblocTM) has long been
realised; however, not so for TeNT. BoNT has been used extensively for
more than 25 years as a therapeutic treatment for a myriad of diseases
caused by muscle disorders (Chen, 2012, Dressler, 2012, Johnson, 1999,
Patil et al. , 2016). It has also found widespread use as a
cosmetic agent (Monheit and Pickett, 2017). As BoNT acts by relaxing
skeletal muscle, it can theoretically be applied locally to any skeletal
muscle, and possibly smooth muscle, and the range of diseases that can
be treated is broadening. According to Dressler (2016), usage is split
approximately evenly between therapeutic and cosmetic applications
(Dressler, 2016).
BoNT has seven known serotypes, A to G, with type A and B being licensed
for human use (Patil et al. , 2016). They are derived fromClostridium botulinum , Clostridium butyricum andClostridium barati and are the most potent toxins found in nature
(Poulain and Popoff, 2019). Together with TeNT (derived fromClostridium tetanii ) they comprise the family of clostridial
neurotoxins. Although structurally and functionally related, BoNTs and
TeNT have quite different effects on muscle, with BoNTs causing flaccid
paralysis and TeNT spastic paralysis (Connan and Popoff, 2017). This is
because BoNTs act on the motor neurones, directly inhibiting them, while
TeNT is retrogradely transported up the motor neuron to the central
nervous system (CNS), where it inhibits transmitter release in
inhibitory neurones. This has the effect of reducing inhibition of motor
neuron firing, resulting in greater neurological muscle signalling,
leading to greater tone and eventually contraction.
This begs the question: Why is TeNT not being used as a therapeutic in a
similar manner to BoNT, given that there are many diseases that could
benefit from increasing muscle tone. TeNT is a candidate for treating
obstructive sleep apnoea (OSA) and spinal cord injury after
proof-of-principle was established in dog studies (Hesse et al. ,
2020, Conduit et al. , 2007, Sasse et al. , 2005). Some
other candidates for such treatments are motor neuron disease,
neuropathies, myelopathies and myopathies involving decreased motor
neuron output, pelvic floor muscular disorders, and disorders regarding
muscular sphincter tone. The greatest barrier to the use of TeNT is
widespread vaccination with tetanus toxoid, particularly in developed
countries where coverage rates can exceed 90 % (Seither et al. ,
2019). In immune individuals it is expected that low doses of TeNT,
equivalent to those used for BoNT therapy, would be ineffective. In a
model using mice either passively or actively immunised against the
toxin, local tetany could only be induced with over 10,000 times the
dose required in naïve animals (Fishman et al. , 2009). These
levels are lethal in non-immunised mice.
For human use, a reduction in the amount of administered toxin to the
lowest possible level while still retaining activity is vital. This
means that neutralising antibody activity towards the toxin must be
minimised or effectively bypassed. We have chosen to do this by
providing an excess of immunogenic but non-functional toxin to act as a
“smokescreen” to minimise the effectiveness of antibodies locally. We
show that this dramatically reduces the active dose required in a mouse
model. This opens the way for development of TeNT as a human
therapeutic.