Chondroitinase gene therapy improves upper limb function following cervical contusion injury

Abstract

Chondroitin sulphate proteoglycans (CSPGs) are known to be important contributors to the intensely inhibitory environment that prevents tissue repair and regeneration following spinal cord injury. The bacterial enzyme chondroitinase ABC (ChABC) degrades these inhibitory molecules and has repeatedly been shown to promote functional recovery in a number of spinal cord injury models. However, when used to treat more traumatic and clinically relevant spinal contusion injuries, findings with the ChABC enzyme have been inconsistent. We recently demonstrated that delivery of mammalian-compatible ChABC via gene therapy led to sustained and widespread digestion of CSPGs, resulting in significant functional repair of a moderate thoracic contusion injury in adult rats. Here we demonstrate that chondroitinase gene therapy significantly enhances upper limb function following cervical contusion injury, with improved forelimb ladder performance and grip strength as well as increased spinal conduction through the injury site and reduced lesion pathology. This is an important addition to our previous findings as improving upper limb function is a top priority for spinal injured patients. Additionally great importance is placed on replication in the spinal cord injury field. That chondroitinase gene therapy has now been shown to be efficacious in contusion models at either thoracic or cervical level is an important step in the further development of this promising therapeutic strategy towards the clinic.

Canine olfactory ensheathing cells from the olfactory mucosa can be engineered to produce active chondroitinase ABC

“…One group has taken the approach of thermo-stabilizing ChABC and achieved sustained delivery of the enzyme for up to 6 weeks using a hydrogelmicrotube scaffold (65). Other groups have pursued gene therapy as a means to improve sustained enzyme delivery (22,23,28,29,62,63). An alternative approach to disabling the inhibitory CSPGs is to target the CSPG receptor present on neurons: protein tyrosine phosphatase σ (PTPσ) (66).…”

“…Digestion of CSPGs with the bacterial enzyme chondroitinase ABC (ChABC), following local delivery to the spinal cord, has led to axon regeneration, plastic neuronal rearrangements and functional recovery following section or crush injury in laboratory animal SCI models (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Encouragingly, these findings have also been found using clinically relevant contusive injury rodent models (22,23) and large animal models such as cats and squirrel monkeys (19,24,25). Despite these advances, a major limitation for the use of ChABC in humans is the rapid decay of enzymatic activity at body temperature, within 24 to 72 hours (26).…”

“…This sequence has been incorporated into both adeno-associated viral vectors and lentiviral vectors as a delivery system of the modified ChABC gene into mammalian cells (22,23,28,29). Lentiviral vectors transduce host cells efficiently and this results in long-term expression of the incorporated transgenes.…”

“…They also are less immunogenic than other viral delivery systems such as adenoviral-based vectors (30,31). In vivo studies testing viral transduction of cells within the spinal cord following intraparenchymal injection of a lentiviral vector containing the mammalian form of the ChABC gene resulted in widespread CSPGs digestion over several spinal segments and this persisted for at least 2 months (22,23).…”

Injectable Hydrogels for Spinal Cord Repair: A Focus on Swelling and Intraspinal Pressure

“…Gene delivery allows for the continued production of bioactive factors by transduced/transfected cells in situ without repeated invasive administration. For example, the single-dose delivery of chondroitinase ABC-encoding lentivirus after contusive SCI results in significant functional improvement [James et al, 2015]. The delivery of genes encoding other therapeutic biomolecules, such as growth factors and anti-inflammatory cytokines, has also been reported to enhance spinal cord regeneration [Tuinstra et al, 2012;Thomas et al, 2014].…”