The pain and neurology pipeline comprises several distinct therapeutic modalities. A neuropathic pain program today may be a small molecule sodium channel blocker, an antibody, a botulinum toxin, or an AAV carrying a microRNA to the dorsal root ganglion. It may equally be a live bacterial strain acting through the gut, a nerve conduit, or a local anesthetic combined with an anti-inflammatory in a release polymer. These candidates can be evaluated in the same disease model. The modality determines the route by which the test article reaches its target, the study duration required to observe the effect, and the measurements that confirm target engagement. MD Biosciences has evaluated small molecules, biologics, cell based therapies, AAVs, bacteria, natural compounds, medical devices and combination products across its models, by all standard routes and by direct nerve, intrathecal, intracerebral and infusion pump administration. The sections below describe the study design requirements of each modality.
The small molecule study is the reference design. Dose response and time course are assessed on behavioral endpoints, and pharmacokinetic sampling relates both to exposure. In the pig peripheral neuritis trauma model, gabapentin raises von Frey withdrawal thresholds in a dose- and time-dependent manner. In the pig incision models, bupivacaine, ropivacaine and their formulations are followed over hours and days with plasma sampling in parallel. Because pigs accept human-scale dose volumes, a two milliliter gel instilled into a surgical site is tested at its intended clinical volume rather than scaled to a rodent.
Antibodies, fusion proteins and toxins act on defined molecular targets, and the study is designed to demonstrate target engagement. In collagen-induced arthritis, etanercept lowered the arthritis score and anti-collagen type II antibody levels, so the immunological effect and the clinical effect were measured together. In the pig skin and muscle incision model, intradermal abobotulinumtoxinA reversed mechanical allodynia from day three. Spinal cord histology demonstrated cleaved SNAP25 in the dorsal horn, direct evidence of toxin activity at the site of action, together with reduced astrocyte and microglial markers. The behavioral result and the tissue evidence of mechanism were obtained from the same animals.
Gene therapy imposes three design requirements. The vector must reach the target tissue, transgene expression develops over time, and follow up is measured in months rather than days. In pain, the target tissue is often the dorsal root ganglion, and the routes are intrathecal and intra-DRG. MD Biosciences has validated direct intra-DRG injection as a delivery route. In the method validation, a dye injected at a slow controlled rate distributed through serial sections of the L5 ganglion. Animals gained weight normally through day 28, a transient mechanical sensitivity on von Frey testing resolved over three to four weeks, and open field walking distance showed no motor deficit. This profile satisfies the requirement of a vector study for a delivery route that leaves the ganglion intact, so that the effect of the payload can be assessed independently of delivery injury.
The principal safety concern for AAV in the sensory system is toxicity to the dorsal root ganglion. Ganglion toxicity has been reported after AAV delivery in non-human primates and rodents. Hawley et al. (2025) describes inflammatory signals appearing within days and neuronal degeneration in the subsequent weeks, and circulating neurofilament has been proposed as a biomarker for monitoring it. A preclinical gene therapy study in pain therefore assesses DRG and nerve histopathology together with sensory behavior and nerve conduction over the expression window. These assessments are performed in rodents and, where the program requires it, in Göttingen minipigs, whose slow weight gain permits chronic designs. The peripheral neuritis trauma model runs to three months and the nerve repair models to a year, which is the timescale required for a single-dose vector. A vectorized microRNA against SCN9A delivered intrathecally by AAV9 was reported in October 2025 to knock down the target in primate lumbar ganglia, with analgesia through eight weeks in a rat nerve injury model. This program is an example of the study design this modality requires.
Cell based therapies are evaluated within the same framework, with the route and the duration of follow up determined by the product. Live biotherapeutics act through an indirect route. In a mouse study of morphine tolerance, a single bacterial strain given alongside repeated morphine attenuated the development of tolerance, measured on the tail flick test and on sensory evoked potentials recorded from the same animals. The mechanism operates through the gut-brain axis, so the study was designed to detect a central effect of a peripherally delivered organism, with electrophysiology providing the objective readout.
A medical device or a combination product is tested in the anatomy for which it is designed, which usually means the pig. In the Göttingen minipig nerve repair model, a three centimeter segment of the peroneal nerve is removed and the repair, a conduit, wrap or filler, is followed for six months to a year. Endpoints are gait analysis, compound muscle and sensory nerve action potentials, and histology of the regenerated nerve. The rat tibial nerve model is run in parallel with commercial conduits as the positive control. Combination products combine a drug with its delivery system. The bupivacaine and meloxicam extended release formulation tested in the pig flank incision model is the reference case. In that study the polymer, the anesthetic and the anti-inflammatory were evaluated as a single article against bupivacaine alone, meloxicam alone and saline.
The endpoints are constant across modalities. Von Frey, thermal testing, weight bearing and open field quantify behavior. Sensory nerve conduction velocity, compound muscle and sensory nerve action potentials, and evoked potentials quantify physiology. Histology, immunohistochemistry and biomarker panels characterize the tissue, and PK quantifies exposure where exposure is the relevant measure. Because the platform is constant, a sponsor comparing a small molecule with a gene therapy for the same indication, or transitioning a program from one modality to another, obtains directly comparable data.
MD Biosciences runs its pain, neurodegeneration, nerve repair and wound healing models in rodents, domestic pigs and Göttingen minipigs in a single facility. The facility includes treatment rooms for new chemical entities, biologics and medical devices, microsurgical suites for direct nerve, intra-DRG, intrathecal and intracerebral dosing, and electrophysiology, histology and biomarker laboratories. Study design conversations for any modality are welcome at neuro@mdbiosciences.com.
References:
Hawley ZCE et al. Dorsal root ganglion toxicity after AAV intra-CSF delivery of an RNAi expression construct into non-human primates and mice. Molecular Therapy, 2025.
Circulating neurofilaments to track dorsal root ganglion toxicity risks with AAV-mediated gene therapy. Molecular Therapy Methods & Clinical Development, 2022.
Cornet S et al. Scientific Reports, 2022.
Ottoboni T et al. Regional Anesthesia and Pain Medicine, 2019.