Nicolas Granger

Mesoangioblast stem cells ameliorate muscle function in dystrophic dogs.

Duchenne muscular dystrophy remains an untreatable genetic disease that severely limits motility and life expectancy in affected children. The only animal model specifically reproducing the alterations in the dystrophin gene and the full spectrum of human pathology is the golden retriever dog model. Affected animals present a single mutation in intron 6, resulting in complete absence of the dystrophin protein, and early and severe muscle degeneration with nearly complete loss of motility and walking ability. Death usually occurs at about 1 year of age as a result of failure of respiratory muscles. Here we report that intra-arterial delivery of wild-type canine mesoangioblasts (vessel-associated stem cells) results in an extensive recovery of dystrophin expression, normal muscle morphology and function (confirmed by measurement of contraction force on single fibres). The outcome is a remarkable clinical amelioration and preservation of active motility. These data qualify mesoangioblasts as candidates for future stem cell therapy for Duchenne patients.

Autologous olfactory mucosal cell transplants in clinical spinal cord injury: a randomized double-blinded trial in a canine translational model

This study was designed to determine whether an intervention proven effective in the laboratory to ameliorate the effects of experimental spinal cord injury could provide sufficient benefit to be of value to clinical cases. Intraspinal olfactory ensheathing cell transplantation improves locomotor outcome after spinal cord injury in ‘proof of principle’ experiments in rodents, suggesting the possibility of efficacy in human patients. However, laboratory animal spinal cord injury cannot accurately model the inherent heterogeneity of clinical patient cohorts, nor are all aspects of their spinal cord function readily amenable to objective evaluation. Here, we measured the effects of intraspinal transplantation of cells derived from olfactory mucosal cultures (containing a mean of ∼50% olfactory ensheathing cells) in a population of spinal cord–injured companion dogs that accurately model many of the potential obstacles involved in transition from laboratory to clinic. Dogs with severe chronic thoracolumbar spinal cord injuries (equivalent to ASIA grade ‘A’ human patients at ∼12 months after injury) were entered into a randomized double-blinded clinical trial in which they were allocated to receive either intraspinal autologous cells derived from olfactory mucosal cultures or injection of cell transport medium alone. Recipients of olfactory mucosal cell transplants gained significantly better fore–hind coordination than those dogs receiving cell transport medium alone. There were no significant differences in outcome between treatment groups in measures of long tract functionality. We conclude that intraspinal olfactory mucosal cell transplantation improves communication across the damaged region of the injured spinal cord, even in chronically injured individuals. However, we find no evidence for concomitant improvement in long tract function.

Clinical diagnosis and treatment of suspected neuropathic pain in three dogs

Three dogs were referred to The Queens Veterinary School Hospital at University of Cambridge for chronic behavioural or locomotor disorders associated with pain. All three had been unsuccessfully treated with conventional analgesics, including non-steroidal anti-inflammatory drugs, glucocorticoids and opiate agonists, prior to referral, with minimal or no response. They were investigated by neurological examination plus conventional ancillary diagnostic tests and therapeutic drug trials. Ruling out other causes of pain and applying previously well-described criteria, each case was diagnosed as consistent with neuropathic pain, a poorly recognised condition in domestic dogs. Treatment with the tricyclic antidepressant drug, amitriptyline, or the antiepileptic drug, gabapentin, resulted in either a dramatic improvement or full resolution of clinical signs in all cases.

Designing clinical trials in canine spinal cord injury as a model to translate successful laboratory interventions into clinical practice

Many interventions have been shown to improve outcome after experimental spinal cord injury in laboratory animals. The challenge now is to determine whether any of these can be translated to become an efficacious therapy for clinical lesions – a process that is often difficult and frequently fails. Here, we discuss the steps that are required to make this transition and the need for rigorous clinical trials. A key component is an outcome measure that is amenable to statistical analysis; we describe methods that we have developed to accurately measure function after spinal cord injury in dogs. The general methodology may have parallels in the development of veterinary models to test putative therapies for other diseases of humans and animals.

Corrigendum: Mesoangioblast stem cells ameliorate muscle function in dystrophic dogs

This corrects the article DOI: 10.1038/nature05282

Factors associated with recovery from paraplegia in dogs with loss of pain perception in the pelvic limbs following intervertebral disk herniation

OBJECTIVE To investigate associations between recovery of locomotion and putative prognostic factors in dogs with loss of deep pain perception in the pelvic limbs caused by intervertebral disk herniation (IVDH). DESIGN Prospective cohort study. ANIMALS 78 client-owned dogs evaluated for IVDH that underwent spinal decompression surgery. PROCEDURES Dogs with complete loss of deep pain perception in the pelvic limbs and tail underwent routine examinations, advanced imaging, and spinal decompression surgery in accordance with standards of practice and owner consent. For each dog, information was prospectively collected on duration of clinical signs prior to onset of paraplegia; delay between onset of paraplegia and initial referral evaluation; date of recovery of locomotion, death, or euthanasia (3-month follow-up period); and whether dogs had received corticosteroid drugs before surgery. Severity of spinal cord compression at the lesion epicenter was measured via CT or MRI. RESULTS 45 of 78 (58%) of dogs recovered the ability to ambulate independently within 3 months after spinal decompression surgery. No evidence of prognostic value was identified for any of the investigated factors; importantly, a greater delay between onset of paraplegia and referral evaluation was not associated with a poorer prognosis. CONCLUSIONS AND CLINICAL RELEVANCE In this group of dogs with IVDH, immediacy of surgical treatment had no apparent association with outcome. The prognosis for recovery may instead be strongly influenced by the precise nature of the initiating injury.

Successful treatment of cervical spinal epidural empyema secondary to grass awn migration in a cat

Spinal epidural empyema (SEE) represents a severe pyogenic infection of the epidural space. Clinical signs of the disease are non-specific – increased body temperature, intense neck pain, neurological signs of a transverse myelopathy – and can lead to severe and permanent neurological deficits. This report describes the diagnosis and successful surgical treatment of cervical SEE secondary to grass awn migration in a cat. Although it is uncommon, this disease should be suspected in cats with progressive myelopathy. Early diagnosis and emergency surgery combined with antibiotic therapy are required to allow a complete recovery.

Cell Therapy for Spinal Cord Injuries What Is Really Going on

During the last two decades, many experiments have examined the ability of cell transplants to ameliorate the loss of function after spinal cord injuries, with the hope of developing interventions to benefit patients. Although many reports suggest positive effects, there is growing concern over the quality of the available preclinical data. It is therefore important to ask whether this worldwide investigative process is close to defining a cell transplant protocol that could be translated into human patients with a realistic chance of success. This review systematically examines the strength of the preclinical evidence and outlines mechanisms by which transplanted cells may mediate their effects in spinal cord injuries. First, we examined changes in voluntary movements in the forelimb associated with cell transplants after partial cervical lesions. Second, we examined the efficacy of transplanted cells to restore electrophysiological conduction across a complete thoracic lesion. We postulated that cell therapies found to be successful in both models could reasonably have potential to treat human patients. We conclude that although there are data to support a beneficial effect of cell transplantation, most reports provide only weak evidence because of deficits in experimental design. The mechanisms by which transplanted cells mediate their functional effects remain unclear.

Effect of middle ear effusion on the brain-stem auditory evoked response of Cavalier King Charles Spaniels

Brain-stem auditory evoked responses (BAER) were assessed in 23 Cavalier King Charles Spaniels with and without middle ear effusion at sound intensities ranging from 10 to 100 dB nHL. Significant differences were found between the median BAER threshold for ears where effusions were present (60 dB nHL), compared to those without (30 dB nHL) (P=0.001). The slopes of latency-intensity functions from both groups did not differ, but the y-axis intercept when the x value was zero was greater in dogs with effusions (P=0.009), consistent with conductive hearing loss. Analysis of latency-intensity functions suggested the degree of hearing loss due to middle ear effusion was 21 dB (95% confidence between 10 and 33 dB). Waves I-V inter-wave latency at 90 dB nHL was not significantly different between the two groups. These findings demonstrate that middle ear effusion is associated with a conductive hearing loss of 10-33 dB in affected dogs despite the fact that all animals studied were considered to have normal hearing by their owners.

Radiographic morphology of the cranial portion of the cervical vertebral column in Cavalier King Charles Spaniels and its relationship to syringomyelia

OBJECTIVE To compare radiographic morphology of the atlantoaxial region between Cavalier King Charles Spaniels (CKCSs) and dogs of other breeds and determine whether there was an association between radiographic morphology of the atlantoaxial region and syringomyelia in CKCSs. ANIMALS 65 CKCSs and 72 dogs of other breeds. PROCEDURES The amount that the spinous process of the axis overlapped the dorsal arch of the atlas, the relative size of the spinous process of the axis, and the amount of widening of the atlantoaxial joint that occurred when the neck was moved from a neutral to a flexed position were measured on lateral radiographic projections of the atlantoaxial region. Magnetic resonance images were reviewed to identify CKCSs with syringomyelia. RESULTS The amount of overlap of the atlas and axis and the relative size of the spinous process of the axis were significantly smaller in CKCSs than in dogs of other breeds. However, the amount of widening of the atlantoaxial joint that occurred when the neck was moved from a neutral to a flexed position was not significantly different between groups, and no association was detected between syringomyelia and excessive atlantoaxial joint space widening or between syringomyelia and an excessively small axial spinous process. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that radiographic morphology of the atlantoaxial region in CKCSs differs from morphology of that region in dogs of other breeds, but that these differences do not account for why some CKCSs develop syringomyelia and others do not.