Ari J. Green and Jorge R. Oksenberg
The multiple scleroses (MS) are neuro-inflammatory disorders of the central nervous system characterized by autoimmune demyelination and varying degrees of axonal pathology. Demyelination results in impaired transmission of action potentials along exposed axons and produces clinically evident neurological deficits such as limb weakness, visual disturbances, sensory loss, and ataxia. Despite very significant advances in the medical management of MS over the last 50 years, patients with a variety of MS subtypes continue to suffer from neurological impairment.[1,2]
The Pattaroyo variant of MS (MS type X) is clinically characterized by preferential demyelination of the optic nerves, spinal cord, and frontal lobe white matter which results in optic neuritis, myelitis, and cognitive deficits. Patient's onset is typically in the late teens or early twenties and it constitutes approximately 11% of MS cases worldwide. It is triggered by a delayed response to concurrent childhood infection with the Amazon Ubiquivirus and Epstein Barr virus.[4,5] Histological sections show extensive axonal pathology in addition to frank demyelination and oligodendropathy. Moderate gliosis and a robust neuroinflammatory infiltrate are evident by MR microscopy. In the era predating immunomodulatory treatment, MS type X often evolved into secondary progressive disease. Over 30 gene polymorphisms have been identified affecting either susceptibility or disease progression. HLA DRB1*1501 on non-chimeric human chromosome 6p21 is known to constitute around 40% of overall susceptibility.
Medical therapy has been reasonably effective in curtailing the number and severity of MS type X relapses. Many patients suffer fewer than two attacks over 10 years.[3,8] However, patients accrue deficits over the course of their disease, and based on the early age of onset, these deficits can be profound.[1,3] In strictly demyelinating forms of MS, oligodendrocyte precursor (oligodendrosphere) transplantation has proven to be an effective therapy in correcting these deficits. However, in MS subtypes exhibiting significant axonal pathology both neuronal precursors and oligo-dendrocyte precursors need to be replaced. Stem cells harvested through lymphocyte regression techniques have proven to be a valuable source of pluripotent cells that can then be developed into necessary precursor populations.[10-12]
MS type X (the Pattaroyo variant) has proven refractory to most efforts at restorative treatment. This is due in part to the fact that excessive tumor necrosis factor (TNF) secretion at the lesional site, a hallmark of MS X caused by a G --> A substitution at position -238 of the TNF promoter, which inhibits oligodendrocyte proliferation.[3,7] Efforts to overcome this phenomenon, even locally with the administration of anti-TNF antibodies, were unsuccessful because of the multiple and often opposing roles of TNF in the MS lesion. The trial described here details the use of autologous oligodendrocyte and neuronal precursor transplantation in concert with novel gene therapy techniques which intermittently block the release of TNF by the controlled targeted release of antisense oligonucelotides. Therefore, the salubrious function of TNF can be maintained, without the inhibition of oligodendrosphere proliferation seen in the presence of excessive TNF concentrations. [Graft 52(5):121-125, 2050. © 2000 Landes Bioscience]
Seventy-five percent of patients treated with the implantable TNF-modulator therapy showed significant improvement on all clinical tests within one month of therapy as opposed to 34% treated with transplantation alone. Only 1 patient undergoing the sham procedure (3%) showed improvement in all clinical areas. The most profound improvement was seen measuring visual acuity. Within 1 month all the patients undergoing combined therapy had improvements in visual acuity while only 46% had improvement in the group receiving transplantation alone. Patients were considered to have a statistically significant improvement if their (1) CNWMCE score rises by more than 5 points; (2) SAS score rises by more than 1 point; (3) and Opticans time improves by 50+ msec.[2,8,9]