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Multiple Sclerosis

Multiple Sclerosis (MS) is a progressive autoimmune disease in which parts of the brain and spinal cord (together they form the central nervous system or CNS), are attacked by the patient’s own immune system.  The pathophysiology of MS is tied to the unique anatomy of the mammalian CNS, in which the neurons, or “thinking cells” of the CNS, are connected to one-another by thin, sometimes very long, projections called axons that function like wires, tying neuronal networks together.  There are billions of axons in the CNS, that, just like copper wires in an electrical circuit, need to be insulated to maintain signal integrity and boost communication speed.  The insulating material in the CNS is called myelin.  Myelin is synthesized by another cell type in the CNS called oligodendrocytes or “glia”, which literally wrap the axons with myelin, forming white matter.  The myelinated axons are bundled together into white matter tracts.

MS is the result of an inappropriate cellular immune response in which the body recognizes myelin as foreign, causing an autoimmune attack on the CNS.  During an attack, immune cells flood into the affected area(s) of the CNS, where they destroy myelin.  In parallel, other structures suffer “bystander damage” and neuronal signaling through the area is inhibited or lost.  The lesions appear as gaps in the white matter tracts that can be imaged on MRI scans.  In addition to white matter loss, the cortex and deeper structures in the brain and spinal cord (gray matter) may also be damaged indirectly, causing shrinkage known as atrophy. The combined effects of white and gray matter damage result in the serious and troubling motor, sensory and cognitive deficits of MS.

The most common form of MS is termed Relapsing/Remitting MS (RRMS), in which the disease cycles between outbreaks of neurological impairment or “relapses”, alternating with periods of remission, during which the disease is clinically stable and some function may actually be regained.  Preclinical research conducted by InteKrin has produced encouraging data showing that INT131 interrupts disease relapse and prevents disease recurrence, while also preventing gray matter atrophy.  InteKrin is currently testing INT131 in clinical trials.



INT131 crosses the Blood Brain Barrier

The nervous system is “immune privileged”, which means that under normal conditions, it is isolated from the immune system by the blood-brain barrier (BBB).  The BBB is a physical/chemical structure that prevents most white blood cells and most large molecules, like proteins, from freely entering the CNS.  During times of neural inflammation, such as during MS flare-ups, the BBB is compromised at the sites of MS lesions, allowing white blood cells and antibodies to freely enter the CNS.  These “leaks” in the BBB are transient, and they usually close within 30 days or so after the first appear.  In order for a drug such as INT131 to be effective in preventing MS relapses, it would need to freely cross the intact BBB during disease remission, when the BBB is intact.  As shown in figure 1, when healthy animals with intact BBBs were given INT131 we found significant amounts of the drug in the brain and spinal cord within an hour, but far less in the cerebrospinal fluid (CSF).  This is a normal finding, as drugs are metabolized and excreted from the brain and spinal cord by secreting them into the CSF, from where that are carried into the blood stream for elimination from the body.  By 24 hours, the INT131 levels in the CNS and the CSF were about 25% of the level found in the blood stream, showing excellent transport of INT131 across the BBB, and its subsequent excretion out of the tissue and into the CSF.  The total amount of INT131 found in the CNS was more than adequate to activate the desired anti-inflammatory and neuroprotective PPARγ pathways.  These data are consistent with INT131 penetration of the BBB and its subsequent excretion.

Figure 1

Figure 1.  The percentage of INT131 found in the brain, spinal cord (cord) and cerebrospinal fluid (CSF), compared with that found in the blood at 1, 6 and 24 hours after dosing.


INT131 prevents relapse in a model of MS
Experimental autoimmune encephalomyelitis (EAE) is a rodent model of MS.  Rivers and colleagues first described EAE in 1933, recognizing it as a model of MS.  While it is not a perfect model of MS, it is a closer approximation of the human disease than other models of uniquely human pathologies.  It is characterized clinically by tremors and ataxia (difficulty in movement), and by leukocytic (while blood cell) infiltration into the brain and spinal cord, with an associated myelinopathy.  The major neural histopathologies seen in MS are also present in EAE, and both are examples of tissue-restricted autoinflammation.  Unlike many other rodent models of human disease, the effective treatment of EAE is highly predictive of drug efficaciousness in the treatment of MS.

We have tested the effects of INT131 on disease progression in animals with the MS-like disease EAE.  The symptoms of EAE range from the mild, such as a limp tail, to the more severe- paralysis and death.  In one set of studies we initiated treatment with INT131 when the animals were in remission, after a severe bout of EAE, during which the symptoms included ataxia (uncoordinated muscle movement) and partial paralysis. As shown in figure 2 below, following treatment with placebo (vehicle), approximately three quarters of the animals had relapses.  In contrast, when daily treatment with either 1mg/kg or 3 mg/kg of INT131 was initiated during the first remission, only 9% -16% of the animals showed signs of relapse.  These data are consistent with our demonstration that INT131 readily crosses the BBB, where it acts to prevent or curtail autoimmune neuroinflammation.  Moreover, INT131 treatment prevented relapse in this model.


Figure 2

Figure 2.  Treatment with INT131 during remission prevents relapse of EAE.


At the peak of EAE (and MS) clinical disease the BBB is compromised at the lesion sites.  Initiation of daily INT131treatment resulted in both a sharp improvement in the subjects clinical presentation, and it prevented relapse from occurring.  Histopathological examination of the brainstems of animals with EAE treated with placebo (vehicle) one month after EAE induction showed a severe infiltration of proinflammatory, white blood cells in the tissue.  In contrast, examination of the brainstems of animals treated with INT131 (either 1 or 3 mg/kg) showed a virtual absence of proinflammatory white blood cells (figure 3).  The profound pro-inflammatory white blood cell infiltration in the control animals correlated with the poor clinical course these animals had.  In contrast, the paucity of white cells in the INT131 treated brains correlated with the complete and sustained remission seen in the drug treated subjects.

Figure 3

Figure 3.  Treatment with INT131 at the apex of EAE disease results in a rapid clearance of CD45-positive  (arrows) cells from the brain stems of affected mice.  There was no difference in the leukocyte clearance in the 1 or 3 mg/kg doses.


Taken together, these data demonstrate the efficacy of INT131 for the treatment of autoimmune neuroinflammatory disease.