Originally Posted by Dr. Voskuh

Multiple sclerosis is an auto-immune disease affecting young adults about 20 to 30 years old. The immune cells of a person's own body attack their nervous system or their brain and spinal cord, resulting in paralysis or blindness, depending on where the attack occurs. You can have various symptoms, like blindness, or you won't be able to walk.

Originally Posted by Dr. Voskuh

One in 1,000 people have multiple sclerosis. Almost 0.5 million people in the United States have MS.

Originally Posted by Dr. Voskuh

It's more common in women than men by three to one.

Originally Posted by Dr. Voskuh

Patients generally experience blindness in one eye. It lasts a month or two, then gets better. They will have tingling in one or both hands, and then it will get worse. It will stay bad for a month or two and then get better. Walking difficulties are extremely common. Coordination problems are common. Cognitive problems are frequent. Almost half the patients will have some sort of cognitive problems at some point. It's not like Alzheimer's. It's much more subtle, but highly functioning people know they have problems processing information rapidly.

Originally Posted by Dr. Voskuh

Currently, there are no treatments for cognitive problems in MS. No direct treatments will protect you. All we have now are anti-inflammatory shots, so after a year or few years, they reduce relapses by one-third to one-half. None of them will directly target disabilities. Probably indirectly, after taking them from years and years, a patient will do a little bit better. The real meaning is for something directly neural protective that protects some other function.

Originally Posted by Dr. Voskuh

It would be ideal to have a drug shown to go directly to the brain and protect these cells from dying, like the immune system. Instead of being anti-inflammatory for the immune system, it would be nice to protect from damage if any cell got through.

Originally Posted by Dr. Voskuh

Currently in MS, we have anti-inflammatory treatments, which are shots or injections that relieve the attack of immune cells through the spinal cord. They're really good, to some extent, but we don't have drugs nerve cells in the spinal cord and brain. We need something to directly protect the brain from attack.

Originally Posted by Dr. Voskuh

That's one of the worst things about MS. It's not predictable, and it's progressive -- despite anti-inflammatory treatments. Some things can be used to slow the relapse, but unfortunately, progression occurs over a number of years despite good anti-inflammatories. That's why societies such as the MS Society and other agencies are focused on finding a neural protective agent. We need something to halt the progression, not just slow it down.

Originally Posted by Dr. Voskuh

We used clinical observations known to occur in MS to develop a new strategy. Since women get MS more frequently than men, we wanted to see what in men is responsible for them getting it less frequently. When we looked at it, we found men getting MS were a little older. They were around 40 years old. Interestingly, testosterone declines around age 40. It begins to decline about 1 percent or 2 percent per year at around 30. We think testosterone has been protective, and it's beginning to wan as they age. So a lot of experiments were done by our group and other groups giving testosterone to mice with animal models of MS. We made sure it was protective. So for the first time, we gave testosterone to men with MS to see if it could recapitulate some of that protection. Not many men have MS onset at the age of 20 or 25, whereas most women do.

Originally Posted by Dr. Voskuh

Generally, for the first time, you want to give it to a small group of patients, only about 10 patients. You want to make sure it doesn't make them worse for some unknown reason, and you want to detect efficacy. That means you need a biomarker, like an MRI or immune study, to show something good has happened. If you get that, you can go to a Phase II trial or Phase III trial, where you really look at larger numbers of effect to go to the FDA. Generally, the small studies are pilots. In pilots, we're looking for a hint something good can happen.

Originally Posted by Dr. Voskuh

In a six-month period, untreated patients were followed to get a baseline. Then we treated them with AndroGel. It's a gel shown to be well-absorbed. It's put on the shoulders once a day. It has been used frequently in older men. We gave this gel to the men once a day for a year. Patients had their own control, so we could see what happened during this year they were taking it.

Originally Posted by Dr. Voskuh

First of all, the dose we gave boosted their immune system to a low-normal to high-normal. By checking their blood levels, with respect to MS, we were surprised there was change in cognition. This was quite surprising, because we thought it would cognition would stabilize and decline over a year, but actually, we got even a little improvement. That was pretty exciting. We went on to confirm whether there was biological basis for improved cognition. MRIs were done in every month for 18 months, during six months of pre-treatment and 12 months of treatment. On the MRI, the rate of atrophy occurring from pre-treatment to after 12 months of treatment, the brain changed in way similar to normal aging. In essence, we significantly halted the rate of atrophy in MS.

Finally, we saw improved cognition and slower brain atrophy. We thought it could be due to a substance made by the immune system called brain-derived neurotrophic factor (BDNF). It's a neural protective nerve factor. We questioned if it was possible the immune cells were making this substance during testosterone treatment. It's known immune cells can make it, but we didn't know if testosterone could. We took their immune cells before and after treatment. Sure enough, the immune cells increased after treatment. We thought this could be one of the mechanisms whereby it was neural protected.

Originally Posted by Dr. Voskuh

We're excited about these findings because we would be describing the first neural protective drugs for MS. That would be quite a huge issue. We don't know yet, but they could be combined with a variety of anti-inflammatories. This has to be investigated, but this is where we think the field needs to go to find things directly neural protective. We think testosterone may be neural-protective. We didn't see an anti-inflammatory effect of testosterone, so that's unfortunate, but it's kind of nice because it tells us the neuroprotection wasn't all indirectly through the immune system.

Originally Posted by Dr. Voskuh

Exactly. It took a different route than we thought it would. In our study, patients were not on the shot. We had people who were relatively mildly affected. If they had been severely affected, someone would have told them they must absolutely take shots. There are some people who just really don't want to take shots. It's something they avoid. That's the group we have. They were relatively mildly affected, they were not on shots, and one may wonder whether our results will be the same if we take a different group, for example, people with more aggressive disease. We don't know. That will be something else to look at to see if another group with a more aggressive disease will also be protected.

Originally Posted by Dr. Voskuh

Of the 10 patients, three had no cognitive problem at all. They scored 59 or 60 out of 60. There was no room for improvement in their scores. The other seven had slightly lower scores, but they did all improve.

Originally Posted by Dr. Voskuh

AndroGel can make pre-existing prostate cancer worse. All our patients were screened. They didn't have it. Their PSA levels, which is what people check, were steady throughout the course of study. Those did not change, so no, they didn't have any side effects. There was one interesting good side effect. Patients showed improvement in muscle mass. That's actually known with AndroGel. We didn't know if we'd see it in our patients, but they showed a significant increase in muscle mass. Testosterone is also known to improve bone density, but we didn't see that in our patients, probably because they had no bone marrow density problems in the first place. They were in good shape and walking. If you had patients in a wheelchair with bone density problems, they might benefit. We don't know. They'd need a different group of patients to study.

Originally Posted by Dr. Voskuh

Mostly, they said they felt better. They had more energy and less fatigue. Fatigue is a big component of MS. We didn't have relapses during the study.

Originally Posted by Dr. Voskuh

It is possible. Some testosterone analogs are less masculinizing than what we've used. In another area of research, we're giving high-dose pregnancy estrogen to women with MS. Our philosophy has been to have therapies tailored for side effects. With men taking testosterone, there are not too many downsides. With women taking estrogen, there are not a lot of downsides. We're using a gender-tailored approach, rather than forcing one gender to take something that isn't as well-tolerated. It is theoretically possible we don't have side effects of the primary antigen.

Originally Posted by Dr. Voskuh

The next step is a larger trial where we add anti-inflammatories. We'll follow the same outcomes, cognition and brain atrophy.

Originally Posted by Dr. Voskuh

If we can show it's neural protective in MS, then it re-opens the door to using it in other neurodegenerative diseases such as Alzheimer's and Parkinson's. One question is whether testosterone could be neural protective, because of the link to estrogen. Estrogen has shown to be neural protective in a variety of neurodegenerative diseases. That may be how testosterone is working. It can be converted to estrogen by the body. We don't know that, but it's an interesting way it could work. I think the ramifications for other neurodegenerative diseases beyond MS, Alzheimer's and other neural-degenerative diseases are pretty obvious.

We like taking the hormone approach. A lot of literature shows you can administer one neurotrophic factor, or one agent, and it has little impact. We see hormones as a natural gift. They're synergistic. There's evidence hormones can change a variety of molecules. I think when they all change in concert, there's a potent effect. I like the idea of a more natural cascade of events as opposed to giving just one molecule. One molecule doesn't make much impact, but using an agent induces a variety in timing. It is really nice to capitalize on that situation.

Originally Posted by Dr. Voskuh

Patients would put AndroGel on their shoulders once a day, in the morning, not at night. At night it would get on bed sheets, and their partner might get some on the bed sheets. So they put it on the shoulders once a day. It's not an injection, that's a beautiful thing.