Dr. Steiner addresses the past, present, and future of diagnosing and treating SLOS

Robert Steiner, MD, clinical professor at the University of Wisconsin School of Medicine and Public Health, talks about cholic acid for the treatment of SLOS, as well his hope for gene therapies and other approaches in the future.

Question:

You have been involved in the research and treatment of patients with Smith-Lemli-Opitz (SLOS) syndrome for many years. Can you talk about how the field has evolved since the disease was discovered?

Robert D. Steiner, MD:

In some ways, we’ve really made a lot of progress in learning more about Smith-Lemli-Opitz syndrome over the years. I will say though, that it’s been disappointing that we haven’t come up with a really good therapy or treatment yet. I started studying Smith-Lemli-Opitz syndrome in 1995, and that was before we even knew the genetic or biochemical cause of the condition. Right around that time, 1994, 1995, is when we first discovered the biochemical cause. Then, it was a few years later where we identified the gene that’s abnormal in SLOS. Those advances made it much easier to diagnose patients, and they gave us some good ideas for potential treatments. We are implementing some therapeutic options for people with SLOS, but we still have a long ways to go.

Question:

Can you talk about the genetic testing and diagnostic component of SLOS? What are the hallmark signs and symptoms of the condition?

Robert D. Steiner, MD:

SLOS is suspected based on clinical features. In other words, what are the patients exhibiting, what physical features, what learning and growth features they’re presenting with? Individuals with SLOS, there’s a really wide spectrum, from very severely affected to very mildly affected and everything in between. The most severely affected patients can have birth defects that can affect almost every organ and organ system in the body. The most consistent finding in SLOS is actually webbing of the toes, webbing of the second and third toes, which again, a lot of people who don’t have SLOS have that, but it’s a really almost constant feature. In addition, learning problems, behavior challenges, and intellectual disability are common features. Some of the individuals have brain malformations. As I said, almost every organ system can be affected, so heart defects, problems breathing, and liver disease can be manifestations as well.

Once a clinician suspects that someone might have SLOS, nowadays because of the advances in finding the cause, we can test for it quite easily. Biochemical testing can be diagnostic. In other words, measuring cholesterol and cholesterol intermediates can be diagnostic, because SLOS turns out to be a problem in production of cholesterol in the body. But then, if that testing is either unavailable or doesn’t give a clear answer, genetic testing these days is quite easy to do and not nearly as expensive as it once was. I think that diagnostic ability in SLOS are really quite good these days.

Question:

What are treatment options for patients living with SLOS, specifically the use of cholic acid in the management of these patients?

Robert D. Steiner, MD:

SLOS turns out to be a defect in the body’s production of cholesterol. There’s a deficiency of an enzyme that’s normally present in the body that converts a chemical called 7-dehydrocholesterol to cholesterol. That’s the enzyme that’s not working well in SLOS. In other words, patients accumulate 7-dehydrocholesterol and have a deficiency of cholesterol. The first thought that I think people had once that was identified was, “Why don’t we just give these kids extra cholesterol and help to ameliorate the cholesterol deficiency?” That continues to be one of the mainstays of treatment that we offer to many of our patients. But I mentioned earlier that people with SLOS often have intellectual disabilities, so we really need to get cholesterol into the brain. But cholesterol that’s taken in the diet doesn’t really get into the brain. That remains a real challenge with the treatment.

We do offer our patients, by and large, cholesterol supplementation, either just a high cholesterol diet or a diet where egg yolks are added or, in some cases, chemical cholesterol is given orally or in a gastrostomy tube. These patients often have trouble feeding and growing normally, and many of them have required tube feedings. A second potential therapy is statin drugs. Statin drugs we think of as drugs, medications that help people with high cholesterol, that these medications lower cholesterol levels. We certainly wouldn’t want to do that in SLOS, because the levels are already low. But the way these statin medications work is they block the cholesterol synthetic pathway early in the pathway before the enzyme that’s deficient in SLOS. In other words, if the accumulation of chemicals that aren’t being normally converted to cholesterol, if the accumulation of those chemicals, like 7-dehydrocholesterol, is toxic, then statins will reduce those levels and prevent the toxicity.

If we can give those medications and also give supplemental cholesterol at the same time, that could be therapeutic. I would say, at this point, use of statin medications should really be considered investigational in SLOS, because they haven’t been proven, in my opinion, to be safe and effective. But it’s a potential therapy. Then, the third one that you mentioned is cholic acid. Cholic acid has been tested as an adjunctive therapy in SLOS to be used along with either a high cholesterol diet or cholesterol supplementation to try to improve the cholesterol and 7-dehydrocholesterol levels, but also to potentially make a difference in things like growth and learning and intelligence. Our bodies need certain chemicals to be able to absorb cholesterol well, and one of those chemicals, group of chemicals, is called bile acids. Cholic acid is such a bile acid. Right away, it’s pretty clear that giving cholic acid as a bile acid could help people with SLOS absorb cholesterol better and potentially lead to improvements.

As far as I know, there’s been one significant clinical trial trying to determine whether cholic acid could be useful in the treatment of SLOS, and that trial was relatively short and it was a relatively small number of patients. Now, it’s hard to get a large number of patients with a rare disease in any clinical trial, so I’m not faulting the leaders of the trial, but it was, nevertheless, relatively small. That trial did show that cholic acid can improve the biochemical features of SLOS. In other words, cholic acid can improve the cholesterol levels and decrease the potentially toxic 7-dehydrocholesterol that builds up. There was a suggestion that it might help in growth and weight gain, but that wasn’t proven to be statistically significant.

There was just a signal in that direction. In my experience, and I do treat a number of patients with SLOS, the parents whose children were enrolled in that trial often feel as if the medication was helping, especially with growth and maybe even with behavior. Since cholic acid is available as an FDA-approved medication, it can be prescribed and used off label in SLOS. Many healthcare professionals taking care of individuals with SLOS are prescribing cholic acid. It’ll be interesting to see whether future larger clinical trials can be done or if data can be collected from patients who are receiving cholic acid long-term to see if it can have long-term beneficial effects. I would say those are kind of the main treatments that are being investigated currently.

Question:

Is there ongoing research in this area that you are interested in?

Robert D. Steiner, MD:

Yes. My sense is that it’s really going to take genetic approaches for us to really be able to effectively treat SLOS. Gene therapy or gene editing is an area of great excitement these days for many conditions. I think it’s only a matter of time before such approaches are used in SLOS. There have been early investigations of gene therapies in animal models of SLOS, and those have provided some preliminary results. But since gene therapy and gene editing are being successfully used in other genetic conditions, I think it’s only a matter of time before that begins to be tested in SLOS. I’m not aware of any current clinical trials or even of any laboratory investigations of gene therapy and gene editing for SLOS, but I’m sure that those will be developed in the future. I’m optimistic, in the next several years, will have better approaches for SLOS.

Question:

Will there be a pharmacologic therapy specifically for SLOS?

Robert D. Steiner, MD:

I would hope that there will be pharmacologic therapies for SLOS. Again, I think, in the long term, it’s gene therapy and gene editing, which some people would put in the category of pharmacologic approaches. But in terms of small molecules, drugs in the typical sense, there are some approaches that are being looked at. For example, a group of us are trying to develop chemicals that can be given intravenously or orally that contain cholesterol, but that can be transported to the brain and the cholesterol separated from the rest of the chemical, once it’s in the brain, to allow cholesterol into the brain. Those studies are really very early investigations, not anywhere close to being available for humans. But I think approaches like that are reasonable.

I think it’s likely that a number of very smart investigators will find some way to treat SLOS. But still again, in the really early stages. I think for us as healthcare professionals and researchers to really make the most advances in treating SLOS, we need to diagnose it early. I think efforts toward developing newborn screening tests for SLOS will be very useful in diagnosing SLOS early and being able to treat it early, so I’m a strong advocate for development of newborn screening approaches for the condition.