Share this article on:

For Spinal Muscular Atrophy Prolactin and Early Gene Restoration Show Promise

Robinson, Richard

doi: 10.1097/01.NT.0000407225.67384.a2
Back to Top | Article Outline


Investigators reported in one study that prolactin increases expression of the survival motor neuron (SMN) protein in a mouse model of spinal muscular atrophy (SMA), another mouse study indicated that treatment after onset of symptoms may still offer benefit, although the window of opportunity closes quickly.

Prolactin increases expression of the survival motor neuron (SMN) protein in a mouse model of spinal muscular atrophy (SMA), a new paper in the August Journal of Clinical Investigation shows, suggesting clinical trials may be in the future for this FDA-approved drug. At the same time, another mouse study in the same issue indicates that treatment after onset of symptoms may still offer benefits, although the window of opportunity closes quickly.

SMA, an autosomal recessive disorder, occurs when mutations disable both copies of the SMN1 gene, the principal source of SMN protein, needed for RNA processing. Humans also possess a nearly identical gene, called SMN2, which produces a much smaller amount of SMN protein. Upregulating the SMN2 gene has been the goal of many therapeutic attempts in the disease.

Back to Top | Article Outline


One strategy for upregulating SMN2 is through the STAT5 pathway, according to Alex Mackenzie, MD, PhD, who led the study on prolactin. Dr. Mackenzie, professor of medicine at the University of Ottawa, explained that STAT5 is a transcription factor, which binds directly to the SMN2 gene, to increase transcription.

Unknown to Dr. Mackenzie, Faraz Farooq, a doctoral student in his lab, had searched the literature for blood-brain barrier-penetrant agents that activated STAT5, and came up with prolactin. “I'm taking as much credit as I can,” Dr. Mackenzie joked, “but it was Faraz's idea.” Prolactin binds to receptors within the CNS, setting off a cascade that ultimately brings STAT5 in contact with the SMN2 gene.

The investigators tested prolactin's therapeutic potential in the mouse model of SMA. The mice have no SMN gene of their own, but carry two copies of human SMN2. They display weakness by day five, poor weight gain, and death approximately two weeks after birth.

Mice were injected with prolactin daily for the first six days of life. The treatment led to “an upregulation of SMN in motor neurons,” Dr. Mackenzie said, “more than has been seen previously with other drugs.” Treated mice gained more weight than untreated mice, had better motor control, and lived an extra week — 60 percent longer than untreated mice.

Despite the benefit of treatment, Dr. Mackenzie said, there is a major puzzle in the results. The level of SMN restoration seen was equivalent to that in mice heterozygous for the human SMN1 gene. But those mice live a normal lifespan. “That makes our 60 percent extension seem a little disappointing,” he said. Another recent experiment in the SMA mouse showed that delivery of the SMN1 gene via a viral vector extended lifespan to at least 250 days.

The question, Dr. Mackenzie said, is whether prolactin needs to be delivered earlier, or at a more constant level, or to other cells besides motor neurons. “It could be a combination of all three,” he said. In particular, he explained, cardiomyopathy is common in SMA mice, but cardiac tissue may not be responsive to prolactin. There seems to be less cardiac involvement in humans, though, he said, which means prolactin may have the potential to have a more beneficial effect.

Prolactin may have some unique advantages over other agents considered for SMN upregulation. Prolactin is still under patent, which may increase the likelihood that it will be brought to trial. And the SMN2 gene has multiple STAT5 binding sites, suggesting that it should be particularly amenable to upregulation by prolactin.

“We want to optimize the dosing,” Dr. Mackenzie said, before considering a clinical trial. That means at least a couple more years of work in the mouse, he suggested.

Kathryn J. Swoboda, MD, associate professor of neurology and pediatrics at the University of Utah, where she directs the Pediatric Motor Disorders Research Program, takes issue with that approach. “Since this is a drug that has already been used, with few adverse effects”—prolactin is FDA-approved for inducing lactation—”do we need to spend more time and money doing that in the animal model, when we could be doing that in pilot trials in humans? We don't have any ongoing clinical trials in SMA in the United States,” she said, other than one at her center testing sodium phenylbutyrate in presymptomatic, genetically confirmed infants. Dr. Swoboda wrote a commentary accompanying the two SMA studies in the Journal of Clinical Investigation.

Back to Top | Article Outline


Presymptomatic therapy is likely to be the most effective strategy for treatment of SMA, but without widespread newborn screening, it may not benefit many patients; efforts are under way to develop such a screen. So a crucial question is whether any SMA therapy can be effective if begun after symptom onset, and if so, how late is “just in time”?

That was the question that drove the second study, led by Umrao Monani, PhD, assistant professor of pathology and neurology at Columbia University Medical Center in New York.

“Our study was prompted by one simple question: Can we try to correct the disease in a patient after that patient presents with clinical symptoms?” he said.

To answer the question, Dr. Monani and colleagues at the Jackson Laboratory in Bar Harbor, ME, engineered a mouse with an SMN2 gene that could be turned on, like a light switch, after symptom onset, mimicking a gene therapy rescue in a patient after diagnosis.

“The results are quite encouraging,” he said. When the gene was turned on at day four, after symptoms appeared, there was “near complete rescue” of the mice, with a 23-fold increase in survival in half the mice, and wild-type levels of strength and agility. However, the effect was diminished when the gene was turned on at day six, and nearly absent at day eight.

“If you wait, even if you restore high levels of SMN, the chance of rescue drops,” Dr. Monani said. “It has become apparent that motor neurons tend to become sick at the distal end,” he said, leading to symptoms in the mouse, even while the cell body remains alive. “If you restore SMN to those cells, they will send back axons to the muscle. Later, they are probably at a point of no return.”

“My guess is that we are probably going to see something very similar in humans as well. Every model has its failings, but I think based on this study, if we can catch patients early enough, when their motor neurons are dysfunctional but are still present, we may be able to rescue them.”

“The timing in which you give therapy is going to be crucial,” Dr. Swoboda agreed. “In neurodegenerative disease, we are not giving drugs early enough” in clinical trials. It makes little sense, she said, to expect any therapy to have much of an effect on an infant with advanced disease who has experienced significant motor neuron loss.

The majority of cases of SMA are Type I, the most severe, infant-onset type. “That window may be really small,” she said, and therapy may be needed in the first month or two of life. “It is probably unrealistic to expect otherwise.” In the less severely affected Type II and III patients, the window may be wider, and there may be more time to begin intervention, although, because the population is more heterogeneous, she noted clinical trials in this group may be much more difficult to carry out.

Back to Top | Article Outline


Farooq F, Molina FA, MacKenzie A, et al. Prolactin increases SMN expression and survival in a mouse model of severe spinal muscular atrophy via the STAT5 pathway. J Clin Invest 2011;121(8):3042–3050.
Lutz CM, Kariya S, Monani UR, et al. Postsymptomatic restoration of SMN rescues the disease phenotype in a mouse model of severe spinal muscular atrophy. J Clin Invest 2011; 121(8):3029–3041.
Swoboda KJ. Of SMN in mice and men: A therapeutic opportunity. J Clin Invest 2011(8):2978-2981.
©2011 American Academy of Neurology