Progress with Rett Syndrome could be sooner than expected

Rett Syndrome is a rare neurodevelopmental disorder that effects thousands of children all over the world. With limited resources being allocated to the study and research into treatments for rare disorders, it’s nothing short of incredible that new discoveries have quickly been added as milestones in the history of Rett Syndrome.

A few weeks ago, I sat down with Dr. Lucas Pozzo-Miller, Ph.D., Professor in the Department of Neurobiology at UAB, to talk about his research in Rett Syndrome at the Civitan International Research Center.

“Rett Syndrome was first described as a disease entity by Andreas Rett 52 years ago, but it took 17 years until the first paper was published in English in a medical journal with worldwide distribution,” Dr. Pozzo-Miller begins as he quickly recounts the history of Rett Syndrome. “Then, it took 16 years for the causative gene to be discovered, but only 2 more for the first experimental mutant mice to be generated. Amazingly enough, only 6 years spanned until similar mice were used to demonstrate the genetic reversal of the most serious Rett Syndrome symptoms, including their premature death. Every new discovery comes with shorter and shorter intervals, showing the success of animal research funded by volunteer organizations like Civitan International and, as well as by the federal government” Dr. Pozzo-Miller continued.

For a disorder with such a small patient population, one may assume that any form of treatment would take generations of research and wouldn’t be discovered in a lifetime. However, Dr. Pozzo-Miller believes that viable treatment options for some of the most life-threatening symptoms of Rett Syndrome are only 5-10 years away.

When Dr. Pozzo-Miller first came to UAB, the primary focus of his research was on neurotrophins. “When I set up my lab, I was focusing all our work on the family of proteins called neurotrophins, or neurotrophic factors, which are important for the development and survival of neurons during brain development,” said Dr. Pozzo-Miller.

“Neurotrophins play a role in brain development, and since learning and memory use similar molecular and cellular systems to brain development, I was part of a team that discovered that neurotrophins – especially one of them

BDNF was repurposed for learning and memory in adults,” explained Dr. Pozzo-Miller.

This discovery came only 3 years before the discovery that the MeCP2 gene is responsible for Rett Syndrome. When Dr. Pozzo-Miller arrived to UAB, Dr. Alan Percy, CIRC Medical Director Rare Disease Research Center, encouraged him to pay attention to Rett Syndrome research, because MeCP2 controls the BDNF gene.

“That’s when I realized that we could take everything we knew about BDNF – how it allows neurons and synapses develop and work properly – and try to understand Rett Syndrome from the point of view of the deficits in BDNF, which are due to mutations in MeCP2. At this point, the Pozzo-Miller Lab switched gears “to studying the mouse model of Rett Syndrome, which lack MeCP2, and trying to understand which problems in Rett mice are due to deficits in BDNF, and then test for therapies that boost either BDNF levels or its function.”

Rett Syndrome wouldn’t be the only disorder reaping benefits from BDNF treatments. According to Dr. Pozzo-Miller, BDNF has been involved in Huntington’s, Lou Gehrig’s (or ALS), and Alzheimer’s diseases, and even depression. However, the road to developing BDNF treatments comes with one great roadblock. “For all of those neurological and neuropsychiatric conditions, nobody aims for BDNF itself as the treatment, because you cannot inject it or take a pill, because it will not reach the brain,” explained Dr. Pozzo-Miller.

Between the blood circulating your brain and the brain itself, there is a layer called the blood-brain barrier, which protects your central nervous system from foreign invaders that could cause brain infections. With this, researchers must take a different approach to treatment methods. One successful method is using small molecule mimetics – compounds that can not only mimic the effects of BDNF on its molecular receptor, but also cross the blood-brain barrier.

Dr. Frank Longo, MD, Ph.D. at Stanford University, discovered a family of such small molecules that mimic a portion of the whole BDNF protein, which can bind and activate the receptors of BDNF. Dr. Pozzo-Miller and his team have already conducted experiments using injections of one of these BDNF mimetics in MeCP2 mice with Rett Syndrome symptoms and described improvements in their spatial memory. In addition, the same compound discovered by Dr. Longo improves irregular breathing and breath-holding in studies by Dr. David Katz, Ph.D., Professor of Neurosciences, at Case Western Reserve University.  The next step for these BDNF mimetics is to be submitted to the Federal Drug Administration as an investigational new drug. “I’m very excited about the possibility that this BDNF mimetic can go into the FDA pathway for an eventual human clinical trial in Rett Syndrome individuals,” said Dr. Pozzo-Miller. This next phase, while it may be considered a huge hurdle, will be the next great milestone in the history of Rett Syndrome.