There is no cure for genetic neurological disorders, and treatment can only manage symptoms as the diseases progress, often toward a fatal outcome. But pediatric neurologists at Children's Medical Center in Dallas, part of the Children’s Health℠ system, and UT Southwestern are creating new hope by leading an innovative effort to develop gene therapies to treat – and possibly correct – genetic neurological disorders. The program’s overarching goal is to use gene transfer therapy to correct genetic mutations so brain and spinal cord cells develop as normally as possible.

“Our preclinical research currently focuses on monogenic central nervous system (CNS) disorders with the goal of bringing gene replacement therapies through clinical trials and into clinical use,” says Berge Minassian, M.D., Director of the Neurosciences Center and Pediatric Neurologist at Children’s Health, and Chief of the Pediatric Neurology Division and Professor at UT Southwestern. “As more therapies become available, we’ll have a newborn screening for all these diseases so children can receive treatment earlier. And eventually, we’ll be able to apply our development approach to gene therapies for polygenic disorders.”

Groundbreaking research on monogenic neurological diseases

Gene transfer therapy replaces a mutated or missing gene with the aim of restoring the gene’s proper function. Dr. Minassian and his colleagues are using viral vectors to deliver the genetic material into brain or spinal cord cells. In fact, the program’s co-leader, Steven Gray, Ph.D., Associate Professor at UT Southwestern, is a pioneer in the field of gene therapy research, including the intrathecal injection method for delivering a corrected gene into the CNS.

The Children’s Health gene therapy program was involved in clinical trials of Zolgensma® (onasemnogene abeparvovec), which was approved by the FDA in 2019 to treat children under age 2 with spinal muscular atrophy (SMA). The clinical trials found that Zolgensma can help babies with SMA remain free of breathing and feeding support, improve motor function and stay within a normal weight range. Presymptomatic patients were able to achieve gross and fine motor scores similar to unaffected patients of the same age. Most symptomatic patients increased their event-free survival time (events were defined as death or the need for permanent breathing support). Many symptomatic patients were also able to achieve new motor-skills milestones.

Dr. Minassian hopes to make similar progress against genetic brain diseases. He and his colleagues are currently studying about 40 monogenic neurological diseases and are conducting preclinical studies on therapies for spastic paraplegia 50 (SPG50), giant axonal neuropathy (GAN) and Rett syndrome. The Rett syndrome study builds on Dr. Minassian’s discovery of the location of a genetic mutation that drives Rett syndrome. Children’s Health is one of 15 Centers of Excellence for Rett syndrome, designated by the International Rett Syndrome Foundation.

Dr. Minassian expects the therapies for SPG50 and Rett syndrome to enter clinical trials by April 2023 and the trial for the GAN therapy to begin later in the year.

The team is also leading a Phase 1 clinical trial of a gene therapy for a form of Batten disease called CLN7. This devastating, neurodegenerative disease affects children in toddlerhood, and without treatment, leads to death before their teenage years.

Applying lessons learned: Gene therapy for polygenic neurological diseases

With the approach they’ve developed for monogenic neurological diseases, Dr. Minassian and his colleagues plan to eventually investigate polygenic diseases, which are far more complicated.

For example, consider a hypothetical situation with a polygenic disease that involves five gene mutations. If a person had only three of the mutations, they wouldn’t develop the disease. Gene transfer therapies could be developed to replace two of the genes – thereby preventing the disorder.

Gene transfer therapy could transform care for a wide range of polygenic diseases including amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, autism, epilepsy, multiple sclerosis, Parkinson’s disease and schizophrenia.

“The kids we’re now treating with monogenic therapies are teaching us how we’ll be able to treat adults with polygenic diseases – that’s where this work is going,” Dr. Minassian says.
 

On the horizon: Expanding newborn screening so children can receive treatment earlier

When a child is born with a genetic neurological disease, signs may be apparent at birth, or may not be detected for months or years. Early diagnosis and treatment can help prevent irreversible loss of neuromotor function and other severe symptoms. Fortunately, newborn screening for more of these diseases will be adopted as more gene therapies are developed and approved for clinical use. Case in point: Newborn screening for SMA, for example, is now available in 48 states.

“Much of the suffering that these children and their families go through will be obviated if we catch and treat these diseases early, and our team is doing everything we can to make that a reality, as soon as possible,” Dr. Minassian says.

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