Making the untreatable treatable: the promise of gene-based therapies for neurological disorders

Earlier this summer, NINDS hosted our annual Nonprofit Forum, an annual event in which nonprofit leaders can network with colleagues and engage in discussions with NINDS staff. This year, considerable attention was paid to the emerging field of gene-targeted treatments for multiple neurological conditions. This cutting-edge area of science has opened a new window for the development of new therapies—particularly for disorders for which other drugs have had limited effects. These include well-established, rare, ultra-rare, or even yet undiagnosed neurological conditions for which NINDS is committed to developing treatments.

Currently, about 30 cell and gene therapies are approved for use in the United States. NINDS- and NIH-funded research contributed to the development of Nusinersen (Spinraza®), which was approved in 2016 as the first treatment available for the inherited neurological disorder spinal muscular atrophy (SMA). This group of hereditary diseases can damage and kill motor neurons, which control movement in the arms, legs, face, chest, throat, and tongue, as well as skeletal muscle activity, such as speaking, walking, swallowing, and breathing. Beyond these therapies, many others are being studied and developed, and some like Skysona and Zolgensma have been recently approved by the U.S. Food and Drug Administration (FDA) to treat adrenoleukodystrophy and SMA, respectively. It is a promising time for gene therapy, but many families continue to see these devastating neurological diseases affect loved ones. More needs to be done to improve current therapies and bring new ones to patients.

There is considerable enthusiasm for gene therapy to replace genes that don’t function or to use anti-sense oligonucleotides (ASO) to turn off mutated genes that cause damage. Indeed, recent technological advances have made it possible to accomplish both types of modifications. But no matter how exciting, we are still learning about how to best apply those techniques to make treatments both safe and effective. This is why NINDS is supporting multiple clinical trials through a variety of ongoing programs to advance genomic technologies and their applications.

NINDS is also funding investigators to develop genomic therapies for rare and ultra-rare genetic diseases. The Ultra-rare Gene-based Therapy (URGenT) network was launched by NINDS in 2021 with the goal of supporting the development of state-of-the-art gene-based therapies for ultra-rare diseases—those that affect as few or fewer than one in fifty thousand people. An ongoing funding opportunity exists via the URGenT Network to help bring promising therapies into the clinic: the Translational Efforts to Advance Gene-based Therapies for Ultra-Rare Neurological and Neuromuscular Disorders U01. In addition, URGenT will be adding a gene therapy consortium to support clinical trials for ultra-rare diseases as part of a collaboration with the Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT).

I am delighted to share that URGeNT has launched its inaugural set of awards. One team will leverage RNA technology to lower the amount of prion protein - a misfolding that results in a fatal and untreatable neurodegenerative disease. A second team will develop a lead candidate therapeutic - AAV9/AGA - as a treatment for Aspartylglucasaminuria, a devastating and currently untreatable neurodegenerative disorder. A third team will focus on developing a combination treatment for Menkes disease - an ultra-rare inherited disorder that presents early in life with progressive neurological decline. Collectively, these awards aim to accelerate therapeutic development with the goal of advancing safe and effective therapies.

NINDS is also working with its public and private partners to advance genomic therapy for neurogenetic diseases, including through the Accelerating Medicines Partnership® (AMP®) program’s Bespoke Gene Therapy Consortium (BGTC). In May, the Foundation for the National Institutes of Health (FNIH), which manages the AMP BGTC program, announced the selection of eight rare diseases for inclusion in its gene therapy clinical trial portfolio. Among these are three neurologic disorders: Multiple Sulfatase Deficiency, Charcot-Marie-Tooth disease type 4J, as well as Spastic paraplegia 50 with Elpida Therapeutics. This is a massive effort comprising 33 member organizations, including 11 NIH Institutes and Centers, that has received more than $97 million in financial and in-kind commitments. The AMP goal is to develop a platform for gene therapy that will speed the process of addressing a number of rare disorders. This kind of support through the BGTC is necessary to address the needs of diseases too rare to fit within the traditional commercial therapeutic development pipeline. 

In addition to knocking out harmful gene mutations or replacing missing genes, a new technology, called gene-editing, allows scientists to actually correct a mutation. This is done commonly in the laboratory in experimental models but is only in the clinical trial stage in altering a person’s blood cells to treat cancer or blood disorders. Begun in 2018, the Somatic Cell Genome Editing (SCGE) program is an initiative run through the NIH Common Fund aiming to create high-quality tools for safe and effective human genome editing. Earlier this year, Phase 2 of the program, which is co-chaired by NINDS and the National Center for Advancing Translational Sciences (NCATS) announced its first round of funded projects. The goal of Phase 2 is to accelerate the translation of genome editing therapies into the clinic, and will specifically focus on: developing technologies and assays for safety and efficacy studies; optimizing genome editing-based therapeutic leads to support advancement towards clinical trials; supporting novel genome editing clinical trials for more than one disease; and rostering collaboration and share new technologies and protocols with the public and research community.

Another aspect of this phase of the SCGE program is the TARGETED Challenge, which aims to improve the state of gene editing technology, ultimately providing: 1) a programmable delivery system for gene editing, and 2) the means to cross the blood brain barrier, which is a significant hurdle to overcome when it comes to efficiently editing genes within the central nervous system. Registration for the challenge opened in May, and the Phase 1 deadline for applications is October 5, 2023.

NINDS is also supporting those living with rare diseases through the Undiagnosed Diseases Network (UDN), a research program focused on gaining knowledge and finding answers to people and their families who have been unable to obtain a diagnosis. Beginning this year, NINDS will oversee the network in Phase III of the UDN, with help from 17 other NIH Institutes and Centers and the NIH Office of the Director. Although not directly linked to the development of gene editing therapies, the UDN could help us uncover new, rare diseases that could be targeted by such a therapeutic approach.

Finally, labs right here at NINDS are also working to bring gene therapy into the clinic to treat previously untreatable disorders. The Neuromuscular and Neurogenetic Disorders of Childhood Section within the NINDS Division of Intramural Research aims to leverage genome editing to address early-onset neuromuscular disorders that develop during childhood. The group is currently recruiting participants for clinical trial readiness studies looking at two groups of early-onset dystrophies: COL6-related and LAMA2-related.

Traditional drug-based approaches to therapies have served us well for a number of disorders, yet for many, promising treatments have remained elusive. With these NINDS- and NIH-supported clinical research efforts in the ever-evolving landscape of gene editing technologies, we have the opportunity to find new, more effective treatments for a variety of neurological conditions.