Are Rare Brain Diseases the Next Commercial Frontier for Gene Therapy?

Research into gene therapies began more than 40 years ago, but the first FDA approval in 2017 ignited a fresh wave of interest from investors and drug companies who see the technology’s transformative, even curative potential.

Approximately 80 percent of rare diseases are caused by mutations in a single gene, and these monogenic disorders can be excellent candidates for gene therapies. These mutations can produce devastating symptoms that limit individuals’ ability to achieve independence, pursue an education, start a family, and participate in the economy and the normal activities of everyday living.

As biomedical science continues to advance next-generation treatment paradigms, more companies are engaging their R&D teams and healthcare stakeholders to deliver on the promise of one-time and limited-dose gene therapies that could offer lifetime benefits. For many rare disease patients, gene therapy has become synonymous with hope.

Zeroing in on neurological disorders

The biggest trend in gene therapy development is the potential of several treatments for rare neurological diseases to move from the bench to the bedside.

To date, four gene therapies have been approved for rare monogenic neurological diseases: spinal muscular atrophy; metachromatic leukodystrophy; cerebral adrenoleukodystrophy; and Duchenne muscular dystrophy.

The current biopharmaceutical pipeline for central nervous system conditions includes several promising gene therapies targeting monogenic disorders of the brain. Most are caused by enzyme deficiencies, which have historically been treated with enzyme replacement therapy. However, benefits are often limited by the short half-life of the recombinant enzyme, the production of anti-drug antibodies, and the inability of the enzyme to cross the blood-brain barrier.

Several gene therapies are in development for monogenic lysosomal storage diseases, characterized by an abnormal build-up of various toxic materials in the body’s cells as a result of enzyme deficiencies. Gene therapies in development could provide a much longer therapeutic duration – either by repairing the mutated gene or replacing it with functional copies.

For example, Tay-Sachs disease (TSD) is caused by a defective gene on chromosome 15. In an open-label Phase 1/2 trial of an intrathecal adeno-associated virus (AAV), a gene therapy showed an increase in cerebrospinal fluid HexA activity in these patients, indicating early safety and proof-of-concept in people with TSD.

Three gene therapy candidates are under investigation to treat Gaucher disease, another lysosomal storage disorder. Gaucher disease is caused by mutations in the GBA gene, leading to low or absent levels of the enzyme beta-glucocerebrosidase. One study is delivering a modified AAV vector directly into the liver to increase beta-glucocerebrosidase production. Another uses a lentivirus-based approach that modifies patient blood stem cells to deliver healthy copies of the defective gene. The third uses a modified AAV vector containing a healthy copy of the GBA gene to prevent neurodegeneration.

Fabry disease is a lysosomal storage disorder that occurs when the enzyme alpha-galactosidase-A cannot efficiently break down lipids into smaller components that provide energy to the body. Currently approved treatments for Fabry disease include enzyme therapy and an oral pharmacologic chaperone, however, investigational gene therapies targeting AAV and lentiviral ex vivo transduction could reduce the number of recurring treatments needed by providing a one-time treatment option.

With many neurological diseases being monogenic disorders, there is huge potential for gene therapy in this space by targeting a variety of mechanisms, including AAV, lentiviral vector, and more – and with the volume of studies in these disorders, the life sciences industry and researchers clearly recognize the potential in the space.

What about gene therapy for common brain disorders?

While clinical development is accelerating for rare monogenic neurological diseases, patients affected by more common central nervous conditions do not have obvious causative gene mutations.

Conditions such as Alzheimer’s disease, Parkinson’s disease, and epilepsy are more heterogeneous. For these disorders, gene therapies may be designed to address mechanisms of disease, rather than to deliver healthy copies of a mutated gene. For example, gene therapies in development for Parkinson’s disease focus on delivering dopamine or dopamine-synthesizing enzymes. Several in development for focal epilepsies aim to reverse increases in network excitability that drive seizures rather than attempting to correct a single genetic cause.

The expansion of gene therapy into more prevalent neurological disorders continues to be hampered by challenges in crossing the blood-brain barrier. Scientists are still working on ways to safely and effectively introduce genes into the brain to target specific cells. New viral vector technologies and delivery routes are being developed to address these obstacles.

Due to the sheer diversity of approaches being taken to treat and functionally cure neurological disorders, gene therapy development often requires a unique approach and a team that can execute in uncharted territory. Companies must navigate the challenges of enrolling trials, be able to manufacture and transport the therapy – perhaps using novel devices or surgery to deliver the treatment, develop and validate safety and efficacy assays, and possibly implement specialty biomarker assays for early proof of principle. It takes a village, and we know the patient is waiting!

Photo: Yuichiro ChinoImage, Getty Images

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