Breakthrough on Gene Therapy for Hereditary Spastic Paraplegia

There is no cure for the rare disease Hereditary Spastic Paraplegia (HSP), but researchers from Drexel University’s College of Medicine and the UMass Chan Medical School have achieved proof-of-principle success with “silence and replace” gene therapy — an approach that uses a viral vector to silence genes with disease-causing mutations and replace them with healthy genes — to prevent and even reverse disease progression. In this case, the team, led by Drexel College of Medicine Professor Peter Baas, PhD and Research Instructor Emanuela Piermarini, PhD, who was chief scientist on the project, were able to prevent nerve breakdown and symptoms of HSP in a mouse model of the disease. Their findings were recently published in the journal Molecular Therapy.

HSP can be caused by mutations in any of more than 90 different genes, each with a numbered name, such as SPG1, SPG2 and so on. The team studied SPG4, the most common form of HSP, making up about 40% of cases and caused by mutations in the SPAST gene. Patients are generally categorized as having uncomplicated HSP –– the majority of cases –– categorized by gait defects, such as muscle stiffness and weakness in leg muscles or complicated HSP, which, in addition to muscle weakness and stiffness, may also include symptoms impacting upper limb mobility, speech or intellectual abilities and/or bladder control, among other symptoms.

The number of people living with the disease is uncertain due to misdiagnoses, as HSP shares symptoms with other neurological conditions. There is an estimated between 1 and 5 cases of HSP among every 100,000 individuals worldwide.

Like with many other conditions, families and advocacy groups are among the strongest catalysts for research. Patient advocacy groups connected the team at Baas’ lab at Drexel’s College of Medicine, who have studied the mechanistic basis of SPG4 for many years, with experts on gene therapy from UMass Chan Medical School, led by co-senior author Miguel Sena-Esteves, PhD.

“Our two teams were introduced by parents of children with SPG4 who created foundations seeking therapies or cures for their children,” said Baas, who was co-senior author on the research. “Our team at Drexel University joined forces with Dr. Esteves and his team, who generated the gene therapy vector, which includes both micro-RNA, which turns off the expression of the mutated SPAST genes, and cDNA to replace them with expression of normal human SPAST gene, called spastin.”

Patients can experience significant differences in symptoms, which vary by severity and typically worsen over time. Without a cure, the main options are going to clinicians and physical therapists for help in managing fatigue, spasticity and other effects of the disease. Onset of the disease varies significantly; some patients first experience symptoms as late as their senior years while others first experience symptoms as children. 

“The protein encoded by the SPAST gene is a microtubule-severing protein that is vital for healthy function of nerve cells,” added Baas. “When SPAST mutations occur, and more than 200 different mutations have been identified, certain nerve cells are unable to maintain long axons — which comprise the long tracts that act as connections between the brain, spinal cord and legs—leading to this disease.”

Baas’ team previously developed a mouse model for this disease by introducing the human mutant SPAST gene into mice. The mice developed a gait defect similar to those experienced by human patients.

Through the silence-and-replace strategy, the team swapped the mutant SPAST gene with a healthy human SPAST gene. The researchers introduced the vector in a newborn mouse before it experienced symptoms as a “proof-of-principal” that the technology can work by shutting down the faulty gene and replacing expression with a healthy gene. Then those mice grew up without any gait defects or degenerative symptoms.

“While most patients suffering from SPG4 inherit the mutated gene from a parent, mutations in the SPAST gene can also arise for unknown reasons,” said Piermarini. “In these cases, families don’t know why their kids are having these symptoms, and the symptoms tend to be more severe and start earlier in life.”

Translating this discovery into humans presents new challenges for the research.

“As spastin is a microtubule-severing protein, too much expression would destroy the microtubules and kills the cells,” said Baas. “The variant of spastin that becomes disease-causing when mutated also becomes long-lived and can accumulate in the nerve tracts. Turning off expression from the mutant gene will not necessarily lead to the degradation of the existing protein, so it’s complicated. The spinal and other tracts that potentially degenerate will not necessarily regenerate just because the silence and replace components of the vector are successful in what they can do. This is where a deep understanding of the disease is so important for advancing the work into treatment for patients.”

In addition to gene therapy, Piermarini is also working on blood biomarkers to monitor progression of the disease and assess when to best start the therapy and evaluate how well it’s performing. She also noted that the team is working on another therapy aimed at degrading the mutant protein that has already accumulated in the nerve tracts.

Baas and Piermarini hope to move the gene therapy into symptomatic mice, which is a greater challenge because many axons have already lost their connections. After calibrating just how much good the therapy can do at various stages of disease progression, other therapies can then be added, in combination, to restore what the gene therapy cannot do on its own. For example, they hope that adding in exercise therapy, neurotrophins, and/or neurostimulation will help sprout healthy nerves to restore lost function in areas like speech and movement.

“The success we’re seeing with gene therapy is exciting but will take more work to optimize for human patients,” said Baas. “It’s important that we continue developing this and other therapies, so we get help for patients as soon as possible.”

In addition to Baas, Piermarini and Sena-Esteves, additional authors include Shrobona Guha, PhD, and Liang Qiang, MD, PhD, from Drexel’s College of Medicine, and Heather Gray-Edwards, DVM, PhD, from the UMass Chan Medical School.

The work was supported by the Spastic Paraplegia Foundation, the NIH National Institute of Neurological Disorders and Stroke, the Cure SPG4 Foundation, the Lilly and Blair Foundation, SPG4 Cure for Jack Laidlaw and the Maurya Koduri Foundation.

The paper, “Intracerebroventricular SPAST-AAV9 Gene Therapy Prevents the Manifestation of Symptoms in a Mouse Model of SPG4 Hereditary Spastic Paraplegia,” is available here.