ASOs are short chains of chemically modified nucleotides that curtail the synthesis of new toxic protein by targeting the relevant mRNA. The unknown mechanism of SPG4 can present a challenge for effective ASO studies.

In May 2024, The Lilly and Blair Foundation funded a new mouse model where - for the first time - the mouse SPAST gene will be fully replaced with human SPAST genes (including introns and exons) necessary to mimic the disease mechanisms. This model will help researchers develop and test therapies more effectively, as treatments like antisense oligonucleotides can be tested in this mouse to see how they might work in humans.

Peter Baas, PhD, Professor; Director, Graduate Program in Neuroscience, Department of Neurobiology and Anatomy, Drexel University College of Medicine

Recent research on SPG4 found that a buildup of toxic protein (mutant spastin) reduces important cell structures’ stability, leading to nerve cell damage. A key enzyme, HDAC6, is overly active in this condition, worsening the problem. Blocking HDAC6 with a a drug called Tubastatin A (Tub A) improved movement and prevented nerve damage in mice with SPG4. Similarly, lab-grown human nerve cells with SPG4 mutations showed severe damage, but Tub A treatment helped protect these cells. These findings suggest that Tub A could be a promising treatment for SPG4 and similar nerve disorders.

Liang Oscar Qiang, MD, PhD, Associate Professor, Department of Neurobiology and Anatomy, Drexel University College of Medicine

This ongoing study aims to gather clinical data and blood/saliva samples from patients who exhibited onset of symptom age 18 years old or younger. The objectives are to document the clinical presentation and natural history of early onset forms of SPG4 and to facilitate an early diagnosis, enable counseling and anticipatory guidance of affected families and help define clinically meaningful endpoints for future interventions.

Darius Ebrahimi-Fakhari, MD, PhD, Director, Movement Disorders Program, Boston Children’s Hospital; Assistant Professor of Neurology, Havard Medical School

These drugs have a low molecular weight and can easily penetrate cell membranes, making them effective for diseases within cells. Current studies are showing promise for treatment of upper motor neuron diseases through use of small molecule compounds.

In July 2023, the compound AKV9 was approved by the FDA for Phase 1 studies of it’s safety and tolerability. At this time, the drug’s primary purpose is treatment of the upper motor neuron disease ALS, but there is potential applicability to spastic paraplegia and our team is following this research closely.

Hande Ozdinler, PhD, Associate Professor, Neurology (Neuromuscular Disease), Northwestern University