What is Spastic Paraplegia?

Hereditary Spastic Paraplegia (HSP) SPG4 is a neurodegenerative disease caused by a mutation in the SPAST gene. The disease is characterized by progressive muscle stiffness in the legs and potential paralysis. ‘De' novo’ refers to a random genetic mutation that is not inherited, despite this traditionally being an inherited disease. Lilly and Blair’s specific mutation (SPAST c.1496G>A, p.Arg499His) has been identified in only 16 individuals and is associated with a nano-rare, early-onset and complex diagnosis. This means that in addition to potential leg paralysis, their upper limbs, speech and cognitive abilities can be drastically and progressively compromised in the first decade of life.

Paths to a Treatment or Cure

  • Gene Therapy

    Gene therapy replaces a disease-causing or mutated gene with a new, heathy copy of the gene. Studies of AAV9 vectors have shown promise for all of SPG4, regardless of the specific mutation, by knocking out and replacing the SPAST gene.

    Timeline: 3-5 years
    Cost: $3,000,000

  • Small Molecule Drugs

    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.

    Timeline: 5 years
    Cost: +$1,000,000

  • Antisense Oligonucleotides (ASOs)

    Antisense Oligonucleotides (ASOs)

    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 this disease can present a challenge for effective ASO studies.

    Timeline: 3 years
    Cost: Unknown

Ongoing
Research

  • Overview: This research is focused on studying the etiology of SPG4 and preclinically testing therapies for treatment using novel transgenic mouse models and isogenic human pluripotent stem cell (hiSPC) derived forebrain organoids enriched with upper motor neuronal phenotypes.

    Status: Current goals are to probe mechanisms for haploinsufficiency and gain-of-toxicity of SPG4, elucidate impaired autophagy as one of the major contributors to SPG4, and to investigate neurological interaction in SPG4 via single-cell RNA sequencing and proteomics. Upcoming work will include exploring the pathological modifiers for the early onset de novo cases of SPG4.

    Liang Oscar Qiang, MD, PhD, Drexel University

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

    Status: This study is ongoing.

    Darius Ebrahimi-Fakhari, MD, PhD, Boston Children's Hospital

Together We Can

Time is not on our side, but we hope you will be.