Gene Therapy for Autosomal Recessive Hereditary Spastic Paraplegia with Thin Corpus Callosum
Treatments for the two most common causes of a rare neurological disease
Autosomal recessive hereditary spastic paraplegia with thin corpus callosum (AS-HSP-TCC) is a common subtype of complex HSP. The two most prevalent AR-HSP-TCC types (70% total cases) are SPG11 and SPG15. They are virtually identical clinically; with distinctive features of early-onset parkinsonism, cognitive impairment, white matter changes, mild cerebellar ataxia, retinal abnormalities, and lens opacities. Prevalence of 1.25:100,000 for SPG11 and up to 1.15:100,000 for SPG15 has been estimated.
There are no disease-modifying treatments currently available for SPG11 or SPG15. Symptomatic management is available, like treating spasticity with medication, Botox or muscle‑lengthening surgery. Levodopa is indicated where Parkinson’s is apparent. Exercise and physiotherapy is very important to prevent difficult‑to‑reverse muscular atrophy.
The two main AS-HSP-TCC are caused by mutations in spatacsin/SPG11 and spastizin/ZFYVE26/SPG15. These proteins associate with the AP-5 protein complex and are important for AP-5 cellular trafficking function. More specifically, SPG11 and SPG15 are believed to contribute to autophagic lysosome reformation, which creates a pool of free lysosomes for autophagy, a mechanism for disposal of cellular waste.
Researchers at The University of Sheffield are developing gene therapy approaches to replace faulty SPG11 and SPG15 genes. Because SPG11 and SPG15 protein are above the normal size limit for cargo for our favoured gene therapy vector, AAV9, we have generated a number of reduced-size minigene constructs and also a dual AAV vector approach. They predict that at least one of these constructs will retain the main functions of the full length protein and correct lysosomal abnormalities.
There are no disease‑modifying treatments for AS-HSP-TCC. The newly developed treatments promise to stop disease progression with only one dose.
AS-HSP-TCC is an orphan disease with a limited market. Researchers are working with patient charities including Cure Maddie Foundation, to try and begin a clinical trial of the AS-HSP-TCC gene therapy.
The team is seeking collaborators and funding to continue the development of the AS-HSP-TCC gene therapy programme.
- Know-how based
- Development partner
- Commercial partner
- Seeking investment