Background

Mutations in the AP4B1, AP4E1, AP4M1 and AP4S1 subunits of the AP‑4 adaptor complex cause the AP‑4 associated hereditary spastic paraplegias (AP‑4 HSP) which are named SPG47, SPG50, SPG51 and SPG52, respectively. These diseases become apparent in infancy by causing symptoms of progressive loss of muscle tone, which then progresses to spasticity and loss of lower limb function accompanied by a developmental delay, intellectual disability and epilepsy. Thinning of the corpus callosum is a feature of the diseases. The rate of diagnosis of AP‑4 HSP is thought to be low because of the current lack of awareness of disease. Misdiagnosis as cerebral palsy appears to be an issue. A conservative estimate of prevalence is 3339 children worldwide [Broad Translational Genomics Group, December 13th, 2019]. There are currently no disease‑modifying treatments.

The University of Sheffield is collaborating with leading AP‑4 HSP charity, Cure AP‑4 Inc. to develop gene therapy for the diseases. In parallel, Boston Children’s Hospital is assembling a registry of AP‑4 HSP patients and has conducted a detailed cross-sectional analysis of 156 subjects with AP-4-HSP to inform the natural history of AP‑4 HSP.

Technology Overview

AP4‑HSP is caused by mutations in the AP4 genes, leading to a significant decrease in protein levels of the AP‑4 subunits and a decrease in the normal cellular cargo‑trafficking function of the AP‑4 complex. Gene therapy aimed at restoring AP4 subunit protein expression represents a rational therapeutic approach for AP4‑HSP. The researchers chose first to focus on SPG47. They made an AAV9‑AP4B1 viral vector and tested it for recovery of AP‑4 function in AP4B1 loss‑of‑function cell lines and an AP4B1 loss‑of‑function mouse model. They also have data supporting the safety of the viral vector in mice.

Benefits

There are no disease‑modifying treatments for AP‑4 HSP. The therapeutic approach addresses the cause of the disease and promises to be a single‑dose treatment for the lifetime of the patient. So far, the researchers have demonstrated the validity of their approach by successfully replacing AP4B1 in models of SPG47.

Applications

Treatment of AP‑4 HSP is aim of this programme. The research team are working with patient charities to find as many children as possible who may benefit from the therapies.

Opportunity

The University of Sheffield, together with Cure AP‑4 and Boston Children’s Hospital are planning for a clinical trial of AP‑4 HSP gene therapy. The team has done a pre‑IND meeting with the FDA related to the AAV9‑AP4B1 gene therapy for SPG47 and the key remaining IND‑enabling preclinical experiments are now being planned and conducted. IND for SPG50, SPG51 and SPG52 seems likely to be very similar to SPG47 because of the shared characteristics of the diseases. This project has secured orphan drug designation and rare paediatric disease designation for AAV9‑AP4B1 from the FDA.

The team are seeking collaborative development partners and financial backing to help complete the IND‑enabling package and the clinical trial for AP4B1‑SPG47, as well as to develop therapies for SPG50. SPG51 and SPG52. The researchers believe AP‑4 HSP is underdiagnosed, but acknowledge the market is small nonetheless. The University is flexible in terms of partnering because it is recognised this is not a classic commercial opportunity.

Gene Therapy for AP-4-associated Hereditary Spastic Paraplegia

Patents

IP Status

Seeking