The University of Sheffield

<p><strong>Overview:</strong></p>
<p>The University of Sheffield is a world top-100 university renowned for the excellence, impact and distinctiveness of its research-led learning and teaching. The University’s outstanding performance for excellent teaching and research, as part of a genuinely global community, is consistently confirmed by international independent assessments.</p>
<p>The university takes its public and social responsibility seriously. It is committed to making the world a better place. This approach is embedded in everything they do, from partnerships with local and global organisations to their research and teaching.</p>
<p><strong>Research:</strong></p>
<p>The University of Sheffield has a global reputation for world-leading research that makes a difference. It influences policy, changes lives and helps in understanding the world so that we can make it better. The university has over 180 research institutes, centres and groups. They address challenges from finding a cure for motor neurone disease to building a sustainable economic recovery. The research institutes and centres at the university have been created to address global challenges facing society, today and in the future. They are often interdisciplinary, with external collaboration and funding, and have earned international recognition.</p>
<p>The world-class research being undertaken at the University of Sheffield generates a wealth of new knowledge, much of which has the potential for licensing to innovative organisations seeking to augment their current activities or diversify their operations.</p>
<p><strong>Industry Partnerships:</strong></p>
<p>The University of Sheffield is collaborating with partners in the private, public and third sectors to find real-world solutions to real-world problems.</p>
<p>The university partners with organisations large and small, believing that by working together, we can find novel solutions to real-world problems. In their experience, it leads to world-class research and commercial success to businesses around the world. Together, The University of Sheffield shares knowledge, facilities and industry insight to help influence cultural, social, economic and political change.</p>


<h1 id="background">Background</h1>
<p>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.</p>
<p>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.</p>
<h1 id="technology-overview">Technology Overview</h1>
<p>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.</p>
<h1 id="benefits">Benefits</h1>
<p>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.</p>
<h1 id="applications">Applications</h1>
<p>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.</p>
<h1 id="opportunity">Opportunity</h1>
<p>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. </p>
<p>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.</p>
