SiTraN (funded by The Maddi Foundation)

The Maddi Foundation and Save Our Maddi are engaged with Professor Mimoun Azzouz previously Head of Neurobiology at Oxford Biomedica and one of the leading experts in the UK in the use of gene therapy for neurodegenerative diseases. He leads an extensive programme at the Sheffield Institute for Translational Neuroscience (SITraN) aiming to replace or silence faulty genes in forms of neurodegenerative diseases which are caused by a known gene mutation. University Of Sheffield (SiTran) to develop a gene therapy Proof Of Concept. Gene therapy technology is currently generating great optimism among patients and their families. However, to develop gene-based therapy for SPG15, further extensive studies are needed to refine our strategy before entering clinical application.

Funds are needed to achieve the following aims:

1) Prepare the therapeutic virus for testing in cells and model systems in the lab to generate a proof-of-concept, a critical step before initiating further pre-clinical work;

2) Prepare the therapeutic virus carrier at the quality acceptable for clinical use in humans;

3) Determine the minimal dose of the carrier that generates efficacy in our animal model;

4) Assess potential adverse effects in a regulatory safety study.

5) Secure the licensing needed to initiate human clinical trials.

Cambridge Institute for Medical Research

Dr Jennifer Hirst: I am a researcher at the Cambridge Institute for Medical Research in the laboratory of Professor Margaret Robinson. My field of speciality is ‘cell biology’, with an aim to understand how cells work, and then we can try to understand what happens in disease when cells fail to work.

My focus is understanding the protein machineries that is used by cells to sort cargo proteins for transport to one of a number of destinations. One of these sorting machineries is called AP-5 and involves six proteins working together in a complex – these proteins are the products of the genes SPG15, SPG11, AP5Z1, AP5B1, AP5M1 and AP5S1. My aim is to further understand why faulty versions of SPG11, SPG15 or AP5Z1 have damaging effects on the survival of nerve cells and lead to the rare neurodegenerative disorder hereditary spastic paraplegia. Since we cannot look inside patient’s nerve cells, we look at cells taken from a small skin punch that we can maintain in the laboratory. Using high powered microscopes we see that the ‘recycling plant’ compartment of the cell – known as the lysosome – accumulates material that it is seemingly unable to digest. We believe that it is this build-up of undigested material that is likely to be ‘damaging’ to the health of nerve cells. However, we still do not have a clear picture of the precise roles of AP-5 and SPG11 and SPG15.

We have recently discovered some clues that point to their role in sorting proteins away from the pathway that leads to the lysosome, which we believe would abrogate the damaging accumulation of material in lysosomes. However, we still have a long way to go to understanding the precise function or functions of AP-5, SPG11 and SPG15.