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Neurodegenerative Disorders

Overview

Huntington Disease in southern Africa

Project Leader: Prof. Jacquie Greenberg

PhD Student: Ms. Fiona Baine

In collaboration with:  Prof. Michael Hayden  (UBC Vancouver, Honorary Professor UCT); Prof. Amanda Krause (Wits); Prof. Jeannine Heckmann (GSH/UCT), Dr Lawrence Tucker (GSH/UCT)

Spinocerebellar ataxia

Project Leader: Prof. Jacquie Greenberg

Post Doc: Dr. Lauren Watson & Dr. Danielle Smith

In collaboration with: Prof. Matthew Wood (Oxford UK, Honorary Professor UCT); Prof. Marco Weinberg (Wits); Prof. Susan Kidson (UCT/Human Biology: the iPSC research facility); Dr Robea Ballo (UCT/Human Biology: the iPSC research facility); Prof. Alan Bryer (GSH/UCT).

In consultation with: Dr Janine Scholefield (CSIR).

NHLS Molecular Genetic Diagnostic Laboratory (R&D)

Project Leader: Prof. Jacquie Greenberg

Head of the NHLS Molecular Laboratory: Mrs. Alina Esterhuizen

For many years this department has been investigating the genetic basis of Huntington Disease (HD) and the inherited Ataxias (Spinocerebellar Ataxia & Friedreich Ataxia). The discovery of the gene for HD, and for some forms of Spinocerebellar ataxia has led to an internationally acceptable counselling and testing protocol for these late-onset genetic disorders, established  jointly between the departments of Human Genetics and Neurology at UCT and Groote Schuur hospital.

With regard to Huntington disease (HD) research, we are currently involved with a large national and international collaboration investigating haplotypes associated with HD in South African populations. It is hoped that this will lead to the development of population-specific therapies currently being investigated for HD patients in other parts of the world. In addition, we are investigating the genetic basis of CAG-tract instability in identified population-specific haplotypes, and in families and patients affected by the juvenile form of HD. In terms of the inherited ataxias, we are investigating the molecular pathogenesis of Spinocerebellar Ataxia type 7 (SCA7)  through the generation of SCA7 patient-derived disease-relevant cell types (neuronal cells, RPE and photoreceptors differentiated from induced pluripotent stem cells [iPSCs]), with a view to developing therapies, in particular, a locally developed RNA interference-based therapy for SCA7.  In order to target the disease-causing gene, we are investigating the efficiency of sequence specific small RNAs to directly target the mutant allele of SCA7 using a linked single nucleotide polymorphism (SNP).

The long term research plan has significant therapeutic potential not just for SCA7, in the first instance, but as proof-of-concept for RNAi therapies for neurodegenerative disease in general and for polyQ disorders in particular. This is due not only to our preliminary data from 2008 using  RNAi but also because SCA7 has a retinal phenotype in addition to the neurological phenotype, which would allow initial clinical trials to be initiated by targeting the eye to deliver the gene-based therapy.