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Genetic Manipulation for Inherited Neurodegenerative Diseases: Myth Or Reality? Patrick Yu-Wai-Man1,2,3

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Genetic Manipulation for Inherited Neurodegenerative Diseases: Myth Or Reality? Patrick Yu-Wai-Man1,2,3 BJO Online First, published on August 1, 2016 as 10.1136/bjophthalmol-2015-308329 Review Br J Ophthalmol: first published as 10.1136/bjophthalmol-2015-308329 on 21 March 2016. Downloaded from Genetic manipulation for inherited neurodegenerative diseases: myth or reality? Patrick Yu-Wai-Man1,2,3 1Wellcome Trust Centre for ABSTRACT genetic manipulation seems an obvious solution as Mitochondrial Research, Rare genetic diseases affect about 7% of the general a radical means of correcting the primary patho- Institute of Genetic Medicine, Newcastle University, population and over 7000 distinct clinical syndromes logical process that contributes to neuronal dys- Newcastle upon Tyne, UK have been described with the majority being due to function and disease progression. 2Newcastle Eye Centre, Royal single gene defects. This review will provide a critical Victoria Infirmary, Newcastle overview of genetic strategies that are being pioneered upon Tyne, UK GENE THERAPY PARADIGMS 3 to halt or reverse disease progression in inherited ‘ NIHR Biomedical Research fi Gene therapy is a priori perfectly suited for single Centre at Moorfields Eye neurodegenerative diseases. This eld of research covers gene’ neurological disorders, but some additional Hospital and UCL Institute of a vast area and only the most promising treatment criteria need to be fulfilled, namely: (1) there must Ophthalmology, London, UK paradigms will be discussed with a particular focus on be a relatively clear understanding of the pathways inherited eye diseases, which have paved the way for Correspondence to contributing to neuronal loss to ensure selection of Dr Patrick Yu-Wai-Man, innovative gene therapy paradigms, and mitochondrial the most appropriate therapeutic strategy; (2) the Wellcome Trust Centre for diseases, which are currently generating a lot of debate natural history of the disease must be clearly Mitochondrial Research, centred on the bioethics of germline manipulation. defined and it must afford practical windows of Institute of Genetic Medicine, Newcastle University, opportunity for intervention; (3) the tissue or Newcastle upon Tyne NE1 organ system to be targeted must be relatively 3BZ, UK; Patrick.Yu-Wai- INTRODUCTION accessible; and (4) the specific cells in question [email protected] The genetic revolution of the past 25 years has must be amenable to efficient transfection with a transformed our understanding of the genetic basis suitably designed gene vector.56 Received 4 January 2016 of human neurodegenerative diseases.1 The causa- Revised 18 February 2016 Genetic diseases caused by recessive null muta- Accepted 28 February 2016 tive genes for a large number of well-recognised tions represent the most straightforward group as fi clinical entities have been identi ed, and the pace the replacement of the missing wild-type protein of discovery will only accelerate further as next- should prove effective in rescuing the disease pheno- generation whole-genome sequencing becomes rou- type.7 Gene therapy for autosomal-dominant disor- tinely available to clinicians. In addition to classical ders can be more challenging if the mechanism is monogenic diseases with high penetrance, it is now not due to haploinsufficiency, but secondary to a clear that the majority of common late-onset neuro- gain-of-function mutant allele that produces an degenerative disorders are heavily determined by a aberrant protein with dominant negative proper- complex cluster of genetic variants, each contribut- ties.8 The mutant protein can either interfere with ing to the overall risk of developing overt clinical the wild-type protein to block its normal function http://bjo.bmj.com/ disease, and in some cases having a synergistic dele- or it can have a direct toxic effect on specific cellular 23 terious interaction with environmental triggers. processes. In this scenario, simply increasing the fi Unfortunately, the signi cant advances made in production of the wild-type protein with a gene deciphering the genetic factors that contribute to therapy replacement approach might not be able to the underlying neuropathological process have so reverse the negative effect of a dominant fi far resulted in limited therapeutic bene ts for gain-of-function mutation. Despite these challenges, patients. A number of factors have contributed to Alfred Lewin and colleagues have shown in a mouse on September 23, 2021 by guest. Protected copyright. this frustrating translational gap and the challenges model of autosomal-dominant retinitis pigmentosa that remain are daunting. carrying the P23H RHO mutation that increasing the production of normal rhodopsin can suppress THE BURDEN OF DISEASE the effect of the mutated misfolded protein and The prevalence of monogenic neurological diseases prevent photoreceptor degeneration.9 However, if has been estimated at 1 in 1100 in a recent epi- increasing the level of the wild-type protein fails to demiological study, but when late-onset neurode- rescue the pathological phenotype for an autosomal- generative disorders, such as Alzheimer disease and dominant disorder, the most logical strategy is to Parkinson disease, are included, this figure increases block the expression of the mutant messenger RNA to 1 in 400 of the general population.4 This group transcript and supplement the cell with a wild-type of disorders is an important cause of chronic mor- copy of the gene if required.10 This suppression and bidity and personal suffering, and it further magni- replacement approach is technically more complex fies the socioeconomic impact of an ageing as it requires a delicate balance of gene expression population by exerting additional stress on already to be achieved. The main experimental paradigms To cite: Yu-Wai-Man P. Br J stretched national health services. Treatment for gene silencing are based on the use of antisense Ophthalmol Published remains largely supportive and so far, conventional oligonucleotides, ribozymes or RNA interfer- Online First: [please include – Day Month Year] pharmacological approaches aimed at neuroprotec- ence.11 14 doi:10.1136/bjophthalmol- tion have failed to deliver effective disease- If the causative gene for a rare monogenic 2015-308329 modifying drugs. To palliate for these inadequacies, disease has not been identified or the mode of Yu-Wai-Man P. Br J Ophthalmol 2016;0:1–10. doi:10.1136/bjophthalmol-2015-308329 1 Copyright Article author (or their employer) 2016. Produced by BMJ Publishing Group Ltd under licence. Review Br J Ophthalmol: first published as 10.1136/bjophthalmol-2015-308329 on 21 March 2016. Downloaded from inheritance is complex as in late-onset neurodegenerative dis- of an appropriate promoter sequence that can efficiently drive eases, gene therapy can still be contemplated as a treatment the expression of the transgene within the target cell. strategy.15 The approach in these situations involve transfecting Depending on the therapeutic aims, the viral vector can be the cell with gene constructs that upregulate the expression of tailor-made with additional promoter elements that titrates the trophic factors, which in turn serve to rescue neuronal cells level of gene expression or even limits its action to specific cell from impending death or at least prolong their survival. These types. blanket neuroprotective strategies could also be used to supple- ment more targeted gene therapy in monogenic diseases and RETINAL NEURODEGENERATIVE DISEASES conceptually, these could provide a synergistic beneficial effect. The eye represents a target organ of choice for gene therapy as A completely novel approach for neurodegenerative diseases is it is easily accessible and rather advantageously, it is an immuno- optogenetics, which involves the introduction of light-sensitive logically protected space.5 It is therefore hardly surprising that protein sensors into neurones making them functionally photo- inherited retinal diseases have led the way both in terms of pio- sensitive.16 17 Ion channel proteins of the channelrhodopsin, neering the clinical application of gene therapy and the refine- halorhodopsin and archaerhodopsins families are able to confer ment of the protocols for achieving efficient gene delivery in these unique properties by modulating neuronal membrane vivo. Advances in minimally invasive intraocular surgery have potential and the balance between depolarised and hyperpo- also made it possible for ophthalmic surgeons to safely access larised states. Optogenetics is being used to convert non- various retinal layers providing a direct route for the delivery of photosensitive retinal cells into artificial photoreceptors, and the gene therapy vector. We will now review some key examples also to deliberately switch on and off specific central nervous of neurodegenerative disease affecting the retinal pigment epi- system pathways in an attempt to circumvent the damaged cir- thelium (RPE), photoreceptors, and retinal ganglion cells cuitry in anatomically diseased areas.16 17 (RGCs) to illustrate some of the groundbreaking innovations that have been achieved to establish gene therapy as a viable GENE DELIVERY SYSTEMS treatment option for a broad range of ocular disorders. The success of gene therapy is contingent upon an effective delivery system and various vectors have been developed to Correcting gene expression deliver the genetic construct, which is more commonly DNA, Leber congenital amaurosis (LCA) is a severe form of inherited but sometimes RNA.18 The use of non-viral vectors has obvious blindness that affects at least 1 in 50
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