Professor Gustavo Aguirre discusses the context of his research studies at the University of Pennsylvania, which are currently concentrating on the degenerative disease, retinitis pigmentosa

Aguirre, Gustavo D

English

Kosmopolis

University of Pennsylvania
ScholarlyCommons
Departmental Papers (Vet) School of Veterinary Medicine
10-2010
Window Into Retinal Studies
Gustavo D. Aguirre
University of Pennsylvania, gda@vet.upenn.edu
Follow this and additional works at: https://repository.upenn.edu/vet_papers
Part of the Veterinary Medicine Commons
This paper is posted at ScholarlyCommons. https://repository.upenn.edu/vet_papers/79
For more information, please contact repository@pobox.upenn.edu.
Recommended Citation
Aguirre, G. D. (2010). Window Into Retinal Studies. Healthcare, 108-110. Retrieved from https://repository.upenn.edu/vet_papers/
79
Window Into Retinal Studies
Abstract
Professor Gustavo Aguirre discusses the context of his research studies at the University of Pennsylvania,
which are currently concentrating on the degenerative disease, retinitis pigmentosa.
Keywords
blindness, dogs, animals, Retinitis Pigmentosa GTPase Regulator, X-linked RP
Disciplines
Medicine and Health Sciences | Veterinary Medicine
This other is available at ScholarlyCommons: https://repository.upenn.edu/vet_papers/79
 | June 2010: Healthcare |  
A world leader in 
healthcare 
research
PROFESSOR HARRIET 
WALLBERG-HENRIKSSON
President, Karolinska Institutet
Disseminating science, research and technology
 | Healthcare: October 2010 |  
RESEARCH SPOTLIGHT
Japan Science and Technology Agency • Chief Scientifi c Advisor to the Government of Ireland • Luxinnnovation 
EC-US Task Force on Biotechnology Research • Research and Development Council of the Czech Republic 
The European Association for Cancer Research • National Health and Medical Council, Australia
SPECIAL FOCUS: 
ORAL AND DENTAL SCIENCES
We feature a variety of researchers 
and organisations spearheading the 
dental science movement
Professor Gustavo Aguirre discusses the context of his research studies at the University of 
Pennsylvania, which are currently concentrating on the degenerative disease, retinitis pigmentosa
Firstly, can you outline the broader aims and 
objectives of your research?
There are many inherited diseases that have 
been found to affect the retina and cause 
blindness. Beyond fi nding the disease-causing 
mutations, the aim of the research is to 
understand how these diseases develop, and 
then investigate the pathways that link the 
mutation to the death of the visual cells, and 
determine if these are specifi c or common to one 
or more diseases. From this, we seek to develop 
intelligent therapies that can be used in treating 
the retinal diseases. Most of our work uses dog 
models; in the past we have used cats, monkeys 
and humans, but the work we do to develop 
translational studies primarily involves dogs.
Can you provide an overview of the discovery of 
X-linked retinitis pigmentosa (XLRP) diseases?
There are several retinal diseases in humans that 
are known to have X-linked inheritance. There are 
only two where the gene has been found: RP-3 
and RP-2. The pioneering work on the mapping of 
these diseases was done in the UK by Professors 
Alan Wright (University of Edinburgh) and Shomi 
Bhattacharya (Institute of Opthalmology) 
beginning in the 1980s. It took a long time to 
refi ne the disease intervals, and many groups 
were working on this diffi cult area. Eventually, the 
Wright and Meitinger groups published a seminal 
paper identifying a very complex gene called 
RPGR (Retinitis Pigmentosa GTPase Regulator). 
They also found part of the gene which had 
previously been very diffi cult to sequence. This 
DNA region – ORF-15 – accounted for about 70 
per cent of mutations in patients with RPGR. After 
this fi nding, my team collaborated intensely with 
Wright and found that dogs had the mutation in 
the same ORF15 region as patients. When you 
take most populations of patients with X-linked 
RP, up to 70 or 80 per cent have mutations in 
RPGR. Thus it is recognised as the most common 
cause of X-linked RP. It is a very severe problem, 
not least because the regions in questions are very 
diffi cult to clone and sequence.
The fi rst gene therapy clinical trials in human 
patients affected with a severe form of 
childhood blindness were reported 2008. Can 
you highlight the developments which have 
been made in this regard, and any further 
challenges clinical trials have thrown up?
The Phase 1 studies in human patients have 
confi rmed that treatment of the study population 
is safe which is the primary goal of any Phase 1 
clinical trial. In addition, the studies have shown 
effi cacy in some patients. What we now need 
is to determine the patient population that is 
amenable to treatment, and the long-term safety 
and effi cacy in treated patients. 
In the studies with LCA-affected dogs over the 
past 10 years, we have shown stable correction 
and safety over this period of time. What we 
still need to know are the structural correlates 
of the restored function. In other words, does 
the treated retina remain normal and, if so, 
can it restore the chemical connections with 
other cells that ultimately are responsible for 
transmitting the visual information to the brain.
The new studies under the direction of Dr András 
Komáromy use a different model of severe visual 
impairment – achromatopsia – that occurs at 
birth. Patients with this severe disease have an 
aversion to light; they are totally blind in bright 
light; their fovea and macula – which contain 
the cone cells that enable colour vision and high 
visual acuity – do not function normally. We 
have published a paper which details that this 
disease can be cured and, with collaborators at 
the University of Florida, are planning to develop 
clinical trials for this disease. In this disease, the 
studies are directed at treating cones – the main 
class of cells involved in macular degeneration. 
If we can develop a treatment targeting cones, 
there is the exciting possibility that we can treat 
other diseases also.
What major, long-standing challenges does 
your fi eld of research present?
From a scientifi c point of view, a main challenge 
now is in eliminating proteins that have an adverse 
effect on tissue, not only in relation to X-linked 
RP, but other dominant diseases in which the 
actual genetic defect produced a protein that has 
a deleterious affect on the retinal photoreceptors. 
One such disease is caused by mutations in the 
rhodopsin gene which is an extremely common 
cause of autosomal dominant RP.
Many disease-causing mutations that are 
inherited as dominant or X-linked result in 
what is known as gain-of-function,  where the 
abnormal proteins produced cause disease. 
For therapy, you fi rst must prevent production 
of the abnormal protein,and then replace it 
with the normal version. In the X-linked RP 
model, which is applicable to a large number of 
dominant diseases, the need to eliminate the 
undesirable mutant protein is a challenge of 
utmost importance.
To what extent has genome sequencing been 
integral in enabling the team to identify likely 
targets for intervention, and can you outline the 
support offered by the Penn Genome Frontiers 
Institute (PGFI)?
The progress made in this regard is remarkable. 
When I fi rst started work in this fi eld in 1992, there 
were absolutely no genome resources available 
for the dog. So we had to carry out cloning for 
ourselves, taking information gained from the 
cloning of genes in mice, cows and humans. When 
I look over the lab books, I recall that people 
would spend several years cloning genes; today 
you simply access the information through a web 
browser. We can use SNP-chips to track diseases or 
identify new diseases, and arrays to look at gene 
expression. The resources available at the PGFI 
have been critical in providing the infrastructure 
and resources needed to do this work.
Window into retinal studies
FIGURE 1. GFP expression in retina with AAV2/5-hGRK1-GFP virus. The virus is AAV2/5 and we are using a reporter gene, in this case green fl uorescent protein-GFP, to determine which 
cells in the retina are modifi ed by the virus. For this study, we are using a human rhodopsin kinase gene promoter (hGRK1) to direct expression in the rod cells (here they have turned 
green). The red cells are cones which are not tranduced by this vector construct and are identifi ed with an antibody that recognises a cone-specifi c protein called cone arrestin. For 
XLRP where cones as well as rods are affected, we also have to use a separate vector construct to direct expression to cones;  in this case the human red cone opsin promoter.
PR
O
FE
SS
O
R 
G
U
ST
AV
O
 A
G
U
IR
RE
108 INTERNATIONAL INNOVATION
FOR THE BEST part of two decades, Dr 
Gustavo Aguirre of the School of Veterinary 
Medicine at the University of Pennsylvania, 
Philadelphia, has dedicated his research efforts 
to the long-term development of therapies for 
degenerative retinal diseases. Presently, Aguirre 
and his collaborators are conducting studies in 
relation to retinitis pigmentosa (RP) linked to 
the X-chromosome. RP represents a group of 
hereditary and degenerative eye conditions that 
invariably induce total blindness in patients. In 
general terms, this group of diseases is associated 
with dystrophies of the photoreceptors of the 
retina and/or the pigment epithelium.
Aguirre and his associate, Dr William Beltran, are 
employing dog models in identifying the genes and 
pathways associated with a form of RP known as 
X-linked PRA2 (XLPRA2). This naturally occurring 
canine disease is a close correlate of early-onset 
XLRP in humans. This work has great potential for 
translational studies to harness a novel therapy for 
XLRP caused by mutations in the ORF-15 region of 
the RPGR gene. Signifi cantly for XLRP, mutations in 
this gene account for 8-10 and 15-20 per cent of 
early onset retinal diseases in the U.S. and Europe 
respectively. With this in mind, it is clearly manifest 
that Aguirre’s studies bear enormous potential and 
relevance in clinical terms; however, the industry 
and dedication shown by Aguirre and his team up 
to this point also warrant attention.
RP STUDIES IN FOCUS
Restoring vision in patients is the overall goal of 
basic and applied research in this fi eld. However, in 
past decades, a signifi cant proportion of studies and 
investigations have focused on slowing the rate of 
vision loss in patients with RP through nutritional 
supplementation, because of the limited availability 
of therapeutic alternatives. Another approach to 
combating the disease has seen neuroprotective 
agents, such as CNTF, being transported to the 
retina through ECT technology, which utilises 
genetically engineered cells that are encapsulated 
and placed in the eye. Whilst studies employing 
these techniques have delivered important fi ndings, 
there is consensus that advancements in molecular 
science are integral to understanding the causes of 
RP. This, in turn, has engendered further hope for 
the development of effective treatment options. 
Molecular science has enabled signifi cant progress 
to be made in identifying loci and genes linked to 
retinal dysfunction; unfortunately, this progress has 
not been mirrored to the same extent where the 
development of treatments is concerned. Indeed, 
whilst encouraging fi ndings have emerged from a 
large number of experimental studies in animals, 
there is still a paucity of approved treatments for 
patients diagnosed with RP.
However, work recently undertaken by Aguirre’s 
group and associates has garnered extremely 
encouraging results that have unlocked potential 
human therapies, currently in Phase I trials by 
various groups of investigators in Europe and the 
U.S. The study relates to a mutation in the RPE65 
gene in patients with a form of RP known as Leber 
congenital amaurosis (LCA).
In light of this notable achievement, Aguirre’s 
team remain focused and determined to 
continue to deliver important contributions in the 
development of therapies for RP; they envisage 
each investigation as part of an incremental process 
where knowledge relating to the mechanisms 
which lead to RP is steadily enhanced and used in 
formulating new treatments. As such, the success 
registered by the team in regard to RPE65-LCA has 
provided a basis from which they can explore more 
complex disorders. In this sense, the team’s latest 
proposal regarding RPGR-XLRP marks their next 
developmental stage in addressing forms of RP.
CURRENT INVESTIGATIONS
While a considerable proportion of patients 
with retinal diseases carry mutations in the 
RPGR gene, signifi cant gaps persist in our 
understanding of the function of the protein, as 
well as the molecular mechanisms that lead to 
photoreceptor degeneration.
In addressing this issue, part of Aguirre and 
his investigators’ latest research involves the 
identifi cation of genes and pathways associated 
with Retinal Dysfunction (RD) in dogs affected 
with XLPRA2, also known as RPGR2. This is a 
canine model of early-onset XLRP caused by an 
RPGR exon ORF15 microdeletion. The connection 
between RPGR2 in dogs and RPGR in humans is 
extremely useful: should the team determine that 
the molecular mechanisms underlying XLPRA2 in 
dogs are the same as those of XLRP in humans, it 
is anticipated that therapies proven effective in 
canine models will be likely to induce comparable 
effects in patients.
The team’s investigations in canine models will 
run in parallel with a comprehensive study in 
patients seeking to enhance knowledge regarding 
the range and history of XLRP. This corresponding 
study, carried out by Drs Samuel Jacobson and 
Artur Cideciyan at the University of Pennsylvania, 
Seeing is believing
A research team based at the University of Pennsylvania are conducting 
essential research which could lead to promising therapies for X-linked 
retinitis pigmentosa, an hereditary disease that leads to blindness
PROFESSOR GUSTAVO AGUIRRE
WWW.RESEARCHMEDIA.EU 109
110 INTERNATIONAL INNOVATION
INTELLIGENCE
MODELS OF X-LINKED RETINITIS PIGMENTOSA
OBJECTIVES
•  To develop specifi c gene-based therapies for RPGR-
XLRP past the proof-of-principle stage so that 
clinical trials are then generated
•  To assist collaborators, Drs S Jacobson and A 
Cideciyan, to conduct prospective studies in RPGR-
XLRP patients to assess the feasibility or facility of 
translating pre-clinical therapy to the clinic
•  To carry out complementary in vivo studies in the 
canine model to quantify photoreceptor laminar 
structure and function, with emphasis on the central 
retina, at comparable disease stages as the patients, 
to establish the morphological/immunocytochemical 
correlates to the observations made in dogs that can 
be extrapolated to patients
PARTNERS
School of Veterinary Medicine, University of 
Pennsylvania:
William A Beltran, DVM, PhD
Sem Genini, PhD
András M Komáromy, DVM, PhD (achromatopsia)
Scheie Eye Institute, School of Medicine, 
University of Pennsylvania:
Samuel G Jacobson, MD, PhD
Artur V Cideciyan, PhD
Departments of Ophthalmology, Molecular 
Genetics and Microbiology, School of Medicine, 
University of Florida:
William W Hauswirth, PhD
Alfred S Lewin, PhD
CONTACT
Gustavo Aguirre, VMD, PhD
Professor of Medical Genetics and Ophthalmology
School of Veterinary Medicine
University of Pennsylvania Ryan-VHUP, Room 2050 
3900 Delancey St.
Philadelphia, PA  19104-6010
USA
T +1 (215)-898-9426
F +1 (215) 573-2162
E gda@vet.upenn.edu
GUSTAVO D AGUIRRE is Professor of Medical 
Genetics and Ophthalmology at The School of 
Veterinary Medicine, University of Pennsylvania. He 
earned undergraduate, veterinary, and doctoral degrees 
at the University of Pennsylvania, and joined the faculty 
at Penn in 1973. Dr Aguirre has received numerous 
awards, including the Foundation Fighting Blindness 
Trustee Award, Scientist of the Year, and he was a 
co-recipient of the Paul Kayser International Award 
in Retina Research. He was recently elected Fellow, 
Association for Research in Vision and Ophthalmology.
will aim towards the development of a 
set of outcome measures tailored to pre-
clinical treatment strategies. The concept of 
running concurrent studies is ambitious; yet, 
given the capabilities of the investigators, it 
would seem that their bold objective is well-
placed and feasible.
A MULTIDISCIPLINARY APPROACH
The complexity and breadth of this 
research programme requires the expertise 
of a team with proven experience in 
translational research.  The group members’ 
collective ability to engage in throughput 
investigations – dealing with science-based 
ideas to clinical application of therapies – is 
perhaps epitomised in their harnessing of an 
effective treatment for LCA. The antecedent 
study, in which the team translated dog and 
murine results to human RPE65-LCA, has 
cultivated a greater appreciation that proof-
of-principle treatments in animal models 
generate a multitude of questions regarding 
exact human application.
Crucially, over the years Aguirre has forged 
and enjoyed fruitful partnerships with 
other leading researchers and clinicians 
across the U.S. and beyond. In regard 
to interaction and studies in patient 
populations, the research benefi ts from 
cooperative efforts, as Aguirre highlights: 
“Drs Samuel Jacobson and Artur Cideciyan, 
collaborators at the Scheie Institute 
who also run the Center for Retinal 
Degenerations here at the University of 
Pennsylvania, are really crucial in this 
respect because they see the actual patient 
population”. He continues: “They have 
a great interest in the diseases in dogs, 
enabling them to better delineate these 
diseases in humans”.
Furthermore, the development of virus 
vectors – which are required to transport 
genes to the retina – is conducted by 
external partners, Drs William Hauswirth 
and Alfred Lewin, at the Departments of 
Ophthalmology, Molecular Genetics and 
Microbiology, and the Powell Gene Therapy 
Center, University of Florida. This valuable 
collaboration is pivotal to the advancement 
of studies which require specifi c targeting 
of the retinal cells, elimination of the 
mutant gene product and replacement 
with a normal copy of the gene.
Looking beyond the current research 
programme, Aguirre is excited by the 
prospects and promise held in the laboratories 
at Penn. His praise is unreserved: “It is a joy 
to have here at Penn a group of scientists 
who are young, talented, productive and 
enthusiastic, and it is reassuring to know that 
they will be here to continue the work in the 
long term,” he comments.
The tools, it would appear, are in place; it 
will only be a matter of time before Aguirre 
and his wider team make further valued 
contributions to this fi eld of enduring and 
essential research.
András M Komáromy, DVM, PhD (achromatopsia) and William A Beltran, DVM, PhD 
from the School of Veterinary Medicine, University of Pennsylvania


Window Into Retinal Studies

ScholarlyCommons@Penn

University of PennsylvaniaScholarlyCommonsDepartmental Papers (Vet) School of Veterinary Medicine10-2010Window Into Retinal StudiesGustavo D. AguirreUniversity of Pennsylvania, gda@vet.upenn.eduFollow this and additional works at: https://repository.upenn.edu/vet_papersPart of the Veterinary Medicine CommonsThis paper is posted at ScholarlyCommons. https://repository.upenn.edu/vet_papers/79For more information, please contact repository@pobox.upenn.edu.Recommended CitationAguirre, G. D. (2010). Window Into Retinal Studies. Healthcare, 108-110. Retrieved from https://repository.upenn.edu/vet_papers/79Window Into Retinal StudiesAbstractProfessor Gustavo Aguirre discusses the context of his research studies at the University of Pennsylvania,which are currently concentrating on the degenerative disease, retinitis pigmentosa.Keywordsblindness, dogs, animals, Retinitis Pigmentosa GTPase Regulator, X-linked RPDisciplinesMedicine and Health Sciences | Veterinary MedicineThis other is available at ScholarlyCommons: https://repository.upenn.edu/vet_papers/79 | June 2010: Healthcare |  A world leader in healthcare researchPROFESSOR HARRIET WALLBERG-HENRIKSSONPresident, Karolinska InstitutetDisseminating science, research and technology | Healthcare: October 2010 |  RESEARCH SPOTLIGHTJapan Science and Technology Agency • Chief Scientiﬁ c Advisor to the Government of Ireland • Luxinnnovation EC-US Task Force on Biotechnology Research • Research and Development Council of the Czech Republic The European Association for Cancer Research • National Health and Medical Council, AustraliaSPECIAL FOCUS: ORAL AND DENTAL SCIENCESWe feature a variety of researchers and organisations spearheading the dental science movementProfessor Gustavo Aguirre discusses the context of his research studies at the University of Pennsylvania, which are currently concentrating on the degenerative disease, retinitis pigmentosaFirstly, can you outline the broader aims and objectives of your research?There are many inherited diseases that have been found to affect the retina and cause blindness. Beyond fi nding the disease-causing mutations, the aim of the research is to understand how these diseases develop, and then investigate the pathways that link the mutation to the death of the visual cells, and determine if these are specifi c or common to one or more diseases. From this, we seek to develop intelligent therapies that can be used in treating the retinal diseases. Most of our work uses dog models; in the past we have used cats, monkeys and humans, but the work we do to develop translational studies primarily involves dogs.Can you provide an overview of the discovery of X-linked retinitis pigmentosa (XLRP) diseases?There are several retinal diseases in humans that are known to have X-linked inheritance. There are only two where the gene has been found: RP-3 and RP-2. The pioneering work on the mapping of these diseases was done in the UK by Professors Alan Wright (University of Edinburgh) and Shomi Bhattacharya (Institute of Opthalmology) beginning in the 1980s. It took a long time to refi ne the disease intervals, and many groups were working on this diffi cult area. Eventually, the Wright and Meitinger groups published a seminal paper identifying a very complex gene called RPGR (Retinitis Pigmentosa GTPase Regulator). They also found part of the gene which had previously been very diffi cult to sequence. This DNA region – ORF-15 – accounted for about 70 per cent of mutations in patients with RPGR. After this fi nding, my team collaborated intensely with Wright and found that dogs had the mutation in the same ORF15 region as patients. When you take most populations of patients with X-linked RP, up to 70 or 80 per cent have mutations in RPGR. Thus it is recognised as the most common cause of X-linked RP. It is a very severe problem, not least because the regions in questions are very diffi cult to clone and sequence.The fi rst gene therapy clinical trials in human patients affected with a severe form of childhood blindness were reported 2008. Can you highlight the developments which have been made in this regard, and any further challenges clinical trials have thrown up?The Phase 1 studies in human patients have confi rmed that treatment of the study population is safe which is the primary goal of any Phase 1 clinical trial. In addition, the studies have shown effi cacy in some patients. What we now need is to determine the patient population that is amenable to treatment, and the long-term safety and effi cacy in treated patients. In the studies with LCA-affected dogs over the past 10 years, we have shown stable correction and safety over this period of time. What we still need to know are the structural correlates of the restored function. In other words, does the treated retina remain normal and, if so, can it restore the chemical connections with other cells that ultimately are responsible for transmitting the visual information to the brain.The new studies under the direction of Dr András Komáromy use a different model of severe visual impairment – achromatopsia – that occurs at birth. Patients with this severe disease have an aversion to light; they are totally blind in bright light; their fovea and macula – which contain the cone cells that enable colour vision and high visual acuity – do not function normally. We have published a paper which details that this disease can be cured and, with collaborators at the University of Florida, are planning to develop clinical trials for this disease. In this disease, the studies are directed at treating cones – the main class of cells involved in macular degeneration. If we can develop a treatment targeting cones, there is the exciting possibility that we can treat other diseases also.What major, long-standing challenges does your fi eld of research present?From a scientifi c point of view, a main challenge now is in eliminating proteins that have an adverse effect on tissue, not only in relation to X-linked RP, but other dominant diseases in which the actual genetic defect produced a protein that has a deleterious affect on the retinal photoreceptors. One such disease is caused by mutations in the rhodopsin gene which is an extremely common cause of autosomal dominant RP.Many disease-causing mutations that are inherited as dominant or X-linked result in what is known as gain-of-function,  where the abnormal proteins produced cause disease. For therapy, you fi rst must prevent production of the abnormal protein,and then replace it with the normal version. In the X-linked RP model, which is applicable to a large number of dominant diseases, the need to eliminate the undesirable mutant protein is a challenge of utmost importance.To what extent has genome sequencing been integral in enabling the team to identify likely targets for intervention, and can you outline the support offered by the Penn Genome Frontiers Institute (PGFI)?The progress made in this regard is remarkable. When I fi rst started work in this fi eld in 1992, there were absolutely no genome resources available for the dog. So we had to carry out cloning for ourselves, taking information gained from the cloning of genes in mice, cows and humans. When I look over the lab books, I recall that people would spend several years cloning genes; today you simply access the information through a web browser. We can use SNP-chips to track diseases or identify new diseases, and arrays to look at gene expression. The resources available at the PGFI have been critical in providing the infrastructure and resources needed to do this work.Window into retinal studiesFIGURE 1. GFP expression in retina with AAV2/5-hGRK1-GFP virus. The virus is AAV2/5 and we are using a reporter gene, in this case green fl uorescent protein-GFP, to determine which cells in the retina are modifi ed by the virus. For this study, we are using a human rhodopsin kinase gene promoter (hGRK1) to direct expression in the rod cells (here they have turned green). The red cells are cones which are not tranduced by this vector construct and are identifi ed with an antibody that recognises a cone-specifi c protein called cone arrestin. For XLRP where cones as well as rods are affected, we also have to use a separate vector construct to direct expression to cones;  in this case the human red cone opsin promoter.PROFESSOR GUSTAVO AGUIRRE108 INTERNATIONAL INNOVATIONFOR THE BEST part of two decades, Dr Gustavo Aguirre of the School of Veterinary Medicine at the University of Pennsylvania, Philadelphia, has dedicated his research efforts to the long-term development of therapies for degenerative retinal diseases. Presently, Aguirre and his collaborators are conducting studies in relation to retinitis pigmentosa (RP) linked to the X-chromosome. RP represents a group of hereditary and degenerative eye conditions that invariably induce total blindness in patients. In general terms, this group of diseases is associated with dystrophies of the photoreceptors of the retina and/or the pigment epithelium.Aguirre and his associate, Dr William Beltran, are employing dog models in identifying the genes and pathways associated with a form of RP known as X-linked PRA2 (XLPRA2). This naturally occurring canine disease is a close correlate of early-onset XLRP in humans. This work has great potential for translational studies to harness a novel therapy for XLRP caused by mutations in the ORF-15 region of the RPGR gene. Signifi cantly for XLRP, mutations in this gene account for 8-10 and 15-20 per cent of early onset retinal diseases in the U.S. and Europe respectively. With this in mind, it is clearly manifest that Aguirre’s studies bear enormous potential and relevance in clinical terms; however, the industry and dedication shown by Aguirre and his team up to this point also warrant attention.RP STUDIES IN FOCUSRestoring vision in patients is the overall goal of basic and applied research in this fi eld. However, in past decades, a signifi cant proportion of studies and investigations have focused on slowing the rate of vision loss in patients with RP through nutritional supplementation, because of the limited availability of therapeutic alternatives. Another approach to combating the disease has seen neuroprotective agents, such as CNTF, being transported to the retina through ECT technology, which utilises genetically engineered cells that are encapsulated and placed in the eye. Whilst studies employing these techniques have delivered important fi ndings, there is consensus that advancements in molecular science are integral to understanding the causes of RP. This, in turn, has engendered further hope for the development of effective treatment options. Molecular science has enabled signifi cant progress to be made in identifying loci and genes linked to retinal dysfunction; unfortunately, this progress has not been mirrored to the same extent where the development of treatments is concerned. Indeed, whilst encouraging fi ndings have emerged from a large number of experimental studies in animals, there is still a paucity of approved treatments for patients diagnosed with RP.However, work recently undertaken by Aguirre’s group and associates has garnered extremely encouraging results that have unlocked potential human therapies, currently in Phase I trials by various groups of investigators in Europe and the U.S. The study relates to a mutation in the RPE65 gene in patients with a form of RP known as Leber congenital amaurosis (LCA).In light of this notable achievement, Aguirre’s team remain focused and determined to continue to deliver important contributions in the development of therapies for RP; they envisage each investigation as part of an incremental process where knowledge relating to the mechanisms which lead to RP is steadily enhanced and used in formulating new treatments. As such, the success registered by the team in regard to RPE65-LCA has provided a basis from which they can explore more complex disorders. In this sense, the team’s latest proposal regarding RPGR-XLRP marks their next developmental stage in addressing forms of RP.CURRENT INVESTIGATIONSWhile a considerable proportion of patients with retinal diseases carry mutations in the RPGR gene, signifi cant gaps persist in our understanding of the function of the protein, as well as the molecular mechanisms that lead to photoreceptor degeneration.In addressing this issue, part of Aguirre and his investigators’ latest research involves the identifi cation of genes and pathways associated with Retinal Dysfunction (RD) in dogs affected with XLPRA2, also known as RPGR2. This is a canine model of early-onset XLRP caused by an RPGR exon ORF15 microdeletion. The connection between RPGR2 in dogs and RPGR in humans is extremely useful: should the team determine that the molecular mechanisms underlying XLPRA2 in dogs are the same as those of XLRP in humans, it is anticipated that therapies proven effective in canine models will be likely to induce comparable effects in patients.The team’s investigations in canine models will run in parallel with a comprehensive study in patients seeking to enhance knowledge regarding the range and history of XLRP. This corresponding study, carried out by Drs Samuel Jacobson and Artur Cideciyan at the University of Pennsylvania, Seeing is believingA research team based at the University of Pennsylvania are conducting essential research which could lead to promising therapies for X-linked retinitis pigmentosa, an hereditary disease that leads to blindnessPROFESSOR GUSTAVO AGUIRREWWW.RESEARCHMEDIA.EU 109110 INTERNATIONAL INNOVATIONINTELLIGENCEMODELS OF X-LINKED RETINITIS PIGMENTOSAOBJECTIVES•  To develop specifi c gene-based therapies for RPGR-XLRP past the proof-of-principle stage so that clinical trials are then generated•  To assist collaborators, Drs S Jacobson and A Cideciyan, to conduct prospective studies in RPGR-XLRP patients to assess the feasibility or facility of translating pre-clinical therapy to the clinic•  To carry out complementary in vivo studies in the canine model to quantify photoreceptor laminar structure and function, with emphasis on the central retina, at comparable disease stages as the patients, to establish the morphological/immunocytochemical correlates to the observations made in dogs that can be extrapolated to patientsPARTNERSSchool of Veterinary Medicine, University of Pennsylvania:William A Beltran, DVM, PhDSem Genini, PhDAndrás M Komáromy, DVM, PhD (achromatopsia)Scheie Eye Institute, School of Medicine, University of Pennsylvania:Samuel G Jacobson, MD, PhDArtur V Cideciyan, PhDDepartments of Ophthalmology, Molecular Genetics and Microbiology, School of Medicine, University of Florida:William W Hauswirth, PhDAlfred S Lewin, PhDCONTACTGustavo Aguirre, VMD, PhDProfessor of Medical Genetics and OphthalmologySchool of Veterinary MedicineUniversity of Pennsylvania Ryan-VHUP, Room 2050 3900 Delancey St.Philadelphia, PA  19104-6010USAT +1 (215)-898-9426F +1 (215) 573-2162E gda@vet.upenn.eduGUSTAVO D AGUIRRE is Professor of Medical Genetics and Ophthalmology at The School of Veterinary Medicine, University of Pennsylvania. He earned undergraduate, veterinary, and doctoral degrees at the University of Pennsylvania, and joined the faculty at Penn in 1973. Dr Aguirre has received numerous awards, including the Foundation Fighting Blindness Trustee Award, Scientist of the Year, and he was a co-recipient of the Paul Kayser International Award in Retina Research. He was recently elected Fellow, Association for Research in Vision and Ophthalmology.will aim towards the development of a set of outcome measures tailored to pre-clinical treatment strategies. The concept of running concurrent studies is ambitious; yet, given the capabilities of the investigators, it would seem that their bold objective is well-placed and feasible.A MULTIDISCIPLINARY APPROACHThe complexity and breadth of this research programme requires the expertise of a team with proven experience in translational research.  The group members’ collective ability to engage in throughput investigations – dealing with science-based ideas to clinical application of therapies – is perhaps epitomised in their harnessing of an effective treatment for LCA. The antecedent study, in which the team translated dog and murine results to human RPE65-LCA, has cultivated a greater appreciation that proof-of-principle treatments in animal models generate a multitude of questions regarding exact human application.Crucially, over the years Aguirre has forged and enjoyed fruitful partnerships with other leading researchers and clinicians across the U.S. and beyond. In regard to interaction and studies in patient populations, the research benefi ts from cooperative efforts, as Aguirre highlights: “Drs Samuel Jacobson and Artur Cideciyan, collaborators at the Scheie Institute who also run the Center for Retinal Degenerations here at the University of Pennsylvania, are really crucial in this respect because they see the actual patient population”. He continues: “They have a great interest in the diseases in dogs, enabling them to better delineate these diseases in humans”.Furthermore, the development of virus vectors – which are required to transport genes to the retina – is conducted by external partners, Drs William Hauswirth and Alfred Lewin, at the Departments of Ophthalmology, Molecular Genetics and Microbiology, and the Powell Gene Therapy Center, University of Florida. This valuable collaboration is pivotal to the advancement of studies which require specifi c targeting of the retinal cells, elimination of the mutant gene product and replacement with a normal copy of the gene.Looking beyond the current research programme, Aguirre is excited by the prospects and promise held in the laboratories at Penn. His praise is unreserved: “It is a joy to have here at Penn a group of scientists who are young, talented, productive and enthusiastic, and it is reassuring to know that they will be here to continue the work in the long term,” he comments.The tools, it would appear, are in place; it will only be a matter of time before Aguirre and his wider team make further valued contributions to this fi eld of enduring and essential research.András M Komáromy, DVM, PhD (achromatopsia) and William A Beltran, DVM, PhD from the School of Veterinary Medicine, University of Pennsylvania

https://repository.upenn.edu/cgi/viewcontent.cgi?article=1073&amp;context=vet_papers

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