Clinical trial of gene therapy for the treatment of achromatopsia

Achromatopsia (ACHM) is a severe inherited retinal disorder with a population frequency around 1/30000, characterised by the absence of daylight vision from birth, photophobia and a slowly progressing loss of cone photoreceptors. Approximately half of ACHM cases are caused by mutations in the CNGB3 gene, which encodes one of two subunits of the cone-specific cyclic nucleotide-gated channel, an essential component of the phototransduction cascade. Thus far no successful treatments exist for this inherited retinal dystrophy. However, three independent clinical trials of AAV2-mediated gene therapy, including one performed by our group, have shown improvements in retinal sensitivity and vision in a rapidly progressing form of inherited retinal dystrophy: Leber congenital amaurosis caused by RPE65-deficiency. These trials have suggested that gene supplementation therapy can be a suitable strategy for the treatment of recessively inherited retinal disease.
Achromatopsia caused by mutations in the CNGB3 gene has several characteristics that make it a good candidate disease for a proof of principle gene therapy trial. The disorder can be stationary or slow-progressing, which creates a large window of opportunity where treatment would be expected to lead to clinical benefit. More importantly, a potential restoration of previously absent cone function and the expected ensuing improvement in daylight vision should allow a rapid and robust assessment of treatment efficacy. In a previous study using a murine model of CNGB3 deficiency, we have been able to show successful gene supplementation and consequently substantial rescue of cone photoreceptor function and survival (Carvalho et al, Hum Mol Genet (2000) 20: 3161-75). This study constitutes one of the most effective rescues of an animal model of retinal dystrophy due to a photoreceptor defect reported to date, suggesting that this disorder may be particularly amenable to gene supplementation therapy.
For the first milestone (duration 2 years) we will produce the gene therapy vector (AAV2/8.hCAR.hCNGB3) to GMP standards at the production facility of the UCL gene therapy consortium. Vector toxicity studies and treatment efficacy studies will be performed in-house, according to established protocols. Successful completion of this milestone will be defined as permission from the regulatory authorities to commence a clinical trial.
The second milestone (duration 3 years) will be the completion of the clinical trial, including a 1 year follow-up of the trial subjects. Successful completion of this milestone will be defined as any sustained improvement in cone-derived visual function (as determined by an array of psychophysical, electrophysiological, and fMRI techniques), that is greater that the test-retest variation for each test, and the absence of toxicity, as defined by a Grade III or IV ocular adverse event, or a non-ocular SUSAR.
Currently, more than 150 genes have been identified that, when mutated, can give rise to inherited retinal degeneration. As most of these forms of the disease are caused by photoreceptor cell defects, an efficient and safe method of gene transfer to the photoreceptors is essential in the development of retinal gene therapy. Animal experiments have shown that the AAV2/8 pseudotyped vector gives transduces the photoreceptor cells with higher efficiency and leads to higher levels of transgene expression than the AAV2 vector that has been used in the clinic thus far. The results of this trial will therefore not only be of relevance for gene therapy to treat achromatopsia, but a successful outcome will pave the way for the future development of gene therapy for many other inherited retinal dystrophies.

Achromatopsia (ACHM) is a severe inherited retinal disorder with a population frequency around 1/30000, characterised by the absence of daylight vision from birth, photophobia and a slowly progressing loss of cone photoreceptors. Approximately half of ACHM cases are caused by mutations in the CNGB3 gene, which encodes one of two subunits of the cone-specific cyclic nucleotide-gated channel, an essential component of the phototransduction cascade. Thus far no successful treatments exist for this inherited retinal dystrophy. In a study using a murine model of CNGB3 deficiency, we have been able to show successful gene supplementation and consequently substantial rescue of cone photoreceptor function and survival (Carvalho et al, Hum Mol Genet (2000) 20: 3161-75). This study constitutes one of the most effective rescues of an animal model of retinal dystrophy due to a photoreceptor defect reported to date, suggesting that this disorder may be particularly amenable to gene supplementation therapy.
The overall objective of this study is to produce clinical grade AAV2/8 vector and conduct a combined phase I/II clinical trial of gene therapy for the treatment of achromatopsia, caused by CNGB3 mutations. The primary objective of the clinical trial will be to establish whether subretinal administration of AAV2/8 is safe, as determined by routine clinical assessments, analysis of immune responses to the vector or the transgene product, as well as for the presence of vector genomes extraocularly. The secondary objective of the trial will be to establish whether gene therapy for achromatopsia type 3 is efficacious. The endpoint for efficacy for each subject is defined as any improvement in cone-derived visual function (as determined by an array of psychophysical, electrophysiological, and fMRI techniques), that is greater that the test-retest variation for each test.

Achromatopsia is a recessively inherited retinal disorder, characterised by poor visual acuity, nystagmus, and disabling aversion to light (photophobia) from birth or early infancy. There is no effective treatment available currently to improve visual function in achromatopsia patients. One of the most common causes of achromatopsia is mutations in the gene CNGB3. In a previous clinical study undertaken at Moorfields Eye Hospital, mutations in CNGB3 accounted for 40-50% of subjects with achromatopsia in our cohort. Thus far, no established successful treatments exist for any retinal dystrophy, but on-going clinical trials - including one conducted by our group - of gene therapy for Leber congenital amaurosis type 2 have resulted in encouraging improvements in retinal sensitivity and scotopic vision. Achromatopsia caused by mutations in CNGB3 has several characteristics that make it a good candidate disease to demonstrate proof-of-principle in a first-in-man trial of gene therapy for photoreceptor disease. Effective restoration of cone photoreceptor function, which is otherwise completely absent in this condition, would provide a clear, rapid and reliable measure of outcome. In addition, the extended survival of cone photoreceptor cells in this condition, despite their profound lack of function, presents a wide window of opportunity during which gene supplementation could lead to significant clinical benefit in terms of cone-mediated vision. Although younger subjects may be predicted to benefit most from gene supplementation therapy because of their potentially greater visual plasticity to accommodate an improvement in retinal function, we anticipate that the intervention may be effective across a range of ages and we aim to define this range. For this reason, subjects of various ages will be included in the trial; children will be included once an acceptable safety profile has been established in adults. The young age of the subjects means that an optimally successful treatment outcome could result in years of increased visual acuity and decreased photophobia, with concomitant improvements in self-sufficiency and potentially other economic benefits. Achromatopsia is a relatively rare condition with a population frequency of approximately 1/30,000. In the UK around 50% of achromatopsia cases are caused by CNGB3 mutations and thus potential end-users for AAV-CNGB3 gene therapy. A near-complete take-up of an established therapy is expected.
Retinal dystrophy is a highly diverse group of disorders that can be caused by mutations in as many as 200 different genes. The core technology used in this application - subretinal injection of AAV vectors carrying a transgene - will be suitable for the development of gene therapy protocols for the majority of retinal dystrophies. Robust proof-of-concept studies have been reported for AAV-mediated gene therapy for ten forms of inherited retinal degeneration, of which we have reported five. The results obtained in this project will also facilitate the progression of these therapies to clinical application.