There is currently no cure for achromatopsia. Similar to filtered glasses and contact lenses, color recognizing devices, and other technological aids, treatments are usually focused on improving quality of life.4
Gene therapy is currently being studied. Animal studies using adeno-associated virus therapy have shown great advances. Cone-targeted gene therapy has shown success in animal studies,31–34 in which the therapy improved cone survival and recovered cone electroretinogram amplitudes to near normal levels.
Another treatment option that is being studied is the use of neuroprotective compounds such as the ciliary neurotrophic factor, which has been shown to inhibit progressive degeneration of rod and cone photoreceptors in some animal models and clinical trials. It also improved cone electroretinogram function and vision in dogs with achromatopsia. However, success with therapy based on either genes or neuroprotective compounds would require the cone photoreceptors to be present and viable within the macula. Although there are still many difficulties to solve, stem cell–based therapy is being studied as a potential treatment of retinal degenerative diseases in which patients have already lost their photoreceptors.
Treatment of Manifestations. The current standard of care consists of managing symptoms, including35 dark or special filter glasses or red-tinted contact lenses to reduce photophobia, which may also improve visual acuity and be useful in avoiding light damage to the retina36; low vision aids such as high-powered magnifiers for reading; and social considerations such as preferential seating in the front of the class or social group promotion.
Gene Therapy. Several strategies are currently being studied to restore gene function in cone disorders. A specific vector is always necessary to deliver the target gene into the cell because DNA alone is not able to complete the task. Vector choice depends on the size of the cDNA of the type of targeted cells, the relevant gene, stability of expression, and immunogenicity.37
Adeno-associated viruses have been successfully used as vectors for gene therapy.37 However, restrictions of this technology are its limited cargo size, only enabling the transport of genes up to a specific size, and putative immune responses to the viral capsid that may also limit recurrent treatments.38
The ability of viruses to introduce genetic material into cells has been used to target genetically affected cells. Modified viruses have been developed for this purpose and are known as viral vectors.39
To transduce specific cells, the viral vector has to be introduced close to the targeted cell surface. For example, if retinal pigment epithelium or photoreceptors are the target cells, then the vector usually needs to be administered in a subretinal injection. If the ganglion cells are to be targeted, the intravitreal approach may be a good option.39,40 Future developments may allow the use of the intravitreal route to target the outer retina, avoiding the more difficult and potentially damaging subretinal injection.39
Rescue of cone function structure using adeno-associated viral vectors has been achieved in animal models.41 Recently, three clinical Phase I/II safety trials for gene replacement therapy using adeno-associated viral vectors for achromatopsia association with CNGA3 and CNGB3 have been approved and are recruiting patients ( https://clinicaltrials.gov/ct2/results?cond=Achromatopsia; NCT02610582, NCT02599922, and NCT03001310).
Stem Cell Therapy. Cell replacement therapies using retinal progenitor cells derived from embryonic or induced pluripotential stem cells show great promise in treating early onset degenerative diseases such as cone disorders. In recent animal studies, it was observed that the transplanted cells that were differentiated into adult photoreceptor cells were positioned at the correct location and formed connections with bipolar cells,42 demonstrating the potential of this approach to rescue retinal function in future clinical trials.37
Pharmacological Approaches. Gene replacement therapy is suitable for retinal disorders that result from mutations that cause a loss of function. However, we would need a different viral vector for each gene involved. For this reason, there is interest in developing other therapies. Treatments using neuroprotective agents, growth factors, and anti-apoptosis agents are being investigated. Such approaches would not restore function, but they would be useful when photoreceptors initially function and vision is lost as photoreceptor cells die.39
The ciliary neurotrophic factor was recently shown to improve cone function in CNGB3 mutant achromatopic dogs and CNGB−/− mice.38 Unfortunately, in 2012, a Phase I/II clinical trial (NCT01648452) investigated the effects and safety of an intraocular implant releasing ciliary neurotrophic factor in five patients with achromatopsia and found no objectively measurable enhancement of cone function by assessments of visual acuity, mesopic increment sensitivity threshold, photopic electroretinogram, or color hue discrimination. Subjectively, some patients reported beneficial changes, including reduced light sensitivity and aversion to bright light, but slowed adaptation to darkness, consistent with ciliary neurotrophic factor action on rod photoreceptors.43
In response to this publication,43 Liu and Varnum,44 suggested that this lack of response to treatment might be due to few residual cones failing to produce a detectable change in function. They suggested using high-resolution quantitative retinal imaging techniques for the selection and evaluation of the results of the treatment.44
Pharmacological approaches are particularly suited for disorders caused by a gain of CNG channel function, which can be due to an increase in cGMP affinity.44 One such mutation in CNGA3 (N471S) that was associated with complete achromatopsia was analyzed in Xenopus oocytes and it was demonstrated that treatment with a retinoid (all-trans C22 aldehyde) inhibits these hypersensitive channels and shifts the dose response curve for cGMP back into the normal range.45 This opens up the possibility for these types of products to be used as potential treatments for retinal diseases due to overactive CNG channels.46
When to Treat
One of the challenges for gene therapy is the limited time period to achieve a successful treatment outcome. The progression rate of the different diseases may affect the window of opportunity for treatment. Therefore, treatment opportunities may be explained by determining the viability of cone cell bodies using SD-OCT and adaptive optics.47 However, in patients with early onset cone disorders, gene augmentation therapy should ideally start as early as possible.35
Lee et al.48 suggested that achromatopsia is a continuously altering and progressive process in the developing retina. With human gene therapy trials imminent, their results suggest that therapy should be considered at early ages while the photoreceptors are still developing, thereby potentially facilitating normal retinal maturation.
Thomas et al.26 observed for the first time in SD-OCT that there were progressive longitudinal changes in retinal morphology in achromatopsia. These changes showed that this is a progressive disorder and implementation of gene therapy during the early stages of the disease may provide the best prognosis.26
Dubis et al.49 studied criteria to assess residual photoreceptor integrity in achromatopsia. They presented cone reflectivity as a measure that can be used to characterize cone integrity in achromatopsia. Cone numerosity and/or density combined with cone reflectivity could be used to estimate the therapeutic potential. They suggested that these measurements could be a more immediate indicator of efficacy than behavioral measures, which may take longer to change.49
The lack of a clear association with age suggests that the window of opportunity for intervention by gene therapy is wider in some individuals than previously thought. Potential benefits should be better predicted by specific measurements of the photoreceptor structure.5