Using Stem Cells to Reverse Inherited Eye Defects
Investigative Ophthalmology & Visual Science
Cystinosis is a degenerative hereditary disorder caused by a deficiency in cystinosin, which is encoded by the CTNS gene; this disease affects the eyes and the kidneys. In eyes, it can lead to crystal accumulation in the cornea and ultimately photophobia and blindness. Rocca et al. examined whether hematopoietic stem and progenitor cells (HSPCs) can help prevent crystal deposits from forming in the cornea in a mouse model. HSPCs have previously been shown to rescue the kidneys of transgenic Ctns–/– mice in this disease.
For this study, wild-type HSPCs from the bone marrow of transgenic DsRed mice were isolated and transplanted into the tails of Ctns–/– mice. A year later, the location and function of the HSPCs in the transplanted mice were analyzed by vivo confocal and fluorescence microscopy, quantitative reverse transcription polymerase chain reaction, mass spectrometry, and histology.
The researchers detected engraftment-derived HSPCs in the cornea, sclera, ciliary body, retina, choroid, and lens of Ctns–/– mice. They also found that in mice with high levels of cell engraftment, a single transplantation of the wild-type HSPCs prevented ocular pathology. This included substantial decreases in corneal cystine crystals, restoration of normal corneal thickness, and reduction in intraocular pressure.
The researchers called for additional studies to determine whether similar benefits can be achieved in humans, especially if HSPCs are delivered directly within the eye.
A New Approach to Restoring Lens Transparency in Cataracts
Cataracts occur when crystallins, a major protein component of the lens, begin to aggregate from accumulated damage. Makley et al. investigated whether pharmacological chaperones—small molecules that bind and stabilize the native state of a protein—can halt this aggregation and provide a nonsurgical therapy for treating cataracts.
Using a screening method that tracks the effect of ligands on protein unfolding, the researchers identified several compounds that stabilized the soluble form of α-crystallins and reversed their accumulation. In proof-of-concept studies, one of these compounds improved lens transparency in mice with hereditary cataracts and partially restored protein solubility in lenses of aged mice and humans.
In an accompanying commentary, Quinlan (pp 636-637) discusses the practical implications of this research. He noted that, because of studies such as this, the protein aggregation that accompanies the development of cataracts no longer needs to be seen as an end point. Further, he suggested that the discovery and identification of sterols that improve lens transparency may lead to the development of new pharmaceuticals to treat conditions such as cataract and presbyopia.
Propranolol in the Treatment of Infantile Hemangiomas
British Journal of Dermatology
Published online Oct. 16, 2015
Because oral propranolol is widely prescribed as a first-line treatment for infantile hemangioma (IH), Wedgeworth et al. set out to establish patterns of use for this beta-blocker to help in developing treatment guidelines and designing future intervention studies.
As part of the Propranolol in the Treatment of Complicated Haemangiomas (PITCH) Taskforce, the researchers collected data in 8 European countries on 1,096 patients who were treated for an IH with oral propranolol. Of these patients, 76.1% were female; and 92.8% had a focal IH, while the remainder had a segmental, multifocal, or indeterminate pattern.
The main indications for treatment with propranolol included periocular location with a threat to vision (29.3%), risk of cosmetic disfigurement (21.1%), and ulceration and bleeding (20.6%). In 69.2% of cases, the patients were titrated up to a daily maintenance regimen, which, in a large majority, consisted of 2 mg/kg per day. The median length of treatment was 32 weeks, and most patients (91.4%) had a good or excellent response to treatment. However, the researchers did not find a significant relationship between treatment response and duration of treatment. In addition, although there was a trend toward higher efficacy with larger doses, there was no significant difference in positive responses between those children taking either more or less than the 2 mg/kg dosage.
The median age at treatment cessation was 56 weeks, and rebound growth occurred in 14.1% of patients. Side effects, including sleep disturbances and cold peripheries, occurred in 19.6%. The risk of experiencing such an event doubled for children on a dose of more than 2 mg/kg per day.
The researchers concluded that the optimum dosage remains to be determined. They called for a more adequately powered randomized, controlled trial to compare dose regimens and their effects.
Roundup of Other Journals is written by Michael Mott and edited by Deepak P. Edward, MD.
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