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Macular Degeneration & Stem Cell Therapy
Age-related macular degeneration (AMD) is a medical condition which usually affects older adults and results in a loss of vision in the center of the visual field (the macula) because of damage to the retina. It occurs in “dry” and “wet” forms. It is a major cause of blindness and visual impairment in older adults (>50 years). Macular degeneration can make it difficult or impossible to read or recognize faces, although enough peripheral vision remains to allow other activities of daily life.
Picture of the fundus showing intermediate age-related macular degeneration.
Starting from the inside of the eye and going towards the back, the three main layers at the back of the eye are the retina, which contains the nerves; the choroid, which contains the blood supply; and the sclera, which is the white of the eye.
The macula is the central area of the retina, which provides the most detailed central vision.
In the dry (nonexudative) form, cellular debris called drusen accumulate between the retina and the choroid, and the retina can become detached.
In the wet (exudative) form, which is more severe, blood vessels grow up from the choroid behind the retina, and the retina can also become detached. It can be treated with laser coagulation, and with medication that stops and sometimes reverses the growth of blood vessels. The is a substantial amount of animal model studies showing that stem cells can reverse and or stabilize the vascularization processes, in the retina.
Although some macular dystrophies affecting younger individuals are sometimes referred to as macular degeneration, the term generally refers to age-related macular degeneration (AMD or ARMD).
Age-related macular degeneration begins with characteristic yellow deposits (drusen) in the macula, between the retinal pigment epithelium and the underlying choroid. Most people with these early changes (referred to as age-related maculopathy) have good vision. People with drusen can go on to develop advanced AMD. The risk is considerably higher when the drusen are large and numerous and associated with disturbance in the pigmented cell layer under the macula. Recent research suggests that large and soft drusen are related to elevated cholesterol deposits and may respond to cholesterol-lowering agents.
Central geographic atrophy, the “dry” form of advanced AMD, results from atrophy to the retinal pigment epithelial layer below the retina, which causes vision loss through loss of photoreceptors (rods and cones) in the central part of the eye. No medical or surgical treatment is available for this condition, however vitamin supplements with high doses of antioxidants, lutein and zeaxanthin, have been suggested by the National Eye Institute and others to slow the progression of dry macular degeneration and, in some patients, improve visual acuity.
Vision with Macular Degeneration
Signs and symptoms
Macular degeneration by itself will not lead to total blindness. For that matter, only a very small number of people with visual impairment are totally blind. In almost all cases, some vision remains. Other complicating conditions may possibly lead to such an acute condition (severe stroke or trauma, untreated glaucoma, etc.), but few macular degeneration patients experience total visual loss.
The area of the macula comprises only about 2.1% of the retina, and the remaining 97.9% (the peripheral field) remains unaffected by the disease. Interestingly, even though the macula provides such a small fraction of the visual field, almost half of the visual cortex is devoted to processing macular information.
The loss of central vision profoundly affects visual functioning. It is not possible, for example, to read without central vision. Pictures that attempt to depict the central visual loss of macular degeneration with a black spot do not really do justice to the devastating nature of the visual loss. This can be demonstrated by printing letters 6 inches high on a piece of paper and attempting to identify them while looking straight ahead and holding the paper slightly to the side. Most people find this difficult to do.
There is a loss of contrast sensitivity, so that contours, shadows, and color vision are less vivid. The loss in contrast sensitivity can be quickly and easily measured by a contrast sensitivity test performed either at home or by an eye specialist.
Causes and risk factors
This disorder is now understood to be multifactoral and necessitates the use of multiple approaches to address the underlying etiologies. Below is an overview of the current genetic understanding and chemistries involved.
- Aging: Approximately 10% of patients 66 to 74 years of age will have findings of macular degeneration. The prevalence increases to 30% in patients 75 to 85 years of age.
- Family history: The lifetime risk of developing late-stage macular degeneration is 50% for people that have a relative with macular degeneration, versus 12% for people that do not have relatives with macular degeneration, a fourfold higher risk. (similar lifestyles and of course genetics)
- Macular degeneration gene: The genes for the complement system proteins factor H (CFH), factor B (CFB) and factor 3 (C3) have been determined to be strongly associated with a person’s risk for developing macular degeneration.
- Mutation of the ATP synthase gene: Retinitis pigmentosa (RP) is a genetically linked dysfunction of the retina and is related to mutation of the adenosine triphosphate (ATP) synthase gene 615.1617
- Stargardt’s disease (STGD, also known as juvenile macular degeneration) is an autosomal recessive retinal disorder characterized by a juvenile-onset macular dystrophy, alterations of the peripheral retina, and subretinal deposition of lipofuscin-like material.
- Drusen: CMSD studies indicate that drusen are similar in molecular composition to plaques and deposits in other age-related diseases such as Alzheimer’s disease and atherosclerosis.
- Arg80Gly variant of the complement protein C3:
- Hypertension: Also known as high blood pressure.
- Cardiovascular status: High cholesterol, obesity.
- High fat intake is associated with an increased risk of macular degeneration in both women and men.
- Oxidative stress: It has been proposed that age-related accumulation of low-molecular-weight, phototoxic, pro-oxidant melanin oligomers within lysosomes in the retinal pigment epithelium may be partly responsible for decreasing the digestive rate of photoreceptor outer rod segments (POS) by the RPE.
- Fibulin-5 mutation: Rare forms of the disease are caused by geneic defects in fibulin-5, in an autosomal dominant manner.
- Exposure to sunlight especially blue light: There is conflicting evidence as to whether exposure to sunlight contributes to the development of macular degeneration.
- Smoking: Smoking tobacco increases the risk of macular degeneration by two to three times that of someone who has never smoked, and may be the most important modifiable factor in its prevention.
- Deletion of CFHR3 and CFHR1: Deletion of the complement factor H-related genes CFHR3 and CFHR1 protects against age-related macular degeneration.
The practical application of AMD-associated markers, such as seen above, is in the prediction of progression of AMD from early stages of the disease to neovascularization.
A family of immune mediators has been shown to be plentiful in drusen, the cellular debris associated with macular degeneration. Complement factor H (CFH) is an important inhibitor of this inflammatory cascade and a disease-associated polymorphism in the CFH gene strongly associates with AMD. Thus an AMD pathophysiological model of chronic low grade complement activation and inflammation in the macula has been advanced. Lending credibility to this has been the discovery of disease-associated genetic polymorphisms in other elements of the complement cascade including complement component 3 (C3).
The role of retinal oxidative stress in the etiology of AMD by causing further inflammation of the macula is suggested by the enhanced rate of disease in smokers and those exposed to UV irradiation. Mitochondria are a major source of oxygen free radicals that occur as a byproduct of energy metabolism. Mitochondrial gene polymorphisms, such as that in the MT-ND2 molecule, predicts wet AMD.
A powerful predictor of AMD is found on chromosome 10q26 at LOC 387715. An insertion/deletion polymorphism at this site reduces expression of the ARMS2 gene though destabilization of its mRNA through deletion of the polyadenylation signal. ARMS2 protein may localize to the mitochondria and participate in energy metabolism, though much remains to be discovered about its function.
Other gene markers of progression risk includes Tissue Inhibitor of Metalloproteinase 3 (TIMP3) suggesting a role for intracellular matrix metabolism in AMD progression. Variations in cholesterol metabolising genes such as the hepatic lipase (LIPC), cholesterol ester transferase (CETP), lipoprotein lipase (LPL) and the ABC-binding cassette A1 (ABCA1) correlate with disease progression, Early stigmata of disease, drusen, are rich in cholesterol, offering face validity to the results of genome wide association studies
Stem Cell Therapy
The newest finding confirm that immune mediators of the complement cascade are one of the responsible mechanisms creating this disorder. Immune modulation has been the hallmark of stem cell therapy and is well researched in a number of other diseases. The second mechanism of decreasing inflammation commonly seen post stem cell therapy, is also responsible for the decrease in macular degeneration.
Although there is a limited amount of clinical or published data, considering the very low risk from both the procedure and the use of autologous cells this approach has significant merit. A number of new clinical trials have been approved based on the genetic and immune markers expressions and the active input that stem cells can affect on these pathways.
Unfortunately the studies just announced are for embryonic cell use and will take years to translate to clinical practice. We feel strongly that autologous cells have shown similar potentials, have a high safety index and can be used currently with good to excellent potential outcomes.
Additional medical interventions targeting the lipids (fats) along with the use of antioxidant therapy should maximize the impact of the cellular therapy and result in stabilization or even partial reversal of macular degeneration.
Antioxidant therapy is somewhat controversial due to contradictory results of a number of studies and the conflict of interest suggested by some. The different results may be more of a effect of lack of superior products and proper testing of the patients, prior to supplementation. I believe that most findings suggest strongly that the use of the antioxidants can be a positive input and should be considered for the appropriate patient.
Autologous Stem-Cell Transplant Phases :
After a review of your medical records and discussions with medical staff, a protocol is designed especially for you. Specifics of your condition are addressed along with any special needs. It may be similar to the one illustrated below:
At the clinic you will be examined by our physicians. Information including any risks and expectations concerning your treatment, plus answers to any questions you may have will be addressed. A blood draw, to determine cell counts and other chemistries will be collected and cell expansion medication may be administered. Then you will return to your hotel for a restful day or a good nights sleep.
At the clinic our physician/s will review the laboratory results, determine if the cell count is within range, and discuss the response to the stimulation. They may or may not provide additional cell expansion medications and may add adjunctive treatments. The levels of your response will determine if you would return to the hotel, with little restriction on your activities, or possibly go forward with harvesting and processing your cells.
If the cell count and viability is appropriate for harvest either a bone marrow or adipose collection will be utilized. We typically use local anesthetics for adults and general anesthesia for youngsters. The entire procedure normally takes less than 30 minutes. Although some pain is felt when the needle is inserted, most patients do not find the bone marrow or adipose collection procedure particularly painful.
We recently placed a number of videos on our website interviewing our patient’s who discuss the procedure and their lack of discomfort.
After the collection you may return to the hotel, with some restrictions. The bone marrow or adipose collected is processed in our contract state of art laboratory by trained staff, under the supervision of the laboratory physician.
As an alternative to the above, cord blood may be used based on the patient’s individual medical condition and options.
At the clinic or at the hospital you will be treated by an intrabulbar (into the eye) injection and IV infusion by one of our board certified othalmologist. This allows the stem cells to begin activity in the affected areas directly. When the procedure is performed, you will be given a very mild anesthetic into the eye and be asked to restrict your activities for that day.
At the clinic or hospital the patient will receive a post-treatment examination and evaluation prior to release. Additional therapy and treatments may also be utilized to maximize the placement and activities of the procedure.
Day 6: Optionally there may be the use of additional ancillary therapies to enhance the procedure and additional evaluations.
What makes our treatment different ?
Our approach includes stimulation, prior to collection, processing and expansion of the cell along with the use of growth factors, together with an integrated medical approach. This maximizes the growth and implantation potentials yielding optimized potentials of making changes in your disease.
Our staff physicians are all board certified, in their field with years of experience. Your team includes both primary and ancillary care professionals devoted to maximizing your benefits from the procedures. We enroll you in an open registry to track your changes independently, for up to 20 years.
As our patient we also keep you abreast of the newest developments in stem cell research. This is an ongoing relationship to maintain and enhance your health.
Our promise is to provide you with travel and lodging support, access to bilingual staff members throughout the entire process and most importantly the best medical care possible.
References and Articles:
Volume 120, Issue 9 (September 1, 2010) J Clin Invest. 2010;120(9):3012–3021. doi:10.1172/JCI42951. Copyright © 2010, American Society for Clinical Investigation
Stemming vision loss with stem cells
Valentina Marchetti, Tim U. Krohne, David F. Friedlander and Martin Friedlander
Department of Cell Biology, The Scripps Research Institute, La Jolla, California, USA. School of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
Dramatic advances in the field of stem cell research have raised the possibility of using these cells to treat a variety of diseases. The eye is an excellent target organ for such cell-based therapeutics due to its ready accessibility, the prevalence of vasculo- and neurodegenerative diseases affecting vision, and the availability of animal models to demonstrate proof of concept. In fact, stem cell therapies have already been applied to the treatment of disease affecting the ocular surface, leading to preservation of vision. Diseases in the back of the eye, such as macular degeneration, diabetic retinopathy, and inherited retinal degenerations, present greater challenges, but rapidly emerging stem cell technologies hold the promise of autologous grafts to stabilize vision loss through cellular replacement or paracrine rescue effects.
Therapeutic photoreceptor cell regeneration using stem cells. AMD may be an ideal target for a stem cell–based therapeutic approach for a number of reasons. First, RPE cells can consistently be differentiated from stem cells. Second, AMD is not caused by monogenetic defects and only manifests late in life, meaning that autologous iPSC-derived RPE grafts would not be expected to be rapidly affected by the disease. Third, RPE cell grafts can be readily delivered directly into the correct location under the retina. Finally, unlike neuronal grafts, the transplanted cells do not require synaptic integration into the neuronal retinal network to become functional.
The greatest opportunity to treat these neurodegenerative diseases of the eye (such as retinitis pigmentosa) will come from early intervention with cells providing trophic rescue of existing, albeit “sick,” neurons. In this regard, one of the most potentially efficacious approaches may be to replace and/or rescue diseased RPE cells in patients with AMD.
Published in Volume 114, Issue 6 (September 15, 2004) J Clin Invest. 2004;114(6):765–774. doi:10.1172/JCI21686. Copyright © 2004, American Society for Clinical Investigation
Rescue of retinal degeneration by intravitreally injected adult bone marrow–derived lineage-negative hematopoietic stem cells
Atsushi Otani, Michael Ian Dorrell, Karen Kinder, Stacey K. Moreno, Steven Nusinowitz, Eyal Banin, John Heckenlively and Martin Friedlander
Inherited retinal degenerations afflict 1 in 3,500 individuals and are a heterogeneous group of diseases that result in profound vision loss, usually the result of retinal neuronal apoptosis. Atrophic changes in the retinal vasculature are also observed in many of these degenerations. While it is thought that this atrophy is secondary to diminished metabolic demand in the face of retinal degeneration, the precise relationship between the retinal neuronal and vascular degeneration is not clear. In this study we demonstrate that whenever a fraction of mouse or human adult bone marrow–derived stem cells (lineage-negative hematopoietic stem cells [Lin– HSCs]) containing endothelial precursors stabilizes and rescues retinal blood vessels that would ordinarily completely degenerate, a dramatic neurotrophic rescue effect is also observed. Retinal nuclear layers are preserved in 2 mouse models of retinal degeneration, rd1 and rd10, and detectable, albeit severely abnormal, electroretinogram recordings are observed in rescued mice at times when they are never observed in control-treated or untreated eyes. The normal mouse retina consists predominantly of rods, but the rescued cells after treatment with Lin–HSCs are nearly all cones. Microarray analysis of rescued retinas demonstrates significant upregulation of many antiapoptotic genes, including small heat shock proteins and transcription factors. These results suggest a new paradigm for thinking about the relationship between vasculature and associated retinal neuronal tissue as well as a potential treatment for delaying the progression of vision loss associated with retinal degeneration regardless of the underlying genetic defect.
Received 4 November 2006; Accepted 25 April 2007. Available online 8 May 2007
Subretinal transplantation of bone marrow mesenchymal stem cells delays retinal degeneration in the RCS rat model of retinal degeneration
Yuji Inoue, Aya Iriyamaa, Shuji Ueno, Hidenori Takahashi, Mineo Kondo, Yasuhiro Tamaki, Makoto Araie, Yasuo Yanagi Department of Ophthalmology, University of Tokyo School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan Department of Ophthalmology, Nagoya University School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan
Because there is no effective treatment for this retinal degeneration, potential application of cell-based therapy has attracted considerable attention. Several investigations support that bone marrow mesenchymal stem cells (MSCs) can be used for a broad spectrum of indications. Bone marrow MSCs exert their therapeutic effect in part by secreting trophic factors to promote cell survival. The current study investigates whether bone marrow MSCs secrete factor(s) to promote photoreceptor cell survival and whether subretinal transplantation of bone marrow MSCs promotes photoreceptor survival in a retinal degeneration model using Royal College of Surgeons (RCS) rats. In vitro, using mouse retinal cell culture, it was demonstrated that the conditioned medium of the MSCs delays photoreceptor cell apoptosis, suggesting that the secreted factor(s) from the MSCs promote photoreceptor cell survival. In vivo, the MSCs were injected into the subretinal space of the RCS rats and histological analysis, real-time RT-PCR and electrophysiological analysis demonstrated that the subretinal transplantation of MSCs delays retinal degeneration and preserves retinal function in the RCS rats. These results suggest that MSC is a useful cell source for cell-replacement therapy for some forms of retinal degeneration.
July 11, 2011 By admin 14 Comments
Macular Degeneration Stem Cell Treatment Trials Start in July
Stem cell treatment trials for patients suffering from macular degeneration began in July at the Jules Stein Eye Institute at the University of California, Los Angeles.
Cells derived from human embryonic stem cells will be used in this macular degeneration trial in an attempt to either slow or halt the progression of both macular degeneration and dystrophy.
Twenty-four patients have been selected for this stem cell treatment and will have the cells injected into their eyes as part of this trial. It is hoped this stem cell treatment will heal the damage brought on by the macular eye diseases.
Macular degeneration damages the retinal cells in the eye. This new stem cell treatment will replace the retinal cells but it has proven to be somewhat controversial because the replacement cells are derived from human embryonic stem cells.
Advanced Cell Technology has been developing this new macular degeneration stem cell treatment for 10 years and it is hoped patients suffering from dry macular degeneration will benefit. Twelve of the patients selected have dry macular degeneration and the other twelve suffer from Stargardt’s macular dystrophy which is a version of macular degeneration affecting people 10 to 20 years old.
Each group will receive a number of stem cell treatments and be monitored for the first 12 months to determine the safety of the procedure.
Dry macular degeneration is the most common cause of blindness and the leading cause of vision loss in people aged 55 and over. The number of people expected to be diagnosed with the disease is expected to double in the next 20 years.
Comments: We do not use embryonic cells in our therapies and this limited study will take years to complete. It will provide additional information, alibet of limited use clinically.
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