Kameran Lashkari, M.D.

Harvard Medical School

Assistant Professor of Ophthalmology, Part-Time

Schepens Eye Research Institute of Massachusetts Eye and Ear

Assistant Scientist

Research Summary

Center/Research Area Affiliations

Biography

Dr. Lashkari is investigating novel biomarkers and their impact on the pathophysiology of ocular disease, including AMD, proliferative diabetic retinopathy, and diabetic macular edema (DME). In AMD, he has identified distinct biomarkers associated with intermediate dry, advanced dry (geographic atrophy), and wet AMD. Several of these biomarkers are also potential therapeutic targets in AMD. Dr. Lashkari has identified other therapeutic targets in the super-VEGF family that are particularly helpful in cases of wet AMD that are resistant to anti-VEGF-A monotherapy. In the area of diabetic retinopathy and DME, Dr. Lashkari is also developing biomarkers that may be involved in alterations in tissue permeability and angiogenesis. To this end, Dr. Lashkari has an established long-term collaboration with various local and international pharmaceutical companies.

Dr. Lashkari also investigates the application of retinal progenitor cells (RPC) in tissue replacement and cell-based neurotrophic therapy. He has shown that transplanted RPCs expressing various factors can prevent development of optic nerve damage in experimental glaucoma. This work can be applied to glaucoma, the optic nerve, and retina degeneration.

Additionally, Dr. Lashkari has studied the role of growth factors and down-streak regulators in retinal would healing and RPE cell biology. These include studies on the role of hepatocyte growth factor in retinal laser injury.

Download his CV or biosketch [PDF] for more information.

Education

M.D., New York Medical College (1985)

Postgraduate Training

Internal Medicine Residency, St. Vincent’s Hospital and Medical Center (1986-1988)
Chief Resident, St. Vincent’s Hospital and Medical Center (1988-1989)
Medical Retina and Research Fellowship, Schepens Eye Research Institute of Mass. Eye and Ear (1989-1990)
Ophthalmology Residency, University of Missouri Eye Foundation of Kansas City, (1990-1992)
Chief Resident, University of Missouri Eye Foundation of Kansas City (1992-1993)

Honors

2014-2018: Stone Scholar Endowment Award, Schepens Eye Research Institute of Mass. Eye and Ear (renewed)
2007-2014: Stone Scholar Endowment Award, Schepens Eye Research Institute of Mass. Eye and Ear (renewed)
2002-2007: Stone Scholar Endowment Award
1999-2002 and 1989-1999: Clinical Investigator Award, Schepens Eye Research Institute of Mass. Eye and Ear

Projects

Special Relationship with Industry and track record of Industry-Sponsored Research

Dr. Lashkari has established a special relationship with Industry and performs industry sponsored research collaboration including discovery targets for therapy. He has an excellent track record of collaboration in areas of wet AMD, dry AMD, diabetic retinopathy, and stem cells with industry. Sponsors include Novartis Institute for Biomedical Research, GlaxoSmithKline, Allergan, Regeneron, Ophthea, Pfizer, NeoStem (Caladrius), among others.

Novel Targeted Treatment for Refractory wet AMD and Geographic Atrophy

Neovascular AMD: 

Dr. Lashkari has identified an unmet medical need in management of patients with wet AMD who are resistant to standard anti-VEGF monotherapy. In collaboration with Opthea Inc., he has developed alternative treatments to anti-VEGF-A therapy, utilizing other members of the VEGF family, VEGF-C and VEGF-D and their common receptor, VEGFR-3. In animal models of laser-induced choroidal neovascularization, his laboratory has shown that a trap for VEGF-C and VEGF-D (named OPT-302) can effectively inhibit choroidal neovascularization as effectively as Aflibercept (Eylea) and that humanized traps for VEGF-C/D may be used as an adjuvant to standard therapy. Using our data, Opthea Inc. obtained FDA approval for clinical studies. OPT-302 successfully completed Phase I/IIa clinical trials (both as primary drug or as adjuvant drug), and a larger Phase IIb trial is currently under way. 

Using plasma samples from a large cohort of subjects with dry and wet AMD and age-matched controls, Dr. Lashkari has recently shown that VEGF-C and its soluble receptor sVEGR-3 are elevated in subjects with acute wet AMD. Treatment of subjects with wet AMD using anti-VEGF monotherapy, normalizes the levels of sVEGFR-3 but levels of VEGF-C remain elevated. Using a mixed model statistical approach, we showed that VEGF-C and sVEGFR-3 can be used as diagnostic biomarkers for a blood test for wet AMD. A diagnostic and therapeutic patent was recently issued. 

Using the laser model of choroidal neovascularization (CNV; as a model for wet AMD) and in collaboration with GlaxoSmithKline, Dr. Lashkari recently showed that inhibitors of PI3kinase/mTOR pathway (which signal downstream of many angiogenic receptors including VEGF) are highly effective in reducing leakage and growth of CNV lesions and scar formation. 

Pathogenesis of dry AMD and Geographic Atrophy

As part of collaborative work with GlaxoSmithKline in advanced dry AMD (geographic atrophy), Dr. Lashkari recently identified -amyloid(1-40) and its soluble precursor protein, sAPP as being elevated in plasma of subjects with geographic atrophy. Using novel in vitro assays the collaborative team showed that -amyloid(1-40) binds to complement factor I (CFI), one of the members of the alternative complement pathway. CFI functions as a brake in the system by converting C3 to its inactive form via iC3b and preventing developing of cascades that result in production of membrane attack complex. Binding of amyloid to CFI causes a reduction in CFI bioactivity (hence, removing the brakes from the system). Interestingly, adding a monoclonal antibody to -amyloid in the same reaction mixture restores CFI bioactivity. Using novel methodology, the team calculated CFI bioactivity and was able to measure CFI bioactivity in a variety of biological samples such as in plasma of subjects with AMD. 

In the area of dry AMD, Dr. Lashkari’s lab has has identified unique diagnostic and therapeutic biomarkers. Using clinical specimens from various stages of AMD, he has identified families of pro-inflammatory and pro-angiogenic factors including eotaxins and -interferon-inducible proteins for use as novel early biomarkers of disease progression or potential targets for drug development. Through clinical collaborations he has developed the only existing local repository for AMD tissue, shared upon request with academic researchers. 

Biomarkers in Diabetic Macular Edema (DME)

Dr. Lashkari’s biomarker work has expanded into the area of DME. In collaboration with industry members including Regeneron Inc., he has identified several proangiogenic factors in ocular specimens from a large cohort of subjects with DME, using multiplexing. His lab subsequently examined a second large cohort of subjects with DME and showed that 8 markers remained altered in the new cohort as compared to age-matched controls. Additional target biomarkers are currently being evaluated in an optimized and modified model of STZ-induced rat model of diabetic retinopathy. Using this model, it is possible to identify new biomarkers, novel therapeutic targets and test target engagement.

Retinal Progenitor Cells for Glaucoma and Retinal Degeneration

Other primary research accomplishments are in cell-based therapy for AMD and related degenerative diseases. Dr. Lashkari has characterized and transplanted an adult retinal/neuronal progenitor cell line I derived from surgical specimens from eyes with persistent fetal membranes. A Harvard Stem Cell Institute Seed Grant allowed me to generate data that garnered support from the Canary Charitable Foundation for application of this novel (patented) adult retinal progenitor cells in cell-based therapy in eye diseases including optic nerve degeneration. He was the first to hypothesize that the unique properties of these progenitor cells allow spontaneous penetration of the intact retinal barrier and integrate with the host (Chen et al. Cell Transplantation, 2012). He has shown that engineering these cells to express neuroprotective factors such as insulin growth factor-1 (IGF-1) can protect retinal ganglion cells against death in an experimental model of glaucoma. Transplantation of these human progenitor cells with protective factors would be a viable and practical modality to prevent or retard the course of retinal degeneration including AMD. His work has resulted in multiple patent applications. Two patents have been currently issued.

Publications

H-index

30 (Google Scholar, as of October 2018)

Selected Publications

Dr. Lashkari has published more than 40 peer-reviewed articles. Below is a list of selected publications. View his publications on PubMed or Google Scholar.

  1. Ma J, Mehta M, Lam G, Cyr D, Ng TF, Hirose T, Tawansy KA, Taylor AW, Lashkari K. Influence of subretinal fluid in advanced stage retinopathy of prematurity on proangiogenic response and cell proliferation. Mol. Vis. 2014; (20):881-893.
  2. Wiecek E, Lashkari K. Dakin SC, Bex P. Novel quantitative assessment of metamorphopsia in  maculopathy. Invest Ophthalmol Vis Sci. 2014. 56(1):494-504.
  3. Wiecek E, Lashkari K, Dakin SC, Bex P. A statistical analysis of metamorphopsia in 7,106 Amsler Grids. Ophthalmology.  2015; 122(2): 431-433.
  4. Ma J, Guo C, Guo C, Sun Y, Liao T, Beattie U, Lopez FJ, Chen DF, Lashkari K. Transplantation of human neural progenitor cells expressing IGF-1 enhances retinal ganglion cell survival. PLoS ONE 2015;10(4):e0125695.
  5. Kovacs K, Marra KV, Yu G, Wagley S, Ma J, Teague GC, Nandakumar N, Lashkari K, Arroyo JG. Angiogenic and inflammatory vitreous biomarkers associated with increasing levels of retinal ischemia. Invest Ophthalmol Vis Sci. 2015;56(11):6523-30.
  6. Ma J, Lopez FJ, Adamson P, Kurali E, Lashkari K. Blockage of PI3K/mTOR pathways inhibits laser-induced choroidal neovascularization and improves outcomes relative to VEGF-A suppression alone. Invest Ophthalmol Vis Sci. 2016;57(6):3138-3144.
  7. Feng L, Ju M, Lee KYV, Mackey A, Evangelista M, Iwata D, Adamson P, Lashkari K, Foxton R, Shima D, Ng YS. A Proinflammatory function of toll-like receptor 2 in the retinal pigment epithelium as a novel target for reducing choroidal neovascularization in age-related macular degeneration. American Journal of Pathology. 2017;187(10):2208-2221.
  8. Lashkari K, Teague G, Chen H, Lin Y-Q, Kumar S, McLaughlin MM, Lopez FJ. A monoclonal antibody targeting amyloid b (Ab) restores complement factor I bioactivity: Potential implications in age-related macular degeneration and Alzheimer’s disease. PLoS ONE 2018;13(5): e0195751.

Patents

For a complete list of Dr. Lashkari’s patents, download his CV [PDF].

Electro-Optic Binocular Indirect Ophthalmoscope
Harooni M. & Lashkari K. U.S. Patent No. 5,841,509
This invention describes a system for imaging in the near infrared (NIR) that obviates any need for pupillary dilation. It entails designs for an indirect binocular ophthalmoscope that can image the retina in real time in NIR. It is particularly suited for pediatric exams and triaging patients without the need for pupillary dilation. This invention has military applications, as a simpler version of the ophthalmoscope can be designed to be use by medics in real time.

Electro-Optic Binocular Indirect Ophthalmoscope for Stereoscopic Observation of Retina
Lashkari K & Harooni M. U.S. Patent No. 6,089,716
Continuation of prior art (see above).

Electro-Optic Binocular Indirect Ophthalmoscope
Lashkari K & Harooni M. U.S. Patent No. 6,350,031
Continuation of prior art (see above).

Systems & Method for Multilayer Imaging and Retinal Injury
Mangoubi R, Desai M, Lashkari K & Fazelat A. U.S. Patent No. 13/233,520
This is a method for analyzing NIR images captured by ophthalmoscopes imaging in the NIR wavelength described in our previous patents. The technique describes a series of algorithm for enhancing the signal embedded in NIR images and additionally incorporates a novel design for a camera operating in NIR.

System and method for use of infrared binocular ophthalmoscope in imaging and photodynamic therapy
Lashkari K. U.S. Patent No. 8,888,765
This invention allows for simultaneous examination and treatment of the eye with PDT. It allows for easily performing PDT on peripheral retina, and it is well-suited for pediatric retinal vascular disease and tumors

Isolation and therapeutic application of adult retinal stem cells collected from extra-retinal tissues
Lashkari K, Shatos m & Ng T. Patent No. 0,061,017
This invention describes the use of adult stem cells derived from neovascular tissue for transplantation of retina and retinal ganglion cells that form the optic nerve. Stem cells are derived from eyes with retinopathy of prematurity and persistent fetal vasculature, respectively

Biomarkers for Age-Related Macular Degeneration
Lashkari K, Ma, J, Baldwin, ME. European Patent EP2994758B1
This invention describes the utility of plasma VEGF-C and sVEGFR-3 in diagnosis of wet AMD.

Isolation and therapeutic application of adult retinal stem cells collected from extra-retinal tissues
Lashkari K, Shatos m & Ng T. U.S. Patent No 10,039,790
Continuation of previous invention.

Laboratory

Current Members of Dr. Kameran Lashkari’s Laboratory

Tytelli Turunen, Ph.D. - Postdoctoral Fellow

Alexander Hua, B.S., M.S. - Research Fellow

Gianna Teague, B.S. - Laboratory Manager

Marie Shatos, Ph.D. - Part-time Scientist

Jie Ma, Ph.D. - Visiting Scientist

Alumni

More than 17 trainees have worked in Dr. Lashkari’s laboratory. To view the complete list of alumni, download his CV [PDF].