Moran鈥檚 SCTM Team Broke New Ground in 2021 to Turn Genetic Discoveries into New AMD Treatment Strategies
The promise of personalized medicine is clear: researchers and physicians alike are working toward the day when our genetic makeup can guide disease treatment and prevention.
Yet, realizing this next evolution of care hasn鈥檛 come easily. It requires big money, big data, big collaborations, and time to develop a clear picture of how genetics plus lifestyle factors鈥攖hink smoking, diet, or exercise鈥攑ut someone at risk for or protect them against disease. Since scientists first sequenced the human genome in 2003, the FDA has approved just two gene therapies that introduce genetic material into the body.
But the John A. Moran Eye Center鈥檚 is connecting the dots between genetics and disease and developing personalized treatments for age-related macular degeneration (AMD), a leading cause of blindness for people age 55 and older. The SCTM recently shared its work in a string of research papers appearing in some of the field鈥檚 most respected scientific journals.
The discoveries deepen our understanding of genetic protections against developing AMD and indicate that a therapy the SCTM and its corporate partner are preparing for human clinical trials could benefit even more patients than initially thought.
The SCTM has also provided more evidence supporting its advanced understanding of AMD as not one disease but as at least two biologically distinct diseases.
鈥淚t鈥檚 been a wonderful year for us,鈥 says , executive director of the SCTM. 鈥淚鈥檓 so proud of this team and the strides we鈥檝e made to help patients with AMD. It鈥檚 exciting to share this story with the world.鈥
Genetic Therapy on the Horizon
Years of SCTM research, including conducting one of the world鈥檚 largest ocular gene expression studies, have shown genes on chromosomes 1 and 10 account for about 90% of a person鈥檚 risk for developing AMD. A cluster of six genes on chromosome 1, which plays a critical role in the immune system, directs one form; a pair of genes on chromosome 10, associated with maintaining ocular health as we age, causes a second. Also in the mix are genetic variants that offer protection against developing AMD.
The first treatment developed by the SCTM in conjunction with its corporate partner is a gene therapy that targets chromosome 1-directed AMD by delivering genetic material to the eye through an injection. 鈥淭he ultimate goal is to slow or halt AMD with a single injection into the eye,鈥 says Hageman.
Researchers have been fine-tuning the drug dosage and best injection site in the retina, the light-sensitive layers of nerve tissue at the back of the eye. The SCTM and its corporate partner are seeking clearance from the FDA to start clinical trials in humans, the first step toward FDA approval. The Moran Eye Center and other locations, including Ireland and Israel, would start testing safety in a small number of AMD patients who have already lost their vision. Once clinicians determine the drug is safe over a six-month testing period, the trials would test efficacy over two years in up to 400 patients with chromosome 1-directed AMD.
While working to finalize the therapy for chromosome 1-directed AMD, SCTM scientists made a welcome discovery: the treatment may also help patients with chromosome 10-directed AMD.
Publishing in Human Genomics in fall 2021, SCTM scientists explained combinations of genetic variants, or haplotypes, on chromosome 1 are so protective that they outweigh risk for people with a combination of risk and protective haplotypes. It鈥檚 an ace in the hole that can guard against developing chromosome 1- and hopefully 10-directed AMD.
鈥淭his finding opens up the possibility that therapeutics designed to target the form of AMD driven by risk on chromosome 1 may also be effective in treating a vast majority of AMD, regardless of genetic cause,鈥 explained SCTM researcher , the lead author of the study.
Connecting Genetics to Disease Progression
At Moran鈥檚 , researchers are connecting the genetics of AMD to clinical symptoms of disease. Under the direction of SCTM clinician-scientist Steffen Schmitz-Valckenberg, MD, they are using advanced imaging software and patient study data to link genetics to rates of disease progression and vision loss.
Publishing in the prestigious journal JAMA Ophthalmology in February 2022, the team examined data from three sub颅groups of AMD patients with genetic backgrounds that put them at risk for developing AMD. The scientists determined patients with two copies of genetic risk variants (homozygous) at both chromosomes 1 and 10 reached sight-threatening, late-stage AMD the earliest, within a median of 4.4 years. In comparison, patients homozygous at chromosome 1 only reached late-stage within 6.3 years and patients homozygous at chromosome 10 only within 10.4 years.
鈥淲e can now employ this information to design more effective clinical trials to evaluate new therapies for AMD,鈥 says Schmitz-Valckenberg.
The research provides further support for a new way of thinking about AMD. Schmitz-Valckenberg and SCTM clinician-scientist Monika Fleckenstein, MD, published in collaboration with an international group of researchers in Nature Reviews Disease Primers in 2021 to provide an overview of AMD.
鈥淲e hope to inspire our colleagues to see AMD not as one single disease, but rather as a disease spectrum,鈥 says Fleckenstein, lead author of the Nature Reviews article.
Shaking Up the Field
SCTM research also pointed to a potential treatment for chromosome 10-directed AMD that boosts the amount of a protein called HtrA1 in the retina.
Led by Brandi L. Williams, PhD, the SCTM鈥檚 chromosome 10 research team shared groundbreaking findings in a paper published in Proceedings of the National Academy of Science of the United States of America. Using tissue resources only available at Moran, the research showed for the first time that HtrA1 is essential in maintaining ocular health. The findings contradict previously published research from other teams that suggests reducing HtrA1 can help AMD patients.
The team found that during normal aging, the HtrA1 protein increases in the retina, where it may prevent the accumulation of abnormal deposits.
Yet people with genetic variants on chromosome 10 make half as much HtrA1 in this part of the retina as they age, causing damage to the eye.
鈥淚t is intriguing to think that restoration of normal levels of HtrA1 may be a viable therapeutic option for AMD,鈥 Hageman says.
Spreading the Word
Hageman will travel the world in 2022 to share the SCTM research advances. His invitations include giving the keynote address to an elite group of AMD scientists and clinicians at the Stephen J. Ryan Initiative for Macular Research annual conference.
鈥淲hen Dr. Hageman started his AMD-related research nearly 30 years ago, he was a marine biologist who decided to shift gears at a time when this horrible, blinding disease was simply accepted as something no one could do anything about,鈥 says Randall J Olson, MD, Moran Eye Center CEO. 鈥淗e didn鈥檛 accept that. I didn鈥檛 accept that. In 2009, we teamed up to create what is now the SCTM as a unique academic model鈥nd it鈥檚 working.鈥
The SCTM Approach
A unique approach and unmatched resources drive SCTM research and drug development:
- Donor and Institutional Funds: In a time of limited federal funding, the Moran Eye Center and individuals, corporations, and foundations provide financial support to hire top researchers and rapidly advance their work.
- Better Tools: Since no other organism develops AMD, researchers must work with study subjects and donated human tissue. SCTM resources include the world鈥檚 largest donor eye tissue repository of its kind with nearly 10,000 eyes.
- Combined Expert Knowledge: The SCTM, as part of 91麻豆天美直播, brings together local, national, and international scientists and clinicians from multiple disciplines for research collaboration.
- One of the World鈥檚 Largest Genetic Patient Cohorts: An SCTM study has enrolled over 4,700 people, with and without AMD or a family history of the disease, and has obtained more than 60,000 DNA samples from other AMD-, ethnic-, population-, and disease-based cohorts. Researchers employ the data to fully understand the underlying genetic and biological bases of AMD and its related diseases.