A New Approach to Treating Chronic Kidney Disease Replenishing Your Nephrons

As some of you may know, I have chronic kidney disease (CKD). Thanks to my wife and the scare put into me by my nephrologist, that I would soon have to begin dialysis, I have managed to get my CKD  in remission, or at least under control. My GFR number (that indicates when you must start dialysis) has held steady, or actually gotten better since my wife put me on a strict diet and I have lost about 15 pounds – and my nephrologist took me off of lisinopril (for blood pressure control), which seemed to raise my GFR by about three points. So, it appears I won’t have to go on dialysis any time soon.

All that being said, and with my strong interest in the use of stem cells and gene therapy in treating retinal diseases in ophthalmology, I have been searching the web for research on the use of stem cells to treat kidney disease or to produce new nephrons, the kidney cells that filter the blood as it passes through the kidney – and that go bad or die causing CKD. I think I have found very early research of that possibility.

Earlier this week, I saw a news  release from the University of Queensland in Australia that said that Dr. Melissa Little and her research group at the Institute of Molecular Bioscience (IMB) have found a set of six genes that can prompt some types of adult kidney cells to regress to an earlier stage of development (stem cells) and act like the precursors to the cells of the nephron. Since it is death or damage of nephrons that causes chronic kidney disease, by forcing adult cells to act like early nephrons, they may have potentially found a way to trigger the growth of new filters in the kidney.

All of your nephron cells are formed before birth and people with fewer nephrons are at higher risk of kidney disease.

Note: Dr. Little is one of sources that I had found in my web search as she had published a paper on “Stem Cell Options for Kidney Disease” in 2008, and we had corresponded at the beginning of this year when I began my search for a stem cell answer.

"This discovery is the first of its kind and offers hope to patients with chronic kidney disease. If we can find a way to provide new nephrons to an adult or increase nephron numbers in babies at birth, we could potentially reduce the risk of disease progression," said Professor Little.

This landmark paper, “Direct Transcriptional Reprogramming of Adult Cells to Embryonic Nephron Progenitors”, by Caroline E. Hendry, Jessica M. Vanslambrouck, Jessica Ineson, Norseha Suhaimi, Minoru Takasato, under the supervision of Professors Fiona Rae and Melissa H. Little, was published June 14th in the Journal of the American Society of Nephrology, the world's leading nephrology journal.

Professor Little said, “There was still more work to be done to encourage these reprogrammed early nephron cells to function and integrate. While this is a beginning, we hope it will inspire industry leaders and researchers around the world to invest further in cellular and bioengineering approaches to kidney repair and regeneration."

Stem Cells Australia Program Leader and Chair of Stem Cell Science at The University of Melbourne, Professor Martin Pera welcomed the research findings. "This innovative study provides evidence that adult cells can be reprogrammed to resemble the cells in the embryo that give rise to the kidney. The results pave the way for future studies that will enable researchers to produce human kidney cells in the laboratory, for use in studies of renal disorders, and for testing new drugs. Eventually this technology might help to make cells for transplantation to treat kidney disease," said Professor Pera.

The Technology

I have attempted to read Dr. Little’s paper on reprogramming kidney cells, and with her assistance, this is what I understand she and her colleagues have done, which is a very early step in the long road to someday being able to replenish nephron cells in an adult kidney.

In an earlier paper written by Caroline Hendry and Dr. Little, “Reprogramming the kidney: a novel approach for regeneration”, they discussed the various approaches that might be taken to re-create viable cells within a diseased kidney, including using  induced pluripotent stem cells (iPSCs) derived from skin cells or other sites, or even the use of embryonic stem cells (ESCs) that would be introduced into the kidney to form new nephrons (?), if they could – as shown in the accompanying figure (but how would you control the formation of the new cells?). But they concluded that the best approach would be reprogramming existing kidney cells to the progenitor stage, with the hope that these would develop into the needed new cells, or in this case, nephrons, the approach they ultimately used in this new research.

Figure1 | The application of reprogramming to the kidney, indicating the feasible starting cells and target phenotypes.

(i) Reprogramming may involve the directed differentiation of human embryonic stem cells (hESCs)/induced pluripotent stem cells (iPSCs) to a renal lineage. The iPSCs may be recipient-derived and may be derived from adult kidney cells or any other available adult cell type using the same factors. Directed differentiation is likely to recapitulate development; hence, it is likely to require differentiation through a nephron progenitor intermediate (induced nephron progenitor cell; iNP) but may continue on to more specific mature renal cell types.

(ii) A specific renal lineage may also be achieved via lineage-instructive reprogramming directly to that state from an adult cell type. Again, this may be the renal epithelium, renal stroma, or any other available differentiated adult cell type; however, this is likely to be more successful if the attractor states of the starting and target cell type are as close as possible. Reprogramming may be to the iNP state or directly to a more mature renal cell fate.

(iii) Finally, reprogramming may use the classical Yamanaka factors until the cells pass the point of no return, after which a renal lineage may be reached via the application of the appropriate environmental cues. Such cues may once again target the iNP state or aim to directly induce a more mature renal cell type.

As previously stated, the nephron progenitor population of the embryonic kidney gives rise to all of the nephron cells that will be present in the adult kidney, prior to birth. So, currently, what you’ve got at birth is what you live with.

Using a screening technique, the researchers were able to identify a group of six genes, that activate a network of genes that can reprogram adult proximal tubule cells back to the nephron progenitor stage – which in turn can form adult nephron cells. Although the researchers believe that other factors are required, they concluded that these results suggest that re-initiation of kidney development (nephron cells) from a population of adult cells (proximal tubule cells) by generating embryonic progenitors may be feasible, opening the way for additional cellular and bioengineering approaches to renal repair and regeneration.

In their literature search, they could not find any previous reports of kidney cells being reprogrammed back to a progenitor cell type. Their hope is that this discovery will lead others to follow their lead and begin further work in the possible reprogramming of adult kidney cells for the repair and rejuvenation of diseased kidneys.

Sources:

News Releases:

Research reprograms future of kidney health, Institute for Molecular Bioscience and Stem Cells Australia, June 14, 2013

Papers:

Direct Transcriptional Reprogramming of Adult Cells to Embryonic Nephron Progenitors, Hendry et al, Jnl Am Soc. Nephrology, June 11, 2013

Reprogramming the kidney: a novel approach for regeneration, Hendry and Little, Kidney International, March 21, 2012

Stem Cell Options for Kidney Disease, Hopkins et al, Jnl of Pathology, October 20, 2008


Resource:

Healthline.com recently launched a free, interactive "Human Body Maps" tool. One of the “maps” is of the kidney, showing and explaining how the kidney works to cleanse the body of waste material carried by the blood. To see a "map" of the kidney, and read how it functions, please follow this link.

A Novel Gene Therapy Approach to Treating the Wet Form of AMD The BioFactoryTM From Avalanche Biotech

I originally contacted this company in November 2010, when they were still in “stealth mode” and weren't able to share details about what they were doing. Recently, the company got back in touch to provide an update, having announced, in December 2011, a clinical trial of their gene therapy approach to treating the wet form of AMD.

Since their approach is unique, and possibly “game changing” for the treatment of the wet form of AMD, I asked if I could prepare a writeup about the company and its technology for publication in my online Journal, and the co-founder and CEO Tom Chalberg agreed to answer my questions, as best as he could.

So, here in their own words is what Avalanche Biotech is all about.

The Company

Founded in 2006, as an outgrowth of co-founder Thomas Chalberg’s PhD work in genetics while at Stanford University (along with pioneering work with gene therapy at Prof. Elizabeth Rakoczy’s lab at the Lions Eye Institute in Perth, Australia), Avalanche Biotech is a privately held biotechnology company that develops technologies and products for sustained delivery of therapeutic proteins to the eye to treat wet age-related macular degeneration (AMD), as well as other ophthalmic disorders, such as diabetic retinopathy, retinal degeneration, and glaucoma.

The company was incubated at the Berkeley Entrepreneurship Laboratory at the UC Berkeley Haas School of Business in 2010-2011 while Tom was completing his MBA at that school. The company set up offices in San Francisco’s SOMA district, near the UCSF Mission Bay Campus, in July 2011.

The company’s lead product treats wet AMD by using the body's own cells to produce therapeutic proteins on an ongoing basis after only a single injection. The goal is effective long-term treatment of wet AMD without the burden of frequent, ongoing intra-ocular injections.

In June 2011, Avalanche Biotechnologies licensed additional intellectual property from the University of California, Berkeley, property related to novel adeno-associated virus (AAV) vectors for use with the company's proprietary BioFactory^TM drug delivery platform. A BioFactory™ is a long-term ocular drug delivery technology that secretes a therapeutic protein over years following a single eye injection. The company’s intellectual property includes access to a pipeline of next-generation vectors for non-invasive drug delivery to the retina.

In November 2011, Avalanche began a collaboration with Lions Eye Institute in Perth to commercialize AAV-based approaches, developed using the company’s proprietary BioFactory™ drug delivery platform.

The People – Founders and Management Team

Thomas W. Chalberg, PhD

Co-Founder & Chief Executive Officer

Dr. Chalberg, earned his PhD in Genetics from Stanford University where, as a Howard Hughes Medical Institute Fellow, he focused on retinal diseases and novel technologies for gene therapy. He was interested in retinal diseases, including retinal degenerations and age-related macular degeneration (AMD). During his PhD program at Stanford, he worked with Dr. Mark Blumenkranz, his committee member and a co-founder of Avalanche Biotech, on creating a sustainable solution for sustained delivery of therapeutic proteins to the retina. They were joined by Mitchell Finer PhD, a biotechnology industry expert with experience in gene therapy, and Steven Schwartz MD, an expert in retinal disease and early-stage clinical development.

Prior to joining Avalanche, Dr. Chalberg worked on the ophthalmology team at Genentech, helping to launch Lucentis (ranibizumab by injection), a novel therapeutic for age-related macular degeneration. Dr. Chalberg holds an A.B. from Harvard University, where he graduated magna cum laude and Phi Beta Kappa. He earned a PhD in Genetics from the Stanford University School of Medicine and an MBA from the UC Berkeley Haas School of Business. Tom is a member of the Board of Visionary Scientists for Hope for Vision, a non-profit charity supporting vision research.

Dr. Chalberg joined Avalanche Biotechnologies, Inc. on a full-time basis as President and Chief Executive Officer on October 11, 2010.

Mark S. Blumenkranz, MD

Co-Founder & Director

Dr. Blumenkranz is an ophthalmologist and trained vitreoretinal surgeon at the Byers Eye Institute at Stanford University, where he has served as Chairman of Ophthalmology since 1997. Prior to that, he served on the faculty of the Bascom Palmer Eye Institute in Miami, Florida, and as founder and Director of the Vitreoretinal Fellowship Program at William Beaumont Hospital in Royal Oak, Michigan – two of the top retinal training programs in the United States. His primary clinical interests center on medical and surgical treatment of vitreoretinal diseases, with a specific emphasis on macular problems. Dr. Blumenkranz was also a founding member of the Eyetech Pharmaceuticals Scientific Advisory Board and a founder or director at several Silicon Valley-based biotech startups, including Oculex Pharmaceuticals, MacuSight, Optimedica, and PEAK Surgical. Mark received his B.A. and Master of Medical Science in Biochemical Pharmacology of Brown University and M.D. degree at Brown University followed by a Residency in Ophthalmology at Stanford.

Steven D. Schwartz, MD

Co-Founder & Director

Dr. Schwartz is an ophthalmologist and trained vitreoretinal surgeon at the UCLA Jules Stein Eye Institute, where he serves as Director of the Retina Service. At UCLA, he has served as principal investigator in a number of early-stage clinical trials for retinal diseases, including the initial studies for ranibizumab (Lucentis) and novel products in gene and cell therapy. Dr. Schwartz has held various key positions at Eyetech Pharmaceuticals, and has served on a number of Scientific Advisory Boards, including Genentech, Ophthotech, Optos, and Optimedica. Steve received his B.A. from UC Berkeley and his M.D. from USC School of Medicine, followed by a Residency in Ophthalmology at UCLA and vitreoretinal fellowship at Moorefield's Eye Hospital in London.

Mitchell H. Finer, PhD

Co-Founder & Senior Consultant

Dr. Finer has over 25 years of experience in biotechnology, building and managing companies from discovery through market launch, in addition to pioneering the development of human monoclonal antibodies, and cell and gene therapies. Currently, Dr. Finer serves as a Senior Consultant to Avalanche and is the Chief Scientific Officer of bluebird bio. Previously, he served as senior vice president of development and operations for Novocell (now Viacyte), a stem cell engineering company researching treatments for diabetes and other chronic diseases. Dr. Finer has served as CEO of Intracel Holdings LLC and Genteric Inc., and as vice president of research and development for the Gencell division of Aventis Pharma (now Sanofi). He was also a founder and vice president of research for Cell Genesys Inc., and a founder of Abgenix. Mitch received a B.S. in biochemistry and molecular biology from the University of California at Berkeley and a Ph.D. in biochemistry and molecular biology from Harvard University. He completed a postdoctoral fellowship at the Whitehead Institute for Biomedical Research.

Advisory Boards

On October 1, 2010, Avalanche announced the founding members of its Scientific and Clinical Advisory Board. The Scientific Advisory Board is chaired by Dr. Elizabeth Rakoczy, Winthrop Professor of Molecular Ophthalmology at the Lions Eye Institute, University of Western Australia. Joining her is Dr. Mitchell Finer, Chief Scientific Officer of bluebird bio and a co-founder of Avalanche.

The Clinical Advisory Board will be chaired by Dr. Ian J. Constable, Founder and Professor at the Lions Eye Institute, University of Western Australia. Joining him is Dr. Mark S. Blumenkranz, Chairman of Ophthalmology at the Byers Eye Institute at Stanford, Dr. Steven D. Schwartz, Chief of the Retina Division at the UCLA Jules Stein Eye Institute, Dr. Judy Gordon, a clinical regulatory consultant with extensive experience in ophthalmology products, and Dr. Steven Butler, Consulting Senior Biostatistician.

On September 1, 2011, Avalanche announced the addition of three renowned scientific leaders in academia and industry to its Scientific Advisory Board: Dr. Jean Bennett, F.M. Kirby professor of ophthalmology at the University of Pennsylvania; Dr. Estuardo Aguilar-Cordova, CEO of Advantagene; and Dr. J. Fraser Wright, Director of the Clinical Vector Core at Children's Hospital of Philadelphia. They will join an august group of colleagues on Avalanche's Scientific and Clinical Advisory Boards.

The Technology

The Avalanche Approach

Currently, wet age-related macular degeneration is treated with frequent injections of an anti-VEGF protein directly into the vitreous of the eye, requiring frequent office visits to assess progress and for retreatment injections with the drug, as many as 8-12 retreatments per year. This creates a burden for both patients and physicians, and limits access for those who are not able to comply with frequent visits and injections.

Avalanche’s lead product is AVA-101, currently in clinical testing for the treatment of wet AMD. Following a single injection, AVA-101 creates an Ocular BioFactory^TM that continuously secretes a therapeutic protein over an extended period, avoiding the need for frequent intraocular injections of recombinant anti-VEGF protein. The therapeutic protein is a potent inhibitor of vascular endothelial growth factor (VEGF), a clinically validated target in wet AMD. Drug delivery technology for the Ocular Biofactory™ has been pioneered under the leadership of Elizabeth P. Rakoczy, Winthrop, Professor of Molecular Ophthalmology at the Lions Eye Institute. As of mid-December 2011, Phase I/II clinical trials are in progress to evaluate safety and efficacy of a single subretinal injection of AVA-101 into eyes of patients with exudative age-related macular degeneration (wet AMD).

The Ocular BioFactory^TM

Avalanche has developed a proprietary drug delivery system which uses the body's own cells to produce therapeutic protein on an ongoing basis after only a single injection This, in effect, creates a "BioFactory^TM" in the patient's eye to treat wet AMD.

The Ocular BioFactory^TM

How it Works

Avalanche delivers its therapeutic treatments through the use of a vector made from a small biological nanoparticle called Adeno-Associated Virus (AAV). Humans are commonly exposed to AAV without any known safety issues or association with disease. AAV-based therapies are in development for a wide range of diseases including heart failure, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS), among others, along with a litany of retinal diseases in addition to the treatment of AMD.

To create a safe therapeutic vector, viral genes are removed from AAV and replaced with specific genes encoding a therapeutic protein that specifically treats AMD. AAV can infect a variety of retinal cell types and remain stable, resulting in long-term therapeutic protein expression in a variety of retinal cell types. In clinical studies, AAV appears safe and well-tolerated when injected into the retina.

The Avalanche Difference

As opposed to the current standard of care, which is effective for a short period of time, the Ocular BioFactory^TM continues to express therapeutic protein, gathering momentum and reaching peak expression after 4-6 weeks. At that point, the treatment continues to be maintained on an ongoing basis. The result is a continuous, steady-state level of therapeutic protein, which eliminates the need for frequent re-injections. Based on preclinical studies, the therapeutic effect will be maintained for at least 18 months and has the potential to last for several years following treatment from a single injection.(1)

Collaborations

Avalanche collaborates with leading academic institutions and pharmaceutical companies to develop and market its drug delivery platforms. We are looking for strategic partnerships with companies focused on ophthalmology and drug delivery for eye disease.

Our Partners Include:

Lions Eye Institute

In 1975 the Lions Save-Sight Foundation (LSSF) established the Lions Chair in Ophthalmology at the University of Western Australia (UWA). Professor Ian Constable AO was appointed to this position and subsequently established the Lions Eye Institute (LEI). As LEI's inaugural Managing Director, Professor Constable spearheaded its efforts to eradicate blindness worldwide. LEI conducts first class scientific research into blindness and incorporates one of Australia's largest ophthalmic practices. The Institute also houses the Lions Eye Bank and the LSSF.

As noted above, Avalanche announced its collaboration with the Lions Eye Institute in November 2011, and its first human clinical trial is being undertaken at the institution.

Merck Sharp & Dohme Corporation

Merck (known as MSD outside the United States and Canada) is a global healthcare leader working to help the world be well. Through prescription medicines, vaccines, biologic therapies, and consumer care and animal health products, Merck works with customers and operates in more than 140 countries to deliver innovative health solutions.

The therapeutic protein used in the Ocular BioFactory^TM is exclusively licensed by Avalanche from Merck Sharp & Dohme Corp, formerly Merck & Co., Inc.

The Clinical Trial

The initial clinical trial, Safety and Efficacy Study of rAAV.sFlt-1 in Patients With Exudative Age-Related Macular Degeneration (AMD), NCT01494805, is currently recruiting participants at the Lions Eye Institute, in Perth, Western Australia, and was established on December 14, 2011.

It is a Phase I/II controlled dose-escalating trial to establish baseline safety and efficacy of a single subretinal injection of AVA-101 (rAAV.sFlt-1) into eyes of patients with exudative age-related macular degeneration.

The study will involve 24 patients aged 65 or above who have wet AMD. The patients will be radomized to receive one of two doses of the agent (16 patients) or assigned to the control group (8 patients). Patients in all three groups will be eligible for rescue therapy with ranibizumb (Lucentis). The study is estimated to be completed in three years (December 2014), with a primary completion date of December 2012 (i.e., final data collection for primary outcome measurement). (For more information, please follow the NCT hyperlink above.)

The Future

The company is involved in researching several other therapeutic proteins for the following indications, according to the Clinical Trials and Milestones graphic shown below:

AVA--201 – is in research for the treatment of specific cells in the retina, including possible treatment for rare genetic diseases.

AVA--301 – is in research for the treatment of diseases associated with photoreceptor cells.

Editor’s Comments – As I noted in my introduction, if this approach is successful, it could result in a “game change” in the way wet AMD is treated. Instead of multiple injections to gain control of neovascularization, one injection at the first signs of neovascularization could stop it dead in its tracks and the effect could last, potentially, for several years.

In addition, it is conceivable that patients at risk of developing wet AMD could receive a therapeutic injection of AVA-101 to prevent the occurrence of wet AMD! This would be a definite paradigm shift in the treatment of AMD.

With the human clinical testing now underway, we should have an indication of initial results with this unique approach within about a year.

Stay tuned!

For more on the technical aspects of the company’s technology, please see reference 2.

References:

1. AAV2 Gene Therapy Readministration in Three Adults with Congenital Blindness ; Bennett, J., Ashtari, M., Wellman, J., Marshall, K. A., Cyckowski, L. L., Chung, D. C., McCague, S., et al.; (2012). Science translational medicine, 4(120), 120ra15–120ra15. doi:10.1126/scitranslmed.3002865

2. Preclinical safety evaluation of subretinal AAV2.sFlt-1 in non-human primates; Lai, et al, Gene Therapy, (10 November 2011) | doi:10.1038/gt.2011.169