of Cambridge, MA:
Harnessing the Body's Ability to Heal
Issue 113 (October 26, 2001)
Helping the aging population live longer and more independently is not the stuff of a fantastic, far-off future, but the focus of Curis' diverse research programs. In this company profile, the author examines how Curis hopes to understand and reactivate the body's innate genetic program.
The premise underlying regenerative medicine is that the body possesses an inherent ability to repair damage caused by age, disease, or trauma and to restore function. This innate ability to completely heal diminishes as we age. Recent discoveries of the existence of adult stem cells found in organs, including the brain, heart, pancreas, and skin, indicate that these cells can contribute to healing but may not exist in the adult in quantities necessary for organ regeneration. But since the body's cells tissues, and organs develop from embryonic stem cells, it should be possible to investigate those pathways of embryonic development and exploit them to restore function, says Doros Platika, Chairman of Curis, Cambridge, MA.
Each Person Has a Genetic "Built-In Fountain of Youth"
Curis is building on its knowledge of developmental biology, signaling proteins, growth factors, embryonic and adult stem cells, tissue engineering, functional genomics, and combinatorial chemistry/high-throughput screening of cell-based and developmental biology-based assays to produce therapies for degenerative disorders, malignancies, trauma, and autoimmune disorders. "Our core competency is in the understanding and expertise in the area of developmental biology, which is the study of how the body is made," says Platika. Each person has what might be called a genetic "built-in fountain of youth" -- if one could only reactivate part of the genetic program to replace cells, such as bone, dopamine-producing neurons, or insulin-producing pancreatic beta cells, when they are damaged. Understanding and reactivating the body's innate genetic program is Curis' focus.
While other biotechs are positioning themselves as regenerative medicine companies, most are focusing on one type of tissue development, such as neuronal, cardiac, or mesenchymal cell production. Curis is unique in its broad focus, made possible by its possession of a wide range of technologies likely to be useful in this new field. It may be more than the sum of its parts. Curis was formed from the merger, in August 2000, of three Boston-area companies with complementary technologies: Ontogeny, a developmental biology company with a genomics discovery engine and where Platika served as CEO; Reprogenesis, with tissue engineering expertise developed by pioneers Robert Langer at MIT's Chemical Engineering Department and Anthony Atala of Children's Hospital, Boston; and Creative Biomolecules, which developed OP-1, a recombinant human Bone Morphogenic Protein (BMP) - a growth factor that stimulates the body's own ability to regrow bone, and neoBladder, a tissue-engineered bladder. At present, Curis has one approved product for bone regrowth, four more in clinical trials, and about ten others in earlier stages of development, all of which are aimed at restoring function.
The Demographics Are Ripe for Regenerative Medicine
Now is the right time for the growth of regenerative medicine, says Platika, a neurologist by training who formerly practiced and taught at Albert Einstein College of Medicine in New York City. "First, the demographics of an aging society are creating social and medical needs to improve the quality of life and an economic need to reduce costs," says Platika. "In the next 50 years, the number of 'young old' -- individuals between [65 - 84] years old - is expected to triple and the number of 'old old' -- those [> 85] years of age - will grow sixfold," he calculates. "This aging population is expanding the need for therapies that improve, restore, or preserve the function of organs." The second reason is that it is now possible to utilize the genomic data generated from the Human Genome Project in developing treatments, preventions, and cures for diseases by regulating gene expression.
Curis is using genomics and developmental biology to focus on one group of genes, the hedgehog (Hh) family of proteins - sonic, patched, and desert hedgehog -- which are conserved in animals from Drosophila to humans and which are involved in growth and differentiation. Over the past six years, members of the Hh family of secreted proteins have emerged as key players in a wide variety of vertebrate developmental processes ranging from the control of cartilage differentiation, to the specification of neuronal identity, to the cause of a number of types of tumors in humans.
Stimulating the Hedgehog Pathway May Aid Tissue Repair
"Our research has shown that some molecules responsible for embryonic development -- among them the hedgehog molecules -- are also important in certain disease processes," says Lee Rubin, Senior Vice President of Research and Chief Science Officer of Curis. "When tissue is damaged, the Hh proteins react as part of the tissue repair process." However, the natural regeneration that occurs in adults that involves these proteins and adult stem cells is often insufficient to effect a clinical cure. That's where Curis' Hh agonists come in. "Our scientists have found that stimulating the Hh pathway can have profound and unique effects on cells in the nervous system undergoing degeneration in different diseases, including Diabetic Neuropathy and Parkinson's," says Rubin. "We have discovered agents, both protein and small molecules, that potently activate this pathway."
Curis' researchers have shown that one Hh protein -- sonic -- works in the repair and regeneration of nerve tissue after injury or disease; it is the same protein that is involved in embryonic development of the peripheral and central nervous system. Animal studies with Curis' sonic hedgehog agonist demonstrate that it has a positive dose-dependent effect on motor and sensory neurons in diabetic neuropathy, for which there is currently no effective treatment. Of 15 million Americans with diabetes, about 6 million have neuropathy. Other neurological diseases that could benefit from desert Hh-based therapy include Multiple Sclerosis, chemotherapy-induced neuropathy, Alzheimer's, and Amyotrophic Lateral Sclerosis (ALS). In July, Curis teamed up with Elan Corporation (Dublin, IRELAND), a pioneer in Alzheimer's research, to develop drugs for a number of neurodegenerative diseases using Curis' Hh platform. Elan also has developed a mouse model of neurodegenerative diseases, which Curis will have rights to use in its work.
Antagonists of the Hedgehog Pathway Target Cancers
Some cancers, such as basal cell carcinoma and a subset of prostate and bladder cancer, may be caused by too much activity in the Hh pathway; colon cancer results from an overexpression of a different pathway, Wnt (Wingless N-terminal protein), Platika told HMS Beagle. Curis is developing antagonists for basal cell carcinoma and colon cancer, both in Phase I testing. Sporadic basal cell carcinoma is the most common form of skin cancer, and, while it is highly curable, surgery can disfigure patients, "so there is a pressing need for a better therapy," Platika says. CUR-61414 is a small molecule that is injected locally into a lesion; it seems to shut down the pathway and cause apoptosis.
Curis, in addition to using zebra fish, Drosophila, and other animal models to study development and help identify molecules important in development and repair of the body, is using embryonic stem cells and genomics as surrogates for whole organism drug testing.
With SCAGE (single cell analog of gene expression) technology, licensed from Micromet AG (Martinsried, Germany), Curis is using single stem cells as surrogates for whole embryos to discover gene pathway activation with a lower signal-to-noise ratio. The SCAGE technology will also enable both companies to work together to develop therapeutic antibody antagonists that may be easier to produce as a drug candidate than the actual protein ligand regulating a particular pathway, says Platika. SCAGE technology is also being used to analyze the earliest stages of stem-cell differentiation and for selecting homologous stem-cell populations.
Curis Uses Only Adult Stem Cells Commercially
As the embryonic stem-cell (ESC) controversy in the United States moved toward a presidential decision in August, Platika spoke out repeatedly to the media about how indispensible ESCs are for research, although his company has chosen to develop only adult stem cells commercially. It is currently unclear to stem-cell researchers just how plastic adult stem cells are -- whether they can be pushed to differentiate into all of the body's 200 cell types as ESCs can be. Curis, like other companies focusing solely on adult stem cell therapeutics, is gambling that it will be able to use adult stem cells for regenerative purposes and avoid the moral, political, and funding obstacles inherent in work with ES cells. ( Curis privately funds its ES cell research but can accept public funding for its adult stem cell work.)
Curis is working with adult pancreatic progenitor or stem cells to differentiate them into beta cells capable of secreting insulin for transplantation into patients with diabetes, using IPF-1 (Insulin-Promoting Factor-1), which controls pancreatic function in developing animals, it discovered Rubin plans to employ the commonly-used Edmonton transplantation protocol to transfer the pancreatic islets to patients via a portal vein infusion with immunosuppression. To date, it has been successful differentiating the cells; its main challenge now is amplifying the number of cells that can be used for transplantation.
"Skin Cells Are the Ideal Source of Stem Cells"
At the same time, Curis has been searching for novel sources of more readily available (and plentiful) adult stem cells that can be differentiated into multiple cell types. It recently struck gold; in September, Curis and its collaborators, Freda Miller at the Montreal Neurological Institute and Hospital at McGill University (Montreal, CANADA) and Aegera Therapeutics, published a groundbreaking study in Nature Cell Biology showing that multipotent stem cells of different lineages could be derived from adult human (and rat) dermis . This is the first study to show that stem cells from skin - perhaps the most accessible organ from which to derive these cells -- could differentiate into neurons, glia, smooth muscle cells, cartilage, bone, and fat cells. "Skin cells are the ideal source of stem cells. They're readily available and can be harvested from each patient," says Platika. He is hopeful that these cells will enable Curis to develop autologous cells and tissue therapies for a range of neurodegenerative and cardiac diseases that would not be rejected by the patient and that could be cost-effective. Because these cells have been maintained for two years without losing the capacity to differentiate into various cell types, he believes that they have true commercial potential to treat a range of diseases.
More near-term are a number of cell and tissue therapies:(1) Vascugel for coronary disease, Chondrogel for VesicoUrethral Reflux (VUR) disease in infants, (3) NeoBladder for urinary bladder regeneration, and its first marketed product, OP-1 for non-union fractures and other orthopedic uses.
1. Vascugel is in Phase I testing for restenosis following coronary artery bypass or angioplasty and to prevent thrombosis. It consists of allogeneic endothelial cells seeded on gelatin that is wrapped around the outside of a blood vessel that has been unblocked to prevent reendothelialization. NeoBladder, a replacement or augmentation bladder for patients who have had trauma, surgery for cancer, or congenital defects, is a tissue-engineered organ developed by harvesting urothelial and smooth muscle cells from bladder biopsy specimens that are seeded on two sides of a biodegradable polyglycolic acid polymer scaffold in the shape of a bladder. It is transplanted into the patient and begins to develop normal structure and function within a month after implantation.
Chondrogel Uses Cartilage from Behind a Patient's Ear
2. Chondrogel, a bulking agent derived from autologous cartilage or chondrocytes, is now in Phase III testing for VUR disease, a pediatric congenital defect of the ureter (about [1 - 2] percent of children are born with this defect), which is administered endoscopically to normalize urine flow. Cells are taken from cartilage from behind the patient's ear, expanded for [7 - 8] weeks, then combined with Calcium Alginate to form a biodegradable hydrogel implant that provides a scaffold for the formation of cartilage around the vesicourethral junction, preventing urine reflux upward into the ureters and infection.
3. OP-1, being further developed with Stryker Corporation , is a BMP delivered on a collagen matrix, which prevents its degradation, and in some animal models is superior to autograft in models of spinal fusion. Curis believes that OP-1 will be useful in other types of fractures besides non-union. It is also being tested for spinal fusion and for periodontal disease. Currently, cadaver bone and collagen are used as passive bone conducting matrixes, but they are limited in their utility. BMP can induce bone growth but is water-soluble and subject to rapid degradation.
OP-1 Analogs Are Promising Stroke Therapy Candidates
Surprisingly, developmental biology research into OP-1 also indicates that the molecule is turned on during neuronal development and for some time afterward in the embryo. This clued Curis to test it for neurological treatments. In animal models of stroke, administering OP-1 to the brain within 24 hours of ischemic insult and up to 72 hours after had long-lasting neurorestorative activity, Platika told HMS Beagle. The company is working on a small-molecule version that will penetrate the blood-brain barrier.
Research with Drosophila led to a strange discovery: sonic Hh is involved in the regrowth of hair follicles. Curis scientists found that after modifying Hh expression in fruit flies, they had developed a "hairy" type of fly. Although baldness may not be a major medical problem, Curis is working on a small-molecule compound for male-pattern baldness, which it hopes to bring to the clinic next year. Helping the aging population live longer and more independently is not the stuff of a fantastic far-off future, but the focus of Curis' diverse research programs today.