Alpha-2-macroglobulin may soon revolutionize the treatment of osteoarthritis.
Alpha-2-macroglobulin may soon revolutionize the treatment of osteoarthritis.
In 2001, a fellowship-trained spine surgeon named Dr. Guy Scuderi was accelerating up a ramp onto I-95 when a pedestrian strolled onto the ramp. To avoid the pedestrian, Scuderi maneuvered his motorcycle and crashed, losing the skin on his hands, the bone of his right kneecap, and tragically, the future of his career as an orthopedic surgeon.1
In the following year, Scuderi experienced pain and underwent multiple surgeries. In the process, Scuderi began to wonder where pain originates in the body, and was inspired to search for better ways to treat the condition.1
In an interview, Scuderi stated, “I started looking at joint disease and pain about 10 years ago, and I identified a protein called the FAC, or fibronectin—aggrecan complex, that was synonymous with pain following a joint injury.” For Scuderi, research on FAC was the beginning of a search for the master regulator of pain after a cartilage injury.
Scuderi found that FAC was present in high levels in synovial joints that had been damaged by osteoarthritis. For instance, in the hip synovial fluid of 34 patients with arthritis, investigators measured levels of inflammatory markers before performing surgical interventions. Scuderi and colleagues measured levels of 12 suspected inflammatory cytokines, and an additional marker: FAC.2
In the study, FAC was the only biomarker significantly associated with the severity of osteoarthritis. FAC, which is a byproduct of cartilage breakdown, is a predictor of hip pain.2 Researchers identified similar relationships between FAC levels and the severity of knee, ankle, and spinal damage.2-7
Beyond this association, FAC levels were predictive of outcomes in patients undergoing lumbar discectomy. In a series of 92 patients, high levels of FAC were a positive predictor of clinical improvement 3 months after surgery, with 85% positive predictive value.7
Having identified a reliable biomarker associated with pain and inflammation, the next step was to use information about FAC to find out how the body heals and relieves pain. Scuderi already knew that the body has a significant capacity for healing itself. In the pursuit of that intrinsic healing factor, Scuderi needed funding. According to Scuderi, “A company called Synthes Corporation became interested in what I was doing, and they invested $9.5 million in the company.”
With this infusion of funding, Scuderi, through Cytonics Corporation (which was founded in 2006), was able to investigate the components of the body associated with reducing levels of FAC and reducing pain. “I started investigating fractions of blood…I felt that there are lots of patients who seem to get better on their own, and knew the answer could be found in the blood.”
Eventually, Scuderi and researchers at Cytonics found the factor that helped some patients reduce levels of FAC and the pain and inflammation associated with high levels of FAC. That protein was alpha-2-macroglobulin (A2M).
Alpha-2-macroglobulin protein. Courtesy of Wikimedia Commons.
Scuderi’s team at Cytonics discovered that A2M worked on 3 classes of proteases that degrade cartilage cells or chondrocytes. These proteases include cytokines (tumor necrosis factor alpha and interleukin 1), matrix metalloproteases, and ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs). “Only alpha-2-macroglobulin can stop all 3,” said Scuderi.
Scuderi had found the master pain regulator, but because A2M is present in nature, it could not be patented and developed as a medication. To develop A2M commercially, Scuderi needed to alter A2M in a way that would improve its bioactivity, so he turned to his research team at Cytonics. According to Scuderi, “Of 180 variants we built … we made 4 that were better [than the natural product], and cited patents on alpha-2-macroglobulin in 2010.”
The form of A2M that Scuderi and his team developed was substantially better than the natural protein. Scuderi concluded, “We modified it and were able to enhance its activity up to about 400%.”
Scuderi and his team at Cytonics were hard at work developing A2M when a team of researchers at Brown University independently identified the same master regulator of inflammation and pain that Scuderi and his team had identified and had been developing for years.8
Unlike the researchers at Brown, however, the team at Cytonics has already progressed far beyond the basic research phase. According to Scuderi, “We built a system that concentrates both platelets and alpha-2-macroglobulin.” This system removes, “almost all the white cells, all the red cells, most platelets, and most of the other proteins.” In this way, Scuderi and his team can purify a patient’s own natural A2M and can inject the superconcentrated A2M into joints. So far, approximately 200 patients have received this autologous treatment.
According to Scuderi, “The success has been phenomenal. I can take patients’ pain away in 24 hours…[and] stop cartilage degradation in its tracks.” The autologous A2M treatment, which is derived from 2 mL of whole blood and is typically administered 2 to 3 times per year has led to “4 to 5 months of complete pain relief.”9
The initiation of clinical trials with autologous A2M has been approved by the FDA (see ClinicalTrials.gov entry NCT01613833).9 Meanwhile, the recombinant form of A2M protein, which has several times the activity of the natural protein, is still in laboratory development, although development is progressing rapidly. Scuderi expects to complete development of the recombinant protein to allow trials in animals, “in the fourth quarter of this year .”
Scuderi is already treating patients with A2M-rich therapy at his office in Jupiter, Florida (interested patients can inquire about the therapy by calling his office at 561-747-9334). Other nearby orthopedic specialists in Florida are offering the treatment, as well. One such office is ZehrCenter Orthopedics in Naples, Florida, where Robert J. Zehr, MD, offers the treatment for some patients.
In an e-mail exchange, Dr. Zehr noted that he is using A2M therapy only in patients with knee arthritis, “who would otherwise be candidates for knee replacement surgery.” In addition, for now, Zehr confines the conversation about A2M therapy to patients who “have tried the more conventional treatments but are still reluctant to pursue surgery.” Of the 6 treatments with A2M that Zehr has administered, he noted, “5 patients are satisfied that the treatment is helping, and 1, unfortunately, gave up quickly and proceeded to total knee replacement.”
It should be noted that autologous A2M replacement, according to Zehr, “is not covered by insurance or Medicare.” Despite the barrier of reimbursement, Zehr remains enthusiastic about A2M therapy, which, he said, “represents the first true biologic treatment of osteoarthritis by addressing the actual destructive proteins that attack the articular cartilage and support collagen in our joints.”
The FDA has also shown exuberance with regard to early trials of the A2M therapy. In a press release published on July 22, 2014, by Market Watch, Scuderi spoke about the initiation of a phase I/II clinical trial using Cytonics Corporation’s APIC cell-free system. “This approval by the FDA, 30 days after our initial submission and with no iterative rounds of review, is a testament to the comprehensive and high-quality work that our team has executed,” said Scuderi in the press release. “Cytonics’ accomplishments in the scientific, intellectual property, regulatory, and now clinical aspects of A2M have positioned Cytonics to bring this important new molecular treatment for degenerative cartilage to the clinic and the market.”10
1. White J. Dr. Scuderi’s incredible journey from crash victim to visionary. http://ryortho.com/2013/02/dr-scuderis-incredible-journey-from-crash-victim-to-visionary/. Accessed September 2014.
2. Abrams GD, Safran MR, Shapiro LM, et al. Fibronectin-aggrecan complex as a marker for cartilage degradation in non-arthritic hips. Knee Surg Sports Traumatol Arthrosc. 2014;22(4):768-773.
3. Gajendran VK, Reuter MW, Golish SR, Hanna LS, Scuderi GJ. Is the fibronectin-aggrecan complex present in cervical disk disease? PM R. 2011;3(11):1030-1034.
4. Golish SR, Hanna LS, Bowser RP, Montesano PX, Carragee EJ, Scuderi GJ. Outcome of lumbar epidural steroid injection is predicted by assay of a complex of fibronectin and aggrecan from epidural lavage. Spine (Phila Pa). 1976;36(18):1464-1469.
5. San Giovanni TP, Golish SR, Palanca A, Hanna LS, Scuderi GJ. Correlation of intra-articular ankle pathology with cytokine biomarkers and matrix degradation products. Foot Ankle Int. 2012;33(8):627-631.
6. Scuderi GJ, Golish SR, Cook FF, Cuellar JM, Bowser RP, Hanna LS. Identification of a novel fibronectin-aggrecan complex in the synovial fluid of knees with painful meniscal injury. J Bone Joint Surg Am. 2011;93(4):336-340.
7. Smith MW, Ith A, Carragee EJ, et al. Does the presence of the fibronectin-aggrecan complex predict outcomes from lumbar discectomy for disc herniation? Spine J. 2013.
8. Wang S, Wei X, Zhou J, et al. Identification of α2-macroglobulin as a master inhibitor of cartilage-degrading factors that attenuates the progression of posttraumatic osteoarthritis. Arthritis Rheumatol. 2014;66(7):1843-1853.
9. ClinicalTrials.gov. Serum and synovium protease inhibitor levels in primary and secondary osteoarthritic joints. http://clinicaltrials.gov/ct2/show/NCT01613833. Accessed September 2014.
10. Market Watch. Cytonics announces FDA approval of an investigational new drug application for the APIC cell-free system. www.marketwatch.com/story/cytonics-announces-fda-approval-of-an-investigational-new-drug-application-for-the-apic-cell-free-system-2014-07-22. Accessed September 2014.