Unsere Familiengeschichte ist
Die Cambrooke Story
How GMP came to be…
On 9 July 1992 Lynn and I had our second child, Cameron Lake Paolella. He was a healthy 8 pounds 12 ounces (3.9 kilos), and very engaged with his surroundings when not fast asleep. Like any parents, we were elated with this chubby infant boy with a striking mane of black hair. It was such a remarkable feature, thick and standing at attention, that all the nurses on the ward came by to see ‘Don King’ – the baby with hair that looked like the famous boxing promoter!
Only a few days after bringing Cameron home, we learned of another remarkable but hidden feature of our new son, phenylketonuria. Lynn got the call that forever changed the course of our lives.
Like many of you, we didn’t know what to expect. Our confirmatory diagnostic tests entered Lynn and I into the world of phenylketonuria. Life has not been the same since. In retrospect, we are better for it, and thankful to be a part of this supportive community. What follows is the story of how GMP came to be … an alternative protein source for PKU.
Fortunately, Cameron’s diagnosis came in the first week of life and he began the low-protein diet that many readers here know so well. Lynn, with an instinct for nurturing and feeding our new best friend, faced most of the daily challenges. It is with Lynn that this search for better PKU food and formula begins.
Those first six to eight years we struggled with every emotion – but life got easier as we learned how to manage the diet. In 1997, we were well prepared to welcome our daughter Brooke when she received a classical PKU (R408W/R261Q) diagnosis – thankfully sharing the same alleles as her brother. With the paucity of choices available in the 1990s, food and formula was not very appealing to our son. He was constantly hungry. It became our family’s mission to learn about every option for PKU food and formula. Never satisfied, we engaged both commercial food scientists and university researchers in the field.
While searching to produce better home-made bread, Lynn communicated regularly with Virginia Schuett MS RD (editor of the National PKU News and author of the Low Protein Food List) and Sally Gleason MS, RD. Sally had the insight to work closely with the Center for Dairy Research in Wisconsin. One of their research scientists, Dr Mark Etzel, had patented a process for extracting a dairy whey peptide from the cheese-making process – kappa-casein glycomacropeptide – now often abbreviated just GMP. GMP is a unique 64 amino acid small protein (peptide) that contains not a single molecule of phenylalanine, tryptophan or tyrosine – the aromatic amino acids. She believed it could play an important role as a source of protein for PKU.
In 2000, the team of Lynn, Sally and Virginia had a small supply of this product from Dr Etzel’s lab. Each of them explored the use of GMP to improve the browning of low-phenylalanine (Phe) bread. From 2000-2002 the team experimented with a variety of food applications – with mixed results. Overall, they were encouraged.
By 2002 Cambrooke Foods had been operating for two years and developed more than a dozen low-protein food items distributed in the US and Canada. Sally was determined to see Dr Etzel’s GMP get put to practical use and called me to lead a ‘task force’ for industry and academia to explore its potential. Sally Gleason enlisted an expert research doctor from the nutritional science department to investigate the safety and efficacy of using GMP to treat PKU mice. What could we learn about the physiology of a GMP diet when compared with the conventional amino acid diet for PKU? Dr Denise Ney raised several million dollars from both the NIH and FDA to answer this question. She needed an animal model to compare GMP to an amino acid diet when fed from infancy to adulthood. Dr Ney collaborated with Drs Woo and Harding to arrive at the most appropriate clinical model for this study. (We are indebted to a global network of scientists who share their lifetime of learning to advance our knowledge.) They focused on this little mouse, called the PAH enu-2, as an ideal candidate to test such a diet. Before beginning the study, the team bred a small colony of ‘mice cousins’ in the hundreds with a nearly identical genetic background (PKU mutation). Such ‘models’ are essential to minimise variation in the study design. After two years, UW Madison had their mice and the study began in 2004.
There are several papers published from the data collected during these pre-clinical studies, a summary of which is beyond the scope of this article. What was eye-opening for Lynn and me were the physiological improvements in both the PKU and ‘wild-type’ (normal) mice when fed GMP from birth to adulthood. To my sur- prise, even the healthy mice, when fed an AA diet, had consistently poor health (inflammation, weaker bones, enlarged kidneys and spleen). In contrast, the PKU and wild type mice thrived on the GMP diet. While we know mice are not humans, we also know that nature is very conservative – the biochemistry of phenylalanine metabolism (Phe -> tyr) is very similar in all mammals. These results had us committed to further testing to see if it could help our children’s lifelong health.
Over the next few years, the research team at UW Madison conducted an in-hospital clinical trial of 11 PKU patients, an environment that allowed their diets to be carefully controlled. Each of the subjects served as their own ‘controls’ in a classic ‘cross-over’ design study. From the published data, we learned that GMP was not just a better-tasting source of protein for PKU – but that nearly all of the patients improved on four critical biomarkers in just a few days of GMP diet! (A subsequent four-year study, published in 2016 with 30 PKU patients, confirmed these results.)
In 2008, our little Cambrooke Foods had more than 120 low-protein foods, a 3,000-square-metre processing facility and a ready-to-drink amino acid product line for PKU and MSUD. We were determined to find a supplier to make a commercial-grade GMP to include in a new PKU formula. While there is plenty of whey in America, the small market size, technical sophistication, and investment needed to purify the background whey from the GMP made it very difficult to convince a commercial dairy to manufacture this product just for PKU.
In the spring of 2008, I had the good fortune to meet with the CEO of Arla Food Ingredients in Denmark. At our first meeting, Henrick Andersen shook my hand and said, ‘I’ve been waiting 18 years to meet you!’. Henrick knew something about PKU and knew GMP could be a source of low-Phe protein for us PKU families. We set to work planning our collaboration. Cambrooke would need many millions of dollars for development (which we didn’t have) and Arla would need to build a commercial plant to manufacture this special ingredient for the ~60,000 PKU people in the world who could benefit. (As a side note, Phyllis Acosta, PhD of Ross/Abbott Nutrition, and inventor of Phenex®, later told me she had been interested in GMP as a protein source for PKU, ‘but could never get a source “pure enough” for commercial production.’) Lynn and I would risk everything on the evidence that this intact natural protein would benefit all patients with PKU. Our journey to raise more than 35 million dollars, expand our manufacturing facility and bring GMP to the global PKU market began in 2009.
GMP alone is not an ideal protein. Protein quality is the result of a complete range of essential amino acids (those not made by the human body) in the right proportions. GMP, as mentioned earlier, is devoid of phenylalanine, tyrosine and tryptophan and must be supplemented with five ‘limiting’ amino acids. In addition GMP contains high levels of threonine and other large neutral amino acids (LNAAs) bound in the peptide. (There is evidence that high LNAA concentrations can reduce brain phenylalanine by blocking LAT-1 transport.) To determine the best proportion of supplemental amino acids to balance the GMP protein, the research and development team examined PKU patient serum amino acid levels, gut microbiota and potential renal-acid load (PRAL), among other factors, to determine the optimal formulation for this new protein substitute. The resulting formulation is Cambrooke’s patented Glytactin formulation. We have developed and refined this formulation for the past eight years.
We are proud to say that our little company Cambrooke Therapeutics, in addition to our range of low-protein foods, has more than 18 glytactin products for PKU and four products for tyrosinemia now available. More than 1000 patients worldwide (including Cameron and Brooke) use our Bettermilk product, available in the US since 2009. We now learn from many what it is like to live with PKU.
We know challenges continue for individuals and families with PKU. Although the dietary options have improved greatly since Cameron was born, it is difficult at every stage of life to maintain targeted serum Phe levels for nearly all classical PKU teens and adults. Many symptoms of transient elevated Phe levels plague our children and others with PKU. There are promising new pharmaceutical therapies being studied. Indeed our family has direct experience with two of these. We hope to see a safe and effective alternative to this highly restrictive diet in the near future. Until one or more of these alternatives are available, maintaining a low-phenyl- alanine diet is both safe and effective management of PKU.
Stay healthy today for a better tomorrow!