Pompe disease was first described some by Dr Johannes Pompe in 1932, some 83 years ago, but it is the last 20 years that has seen the most dramatic research leading to benefits for patients and families living with the condition. And it is no coincidence that the Acid Maltase Deficiency Association has been a prime motivator in many aspects of Pompe disease research since their first conference 1996 in San Antonio; a meeting that was to bring researchers together to work collaboratively, rather than in isolation. And collaboration between clinicians, researchers and patient groups was very much a theme of this year’s International Pompe Patient and Scientific Conference in San Antonio, Texas.
An interesting innovation for this conference was the Twitter feed and Hash-tag #AMDAIPA15. This provided a great source of each day’s highlights and has made the writing of this report an easier task!
The conference was opened at a Welcome Dinner for all delegates on Friday 30th October by San Antonio Councilman Roberto Trevino who declared the weekend to be “Acid Maltase Deficiency Association Conference Days”. The evening that followed was a fine spectacle remembering the 20 years of the AMDA.
Creating a conference programme suitable for both patient representatives and scientists can be very difficult, but the scientific presentations were carefully prepared with the non-specialist in mind, and their key points were certainly accessible to all delegates. And those delegates had traveled from all corners of the world to hear the latest developments in Pompe research and share their experiences with others.
The AMDA hope to have all video presentations available early in 2016, but until then here is a taste of the conference highlights:
Hannerieke van den Hout described natural history of Pompe disease and her colleague Dr Chris van der Meijden spoke of the Erasmus/IPA Pompe Survey as one of largest rare disease databases in the world, having 443 patients enrolled. He said that patients true partners in understanding the natural history of the condition and the data helps to assess the effectiveness of new treatments.
A Pompe Registry report was given by Dr Virginia Kimonis. The registry now holds data on 1459 patients worldwide, including 178 infants. It has provided four peer reviewed papers and 32 abstracts.
Sadly it shows that diagnostic rates are still disappointing, even when siblings have died of the condition, highlighting the need for Newborn Screening (NBS).
Dr Bach presented his views and experience of mechanical ventilation for Pompe disease, stating that there is an over-reliance on tracheostomies for Pompe disease, where non-invasive ventilation should be sufficient.
Dr Deeksha Bali discussed various diagnostic techniques, their benefits and issues, after which Stephanie Austin discussed the importance of genetic counselling and gave a case study of a family with very complex mutations of the GAA gene. Stephanie introduced us to the Counsyl prenatal carrier-screening panel that has been verified by the Duke University Laboratory.
Dr Priya Kishnani discussed the need for a multi-disciplinary team approach to managing the care of Pompe patients and discussed the many excellent guidelines for Pompe available worldwide. She highlighted the need to work with a physical therapyist and to maintain good nutrition with the assistance of an understanding dietitian; the need for Vitamin D, Calcium and potassium supplements, and also the importance of the Flu jab.
Dr Barbara Smith reported on the Florida team’s two years experience of Diaphragmatic pacing. The benefits are showing more spontaneous breathing within the cohort and increased time without ventilation. One patient, no longer reliant on a Bipap reported to “feeling good all day”.
Dr Ans van der Ploeg reported on the Erasmus study into Pompe Exercise. It found significant increase in endurance, a slight increase in strength with core strength bringing improved balance. It was also noticed that fatigue was diminished, as was muscle pain. This was the first study to prove the positive effects of training and it intended to extend the study to those more severely affected by Pompe.
An excellent Patient Perspective was provided by Krystal Hayes who described her adaptation to many aspects family life with a child affected by Pompe. The abiding memory will be her definition of “Normal” as being “just a setting on a washing machine”.
Gene therapy is often hailed as the ultimate “cure” for genetic conditions and so, after a layman’s introduction to the subject by Arnold Reuser, four research themes were explored in turn. Dr Andrea Amalfitano described some of the Gene Transfer work using the liver to express GAA into the bloodstream. GAA activity was found to be very high in the liver, but did not show the muscle take-up they had seen in mouse models, despite the low antibody response.
Dr Barry Byrne described the work on AAV delivery of a Gene Therapy. This is most exciting because there is evidence that glycogen storage in the neuro-muscular junction is cleared, improving the signal pathway to muscles. Phase I/II of a clinical study have been completed and it is hoped to begin further studies in the first half of 2016 with systemic dosing being investigated in humans within the next two years.
Dr Dwight Koeberl discussed the advantages of liver-targeted gene therapy. Experiments have shown that GAA is elevated in the blood of a mouse model, with no antibody response. A clinical trial is currently being designed with a very low dose to measure the safety profile over 12 month period and will measure the GAA and glycogen in muscle of Pompe adults.
The fourth G.T. presentation was given by Dr Pim Pijnappel who discussed Lentiviral Stem Cell approaches. He discussed several approaches that may provide improved therapy compared to ERTs that may generate an immune response, cannot cross the blood-brain barrier, and are expensive and invasive.
The key message from this panel of researchers was that Gene Therapy for Pompe disease is “no longer an academic exercise”.
The final session on Saturday afternoon explored what has been learned about ERT so far. Dr. Yin-Hsiu Chien described experience in Taiwan since newborn screening was introduced in 2005. The population has no CRIM- infants, but the results of treating children within 2 weeks are impressive, with every child surviving. Cardiac response to therapy is good but muscle response is not so good and other dosing strategies are being investigated.
Dr Priya Kishnani gave a history of Duke University’s involvement and experience of ERT, highlighting that low antibody titres give better survival rates. Duke has published a paper on alternative dosing for a child during growing and puberty. The alternative regimen is 40 mg/kg every two weeks or 20mg.kg per week. Duke has also investigated adjunctive therapies including Albuterol, Clenbuterol, and also Respiratory Muscle Training.
Dr Benedikt Schoser provided a European perspective of ERT. He said that the way researchers, patient groups and industry had worked together over the past 20 years was an inspiration to other neuromuscular conditions. A European Pompe Consortium (EPOC) of 9 nations has been formed to promote research and develop management and treatment guidelines for the condition. Topics for discussion have included Starting Criteria (taking into account the Burden of ERT), Stopping Criteria and Adjunctive Therapies,.
Dr Ans van der Ploeg briefly covered the long history of the Erasmus MC’s milestones in Pompe disease, including the Pompe Centre’s database that holds 469 GAA mutations. They are also prescribing high doses as early as possible for growing infants (40mg/kg/week in some cases) but do not treat infants under 1 year old who have very poor prospect of a reasonable quality of life. Dr Ploeg closed saying that clinicians and researchers “need to know what is precious to patients”.
The first half of Sunday morning was given to future research. Dr Nina Raben discussed novel approaches to finding a therapy by studying other activity within human cells that might reduce glycogen in the lysosomes, or the accumulation of autophagic debris in muscle cells.
Dr. Pim Pijnappel discussed work investigating satellite cells (stem cells) attached to muscle fibres. In healthy muscles these can grow to replace damaged fibres, but don’t appear to be activated in Pompe disease, even though they remain intact. There is a long way to go in regenerative medicine, but this work holds some hope for the future.
Dr Arnold Reuser gave some interesting insights into how Pompe disease may present in a person when the genetic mutations are known. It is often very difficult to predict the phenotype from the genotype and Dr Casare Danesino discussed some of the influences that may come from modifying factors, such as of other proteins.
Dr Giancaro Parenti discussed biomarkers that might be used to correlate therapies with the patient response, and also those that may help to predict the phenotype.
The conference concluded with presentations from five companies with pipeline products for Pompe disease. Nita Patel gave an overview of Amicus Therapeutics, its next-generation ERT and introduced their patient advocacy team. Suyash Prasad introduced Audentes Therapeutics as the company with experience of gene therapies for other conditions, including Myotubular Myopathy. He stressed the importance of managing expectations of patients and families and the safety of gene therapies; once given they can’t be stopped.
Dr Liron Walsh gave a brief overview of BiMarin’s Phase III trial for Reveglucosidase Alpha, their next generation ERT for Pompe disease. He discussed their choice of primary endpoint and the need for blood-glucose management during infusions.
Dr Susan Sparkes gave an update on Genzyme Corporation’s next generation ERT, NeoGAA. This is expected to enter Phase III trials in the first half of 2016. Genzyme are developing Patient Reported Outcome tools through literature searches, patient and physician interviews, and investigating the use of wearable devices to measure activity.
Finally Dr Wouter Vervecken described a yeast-based platform that is being investigated by Oxyrane. The non-human calls allow extra manipulation of the cells to increase phosphorylation of their replacement enzyme making it potentially more active than other ERTs.
Closing the conference Dr Paul Plotz thanked Tiffany and the AMDA for all their hard work in planning such a “terrific conference” which contained some “marvellous interactions”.