Rare diseases represent a significant unmet medical need, impacting the lives of millions of patients and their caregivers worldwide. At WuXi AppTec, we believe that our ongoing collaborative efforts to raise disease awareness and foster innovative thinking will lead to better and faster breakthrough treatments to address the healthcare challenges of rare diseases. As we continue on this exciting journey to bring transformational medicines to patients, we are thrilled to share with you a new interview series from worldwide leading experts, “Delivering on the Promise of New Therapies for Rare Diseases.”
Thank you for taking the time to join us, Ralph! Before we start, could you please introduce yourself for our audience?
Ralph: My name is Ralph Laufer. I’m the Chief Scientific Officer of Lysogene, which is a gene therapy company located in Paris, France, and we are developing gene therapies for neurological diseases. At Lysogene, we have two clinical stage programs for the treatment of rare neurodegenerative lysosomal storage diseases, namely MPS IIIA, also known as Sanfilippo disease and GM1 gangliosidosis, as well as several discovery and preclinical stage programs that are focusing on Fragile X syndrome, Gaucher disease and related diseases, as well as neurodegenerative diseases.
What inspired your work in the Fragile X field and what issues are you trying to address?
Ralph: Lysogene’s mission is to develop novel gene therapy treatments for neurological diseases, and in particular rare genetic diseases, such as Fragile X. In 2018, we initiated a collaboration with the lab of Dr. Herve Moine from the IGBMC in Strasbourg, France, based on his discovery of a novel downstream target of FMR1 in neurons – the messenger RNA of an enzyme called diacylglycerol kinase kappa. We also call it DGKk in short. And the goal of this collaboration was to evaluate the therapeutic effect of DGKk delivered into the brain using an AAV vector in a mouse model of Fragile X.
What approaches are you taking to gene therapies?
Ralph: So Lysogene’s approach is gene therapy; and the most widely used gene therapy approach, also known as gene transfer or gene addition, involves delivery of a functional gene to substitute a missing or dysfunctional endogenous gene. Predominantly, this approach relies on the use of an innocuous and replication-deficient viral vector to transduce human cells, such as the adeno-associated virus or AAV vector.
However, in the case of Fragile X syndrome, a gene transfer approach using the FMR1 gene presents several important challenges. First of all, FMR1 expression dosage is critical for normal cell condition and neuronal function, and duplications of the FMR1 gene are identified causes of intellectual deficiency. Therefore it would be very difficult to administer a gene therapy treatment which would require such a tight regulation of gene dosage. Secondly, the blood brain barrier, which is constituted by a barrier of cells that surround blood vessels in the central nervous system, impedes crossing of AAV vectors from the bloodstream into the brain parenchyma which is the site where pathology occurs. And therefore, Lysogene’s approach is to target a downstream effector of FMR1, the DGKk gene that I mentioned earlier, as well as to deliver the AAV vector carrying the therapeutic transgene directly into the CNS, bypassing the blood brain barrier.
What is the greatest and differentiated value of your modality or technical approach to the treatment of Fragile X syndrome?
Ralph: The current treatment for Fragile X remains largely insufficient and the care is primarily symptomatic, focusing on disease management without addressing the primary underlying mechanisms of disease. Importantly, current treatments do not constitute a solution for intellectual disability, which is one of the main features of Fragile X. We believe that focusing on DGKk, which is an immediate downstream target of FMR1 and neurons, offers the opportunity to correct one of the major disease mechanisms, and therefore has the potential of being disease modifying.
Could you share with us your progress on this program so far, and what is the next milestone?
Ralph: The approach we have taken is based on the identification by Dr. Herve Moine, our collaborator from the IGBMC, of DGKk, as the most proximal messenger RNA target of FMRP neurons. The absence of FMRP leads to the absence of DGKk, and the latter mimics the effect of FMR1-knockdown, both in vitro and in vivo. So to tackle this problem, we constructed an AAV that carries an FMRP-independent variant of DGKk, and we administered this vector directly into the brain of FMR1 knockout mice, which is a well-known animal model of Fragile X syndrome. And when we did this, it led to the correction of all behavioral abnormalities observed in the knockout mice relative to healthy wild-type mice. Also, treatment with this AAV was not associated with any overt toxicity in the mice. These findings were recently published in EMBO Molecular Medicine. We believe on the basis of these findings that gene therapy with DGKk holds considerable promise as a treatment option for Fragile X, and we are currently performing additional non-clinical studies to advance this candidate therapy into the clinic.
In your opinion, are there any innovative collaborations or partnership models that the Fragile X community can pursue in order to advance the field faster?
Ralph: I would say our collaboration with the lab of Dr. Moine at the IGBMC, as well as with Conectus, which is the technology transfer organization of the Alsace region here in France, were crucially important for the success of this program. The program relies on the combined know-how and expertise of one of the leading academic labs with expertise in Fragile X, molecular biology, and a gene therapy company such as Lysogene, which has expertise in AAV vector design, as well as nonclinical and clinical development of gene therapies, and regulatory affairs in the field. This type of academy-industry partnership, with very close collaboration between the scientists, joint project teams, regular meetings, and joint design of experiments, is in my opinion, a very efficient way to advance basic research into the clinic.
Finally, what does patient-centric drug development mean for the Fragile X field?
Ralph: For Fragile X, patient-centric drug development really means focusing on clinical outcomes that matter to patients. In drug development, there is an increasing focus on assessing patient and caregiver experiences and preferences. This is important for designing clinical trials that will have clinically meaningful outcome measures, but it is also important during nonclinical development, where we try to identify suitable animal models with phenotypes that can either reproduce or be related to a clinical relevant symptom or biomarker.
Thank you very much for your participation and sharing your valuable insights with us.
Ralph: Thank you.
Dr. Ralph Laufer is the Chief Scientific Officer at Lysogene, a gene therapy company based in Paris, focusing on the development of innovative treatments for neurological diseases. Before joining Lysogene in 2018, Dr. Laufer was Senior Vice President and Head of Discovery and Product Development at Teva Pharmaceutical Industries. Prior to that, he held the positions of Scientific Director of IRBM Science Park, a drug discovery partnering organization in Rome, Italy, and Head of Pharmacology at IRBM-Merck Research Laboratories Rome. He is the recipient of the American Chemical Society 2013 Heroes of Chemistry Award for his role in the discovery and development of Isentress (raltegravir), the first integrase inhibitor approved for use in HIV infected patients. Dr. Laufer’s scientific achievements include the discovery of the tachykinin NK-3 receptor and the anti-obesity activity of ciliary neurotrophic factor. He is the author of over 90 peer-reviewed articles and inventor of more than 20 patents. Dr. Laufer obtained his PhD in Biochemistry (summa cum laude) and M.Sc. in Chemistry from the Hebrew University of Jerusalem. He conducted postdoctoral training at the Institut Pasteur in Paris.