Meet Dr. Makiko Yasuda, Porphyria Researcher
The porphyria community is lucky to be supported by dedicated physicians, researchers and advocates who work tirelessly to improve care and develop new treatments for porphyria. The United Porphyrias Association is pleased to introduce you to some of them!
"One thing I love about science is you learn something, then new information comes up and it opens up a whole new set of questions."
-Makiko Yasuda, MD, PhD
Can you introduce yourself and tell us a bit about your connection to porphyria?
My name is Makiko Yasuda and I'm an Associate Professor at Mount Sinai School of Medicine in New York City. I have been working on the porphyrias and heme biosynthesis for nearly 20 years. I was trained as a pediatrician in Japan but have dedicated my career to full-time research.
My lab performs basic and translational research, mainly on the acute hepatic porphyrias (AHPs). A lot of our work aims to uncover the underlying mechanism(s) of the neurologic dysfunction in the AHPs and to develop new treatments for these disorders by applying mouse models.
Your research involves studying acute hepatic porphyria in mice, can you share a bit about how studying mice can help us better understand porphyria in people?
While mouse models aren’t a perfect representation of humans, they have been useful for assessing the efficacy of new treatments for AHPs and for furthering our understanding of how defects in heme biosynthesis may lead to neurologic dysfunction.
We and other groups have used the well-established mouse model for acute intermittent porphyria (AIP), the most common AHP, for pre-clinical evaluation of several new treatments, including givosiran, which is now commercially available. Like human AIP patients, these mice accumulate massive amounts of the porphyrin precursors, ALA and PBG, in their blood and urine when exposed to the prototypic attack-precipitating drug, phenobarbital. As a result, they allow us to test whether new treatments can prevent and/or treat acute attacks.
To give another example, we've generated a mouse model that mimics an extremely rare type of porphyria, known as homozygous dominant acute intermittent porphyria (HD-AIP). While patients with AIP have a mutation in one copy of their HMBS gene, HD-AIP patients have mutations in both copies. This form of porphyria is very severe and characterized by early onset, chronic and progressive psychomotor delay, in contrast to AIP, which presents with episodic acute attacks. The generated mice faithfully recapitulated many of the clinical and biochemical features of human HD-AIP patients. By studying these mice and comparing them to the AIP mice, we found that in HD-AIP, the putatively neurotoxic porphyrin precursors are constitutively elevated in the brain, whereas in AIP, porphyrin precursors massively accumulate only during attacks and is primarily restricted to the liver. This likely explains why the clinical presentation of HD-AIP is vastly different from that of AIP. Importantly, this suggests that liver-targeted therapies for AIP are not effective for HD-AIP, and that efficacious therapies for this condition need to target the central nervous system.
Have there been any findings in your research that have surprised you or changed your understanding of porphyria?
Certainly! One of our concerns when doing preclinical work for givosiran was whether continuous suppression of ALAS1 expression in liver cells (i.e., hepatocytes) would lead to deleterious effects. To address this, we generated mice in which we can selectively inactivate ALAS1 expression in hepatocytes. Since ALAS1 is the first enzyme in heme biosynthesis, our expectation was that as we increasingly inactivated the gene, the mice would become unhealthy due to heme deficiency. Contrary to this, mice with almost no hepatocyte ALAS1 expression were overtly healthy and maintained fairly high levels of heme.
How are these mice able to maintain heme?
These findings opened a new area of research and is now a major focus in my lab. I am very excited to pursue these studies because they challenge the current paradigm that heme content within a cell is controlled primarily by the balance between how much heme is synthesized (via ALAS1) vs how much heme is degraded in that particular cell. Clearly, something else is going on that allows the cells to maintain heme levels in the absence of heme synthesis.
These findings may also have implications for the AHPs. It is currently believed that AHP patients have induced hepatocyte ALAS1 expression during attacks because their heme production is insufficient. But if hepatocytes have a way to maintain heme in the absence of heme synthesis, why do AHP patients end up with induced hepatocyte ALAS1? As a porphyria researcher, my hope is that these studies will also lead to a better understanding of the AHPs.
You’re a member of the UPA’s Scientific Advisory Board and work with the members of the Porphyrias Consortium (PC) and the American Porphyria Expert Collaborative (APEX). How does being involved in these groups inform your work?
Working closely with these groups brings me much closer to the porphyria patients. This is invaluable, because as researchers, we learn so much from the patients and they are the reason we do what we do.
I have benefited immensely by being part of the PC and APEX because they connect me with other porphyria experts with different expertise (e.g., hepatology, hematology, neurology, etc.) who have been extremely generous in sharing their knowledge, experiences, and ideas about porphyrias and heme biosynthesis. It has been amazing to collaborate with them on various projects, and I look forward to continuing working with them.
There are still big outstanding questions in the field, one of them being why the vast majority of individuals who have disease-causing mutations in their HMBS genes (or other AHP genes) never experience an attack, while some suffer from recurring attacks. Are there disease-modifying genes, if so, which genes are involved? One way we are trying to tackle this question is by collecting and studying samples from AHP families that have both symptomatic and asymptomatic mutation-positive individuals. Since AHPs are rare diseases, efforts like this would not be possible without the collaboration of multiple investigators.
You recently attended the International Congress of Porphyrins and Porphyrias (ICPP) in Spain, did you hear anything new or surprising?
At ICPP, there were several talks about patients on givosiran who have well-controlled ALA and PBG levels but are still experiencing acute attack-like symptoms. This was surprising to me. For decades, there were two major hypotheses regarding the pathogenesis of acute attacks: 1) that heme deficiency in nervous tissues and/or the liver leads to attacks; or 2) that toxicity of the porphyrin precursors leads to attacks. The fact that givosiran, which isn’t expected to restore heme content, was highly effective in preventing attacks had me convinced that it was the latter. However, recent reports of AHP patients with normal or only mildly elevated ALA and PBG experiencing symptoms suggest that our understanding is still incomplete.
There were also a few presentations at the ICPP about new therapeutic developments that are still in early stages but seem promising. In general, new and exciting therapeutic platforms are being developed that we may be able to apply to the porphyrias and many innovative tools are now available to us researchers. It’s really an exciting time to be in porphyria research!
Thanks for taking the time to talk with us today. Is there anything you wanted to add?
I would like to add that I really appreciate the UPA, APEX, PC and the porphyria patient community for their continued support of our research. Whether it’s clinical trials or more basic studies such as the modifier gene study, I am grateful for porphyria families for their courage and willingness to participate. Together we can do more!
Meet more of the experts and advocates changing the world for porphyria
Meet more of the porphyria experts and advocates changing the world for porphyria
