José Luis Millán Archives - Sanford Burnham Prebys

Tag: José Luis Millán

Institute News

José Luis Millán joins international initiative to study calcification in aging

AuthorMiles Martin
Date

July 21, 2023

José Luis Millán, PhD

Sanford Burnham Prebys professor José Luis Millán, PhD, has joined a five-year, $13 million program that will study misplaced calcification in the eyes and brains of patients suffering from age-related macular degeneration (AMD) and Alzheimer’s disease (AD).

The initiative is funded by the National Institute on Aging and will be led by Francesca Marassi, PhD, an adjunct professor at Sanford Burnham Prebys and chair of biophysics at the Medical College of Wisconsin.

AMD affects nearly 20 million adults in the U.S. and is the leading cause of central vision loss and legal blindness. AD affects more than 6 million people in the U.S., and it is the top cause of dementia across the globe. Age is a prominent risk factor for both diseases. However, how AMD and AD progress over time is not well understood, and research is needed to drive the development of effective pharmaceutical treatments.

Both diseases are associated with the progressive accumulation of mineralized deposits under the retina and in the brain. Healthy calcification processes are needed to grow and repair bones, but these same processes can cause misplaced deposits in the eye and the brain that contribute to disease. Scientists do not yet know what causes these deposits to form, and answering this question may provide clues to better understand AMD and AD, as well as aid the development of new ways to diagnose and treat these diseases.

The international research team, which also includes scientists from UC San Diego, University of Maryland School of Medicine, and Queen’s University Belfast, will explore the characteristics of misplaced calcifications in both the eye and the brain. They have devised four projects to examine calcifications at varying scales, from their atomic structure up to their accumulation in cells and animals.

Millan will direct the fourth project, which will study how cells and tissues maintain their balance of phosphorus. In human adults, approximately 90 percent of the body’s total phosphorus is crystalized in bone, and these same crystals also are part of the calcified deposits that form in AMD and AD. Dr. Millan’s team will study mice to determine how cells control phosphorus levels and how these biochemical pathways contribute to the formation of calcified deposits in the eye.

The grant, funded by the National Institute on Aging, is titled “Molecular mechanisms of calcification: roles and opportunities in diseases of aging.”

This story is adapted from a press release published by Medical College of Wisconsin.

Institute News

Where science meets patients: Sanford Children’s Research Center hosts inaugural symposium

AuthorMiles Martin
Date

May 10, 2023

Sanford Children’s Research Center symposium group photo

The event celebrated 16 years of progress at the Center and connected scientists with the people most impacted by their work.

The Sanford Children’s Health Research Center at Sanford Burnham Prebys recently hosted its first-ever Children’s Health Research Symposium, which brought scientists and families together to learn about the latest research tackling childhood diseases.

“We’re all here because we want to improve the health of children,” said President and CEO David A. Brenner, MD, during his opening comments. “But this event also shows the amazing amount of collaboration and collegiality across San Diego, because we have all types of people together from different backgrounds who want to develop therapies and cures for children affected by disease.”

The Sanford Children’s Health Research Center was established in 2008 with the help of a generous gift from Institute namesake T. Denny Sanford. Since then, the Center has been a world leader in children’s health research.

“T. Denny Sanford made an investment in children’s health 15 years ago, and I think that investment has paid off pretty well so far,” said Center director Hudson Freeze, PhD, in his introduction to the first scientific session. Freeze is among the world’s leading experts on congenital disorders of glycosylation (CDG), a rare group of genetic disorders that can cause serious, sometimes fatal, malfunctions of different organs and systems in the body.

“We’ve published over 600 scientific papers, and about half of those are translational studies, which means they’re helping turn scientific discoveries into real treatments for patients,” adds Freeze.

Professor Hudson Freeze with the Omler family

Professor Hudson Freeze with the Omler family

The day included presentations from researchers at Sanford Burnham Prebys, as well as from other research organizations studying childhood diseases. However, the highlight of the event was the afternoon reception, in which scientists had the opportunity to mingle and share a meal with families affected by rare childhood diseases.

Professor José Luis Millán (center) with the Fischer family (left) and the Britt family (right)

Professor José Luis Millán (center) with the Fischer family (left) and the Britt family (right)

Each researcher briefly introduced the family affected by the illness the scientist studies. This list included many longtime friends of the Institute, such as Damian Omler, who lives with a rare form of CDG; and Morgan Fischer, who was born with soft bone disease. Today, thanks to the help of a drug developed based on the research of Institute professor José Luis Millán, PhD, Morgan is a thriving teenager. This drug is also helping other children living with soft bone disease, including 10-year-old Aubrey Britt, who was in attendance with her family as well.

“Something so important that we keep as a tradition for scientific events at our Institute is to involve families that have been touched by the work of our faculty,” said Freeze. “They’re why we’re all here.”

The full list of talks included: 

Sanford Children’s Health Research Center

  • José Luis Millán, PhD “Developing therapeutics for soft bones and ectopic calcification disorders”
  • Duc Dong, PhD “From hope for few to drug for many—why rare is precious”
  • Evan Snyder, MD PhD “A clinical trial using human neural stem cells for neuroprotection in perinatal asphyxia, a major cause of cerebral palsy in kids”
  • Anne Bang, PhD “Drug screens of human-induced pluripotent stem cell (hiPSC) derived neuronal networks on multi-electrode arrays”
  • Pamela Itkin-Ansari, PhD “Proinsulin misfolding in diabetes”
  • Yu Yamaguchi, MD PhD “Multiple hereditary exostoses—from genetics to potential drug targets”
  • Hudson Freeze, PhD “Fucose therapy: Revising bedrock biochemistry”

Sanford Health

  • David Pearce, PhD “From rare diseases to type-1 diabetes: Research that impacts children at Sanford Health”

Frontiers in Congenital Disorders of Glycosylation Consortium

  • Eva Morava, MD, PhD “Clinical trials in Glyco-land”
  • Ethan Perlstein, PhD “Precision drug repurposing: Patient avatar to pioneer study to Phase 3 trial”

UC San Diego

  • Lars Bode, PhD “Human milk-based therapeutics and diagnostics to protect preterm babies from necrotizing enterocolitis”
  • Stephanie Cherqui, PhD “Hematopoietic stem cell gene therapy for cystinosis: Mechanism of action and clinical trial update”
Institute News

Enzyme therapy helps rebuild teeth

AuthorBrandon Levy
Date

May 28, 2021

xray image of teeth

Study in mice suggests a new approach to treating periodontal disease

Our teeth are extremely tough, but neglectful oral hygiene practices and certain genetic disorders can still massively damage them. If this deterioration becomes bad enough, teeth can be permanently lost. In a recent study co-authored by José Luis Millán, PhD, professor at Sanford Burnham Prebys, researchers identified a promising new strategy for helping the body regenerate a part of the tooth that is particularly difficult to repair.

When it comes to taking care of our teeth, the enamel coating surrounding the upper portion of teeth tends to get most of the attention. It is, after all, the most visible part of our teeth and the hardest substance in the human body. However, a substance called cementum that surrounds the roots of our teeth is also incredibly important. The cementum helps our teeth remain in our mouths by attaching them to periodontal ligaments connected to surrounding jaw bone.

“The cementum around the tooth root is one of the tissues that has to be repaired to restore the tooth’s function after periodontal disease,” explains National Institutes of Health (NIH) senior investigator Martha J. Somerman, D.D.S, PhD, the new study’s senior author. “A lot of scientists have been focusing on promoting bone regrowth, but if you do that without considering the need for a healthy cementum, you will not restore proper function.”

Unfortunately, damaged cementum doesn’t regenerate very quickly when left to its own devices, if it heals at all, and current approaches to rebuilding it have not proven to be very effective. In the new study, Somerman’s team investigated whether an enzyme naturally found in the human body called alkaline phosphatase (ALP) could help repair damaged cementum by boosting the process that builds teeth and bone, known as mineralization. Prior research had shown that ALP transforms a chemical called pyrophosphate, which inhibits mineralization, into another molecule called phosphate, which promotes mineralization.

The new study utilized a mouse model of periodontal disease that lacks the gene for an important bone- and cementum-building protein called bone sialoprotein. The researchers began by giving five-day-old mice a ‘systemic’ therapy that quadrupled their blood’s level of tissue-nonspecific alkaline phosphatase (TNAP), a form of ALP found in bones. At two months of age, the mice that received the therapy had cementum that was more than twice as thick as the cementum of their untreated counterparts, and they also showed greater growth of the jaw bone that surrounds the cementum. Moreover, their teeth were just as well-attached to the periodontal ligament as the teeth of untreated, genetically normal mice.

“Bone sialoprotein is thought to be a critical molecule for mineralization,” Somerman explains, “so this is a perfect proof-of-principle model to examine whether you can regenerate cementum.”

Next, using five-week-old mice with the same genetic defect, the research team investigated the effects of delivering TNAP directly to the area where the degraded periodontal tissue was rather than raising TNAP levels in the entire body. The treated animals showed similar beneficial effects to the mice that had received the systemic TNAP-boosting therapy. What’s more, the locally delivered TNAP treatment also promoted growth of the cementum and surrounding jaw bone in genetically normal mice.

A final set of experiments in cells showed that ALP corrected mineralization deficiencies in cementum-producing cells, called cementoblasts, that had the same genetic defect as the mice. However, treating those cells with a chemical that disrupts the transport of phosphate into cells diminished the ALP’s beneficial effects, strongly suggesting that the TNAP treatment given to the mice promoted regeneration of the cementum and surrounding bone by increasing the amount of phosphate available for cementoblasts to use for the rebuilding process.

Moving forward, the scientists will continue refining their TNAP treatment and working to move therapies based on their findings into clinical trials. Based on the original research of Millán, TNAP is now FDA-approved for use in humans to treat hypophosphatasia—a debilitating genetic condition that causes soft-brittle bones. This could hasten its adoption as a treatment to help rebuild the cementum and jaw bone of people with severe periodontal disease. Importantly, delivering TNAP directly into the damaged area, as the researchers did in their new study, would likely have fewer side effects than introducing it throughout the body.

“I’m incredibly excited that our past and ongoing research on TNAP is proving to be valuable for conditions that weren’t even on our radar when we started,” says Millán. “We knew that TNAP was very important for the proper mineralization of teeth but employing it as a therapy for periodontal disease is a very novel and promising strategy.

This piece was originally published on the NIH’s “I Am Intramural” blog.  

Institute News

Fighting rare diseases: Finding treatments and bringing hope to families

AuthorMonica May
Date

March 23, 2021

Hudson Freeze, PhD and José Luis Millán, PhD

The majority of rare diseases affect children, most of whom have an underlying genetic cause for their condition that is incurable.

The majority of rare diseases affect children, most of whom have an underlying genetic cause for their condition that is incurable.

Often, their own doctors have never heard of their disease, let alone know how to treat it.

But there is someplace they can turn to for help. The Human Genetics Program at Sanford Burnham Prebys provides insights into the genes and environmental factors that play a role in the development of childhood diseases. Their work often leads to better ways to diagnose, treat, and sometimes, even cure children.

On March 18, 2021, two patients whose lives were saved by discoveries made by Hudson Freeze, PhD, and José Luis Millán, PhD, joined the scientists for a conversation about what this work means to them and how their lives have been impacted. Watch the full discussion below.

Institute News

SBP scientist honored by the American Society for Bone and Mineral Research

AuthorMonica May
Date

September 28, 2018

José Luis Millán, PhD

José Luis Millán, PhD, professor in the Human Genetics Program at Sanford Burnham Prebys Medical Discovery Institute (SBP), has received the 2018 American Society for Bone and Mineral Research (ASBMR) Lawrence G. Raisz Award for his outstanding achievements in pre-clinical and translational research. 

Millán has dedicated his career to understanding the mechanism of initiation of skeletal and dental mineralization. His pioneering research has led to the first-ever FDA-approved drug for a rare soft bone disease, hypophosphatasia (HPP); and a second drug candidate developed through a research collaboration with Daiichi Sankyo Company, Limited (Daiichi Sankyo) that entered a Phase 1, first-in-human clinical trial in 2017. 

ASBMR’s award is named in honor of Lawrence G. Raisz, MD, a prominent scientist, mentor, teacher and clinician in the field of bone and mineral metabolism. Raisz was a founding member of ASBMR and the first editor-in-chief of the Journal of Bone and Mineral Research. 

“Lawrence G. Raisz deeply influenced the skeletal mineralization field, so it is a true honor to receive an award in his memory,” says Millán. “In accepting this award, I want to thank the many individuals who enabled our achievements—from the National Institutes of Health (NIH), which has generously funded our research since the 1980s, to the collaborators and lab members who were instrumental in our scientific advances. I also want to thank SBP for providing state-of-the-art technologies that were invaluable to our research.”

Millán was presented the award onstage today at the ASBMR 2018 Annual Meeting in Montreal. 
 

Interested in keeping up with SBP’s latest discoveries, upcoming events and more? Subscribe to our monthly newsletter, Discoveries.

Institute News

Soft bone disease research — from bench to bedside and back

Authorjmoore
Date

April 7, 2016

Header image

Funding for the laboratory of José Luis Millán, PhD, professor in the Human Genetics Program, has been renewed by the NIH to the tune of $3 million over the next five years. The grant ensures that they can continue to advance understanding of and develop treatments for the rare disease called hypophosphatasia (HPP). This disease—also known as soft bones—can cause skeletal deformities of the limbs and chest and result in frequent fractures and premature loss of teeth. HPP is estimated to affect approximately one per 100,000 live births.

The Millán lab’s decades of research have already led to the first-ever treatment, asfotase alfa, an enzyme that’s injected three to six times per week to help harden bones. This drug is a functional version of the enzyme that’s defective or missing in HPP patients, tissue-nonspecific alkaline phosphatase, that is modified to help it reach mineralizing tissues such as bone. Asfotase alfa is manufactured by Alexion Pharmaceuticals and was approved by the FDA last year.

The new therapy has transformed the lives of patients who received it as part of the clinical trial. For example, San Diego’s own Morgan Fischer couldn’t walk before receiving it, but she has since started skiing, riding ponies, and joined a kids’ baseball team.

“It is a rare privilege for a basic research scientist like myself to be able to translate our laboratory work to the clinic and impact patients’ lives,” said Millán. “It’s been extremely rewarding to see how much this treatment has helped these children, and now also adults, afflicted by this genetic disorder.”

“But our work is not done.”

With their current NIH support, Millán’s research group will address asfotase alfa’s limitations. For one, it doesn’t prevent premature fusion of skull bones, which means that many patients still need surgery to allow the brain to grow properly. Investigating other factors regulating skull development could identify targets for future drugs that could be used in combination with enzyme replacement.

Another potential problem with asfotase alfa is that it may contribute to hardening of the arteries in adults. This may result from the way the enzyme is modified, which could also lead to accumulation in arteries. The researchers will examine whether alternative forms of the enzyme can lessen this effect.

“While our earlier research went from the bench to the bedside, now we’re taking what we’ve learned from patients back to the bench. Hopefully, our studies will lead to insights that allow hypophosphatasia patients to live long, healthy lives,” Millán added.