Meet the CRND Researchers

Rare Disease Day Celebration Community Forum

Demystifying Drug Resistance in

Malaria

2014-2015 Academic Year in Review

RareND Student Club Activities

Winners of the First CRND Award for Excellence in Research

News from the Boler-Parseghian Center for Rare and Neglected Diseases

SIGNAL

2 Signal : July, 2015

About the Cover The Moei river, a small, natural boundary between Thailand and Myanmar breached by malaria parasites resistant to frontline artemisinin drugs, in their westward spread. The study by Mbengue, Bhattacharjee et al. describes a molecular mechanism that renders malaria parasites resistant to artemisinins

Page 8

A dedication to rare and

neglected diseases research

How a gift is making a difference in

pushing the research at Notre Dame

Page 3

Rare Disease Day Celebration

Engaging with researchers, physicians

and patient families to battle rare

diseases

Page 4

Demystifying drug resistance in

malaria

Boler-Parseghian Center scientists

lead an international team to tackle

the global problem of emerging

resistance to the most effective

malaria drug

Page 8

The Midwest Neglected

Infectious Diseases Meeting

Registration open for the 4th annual

meeting to be held on August 29-29th

on the Notre Dame Campus

Page 10

Meet the CRND researchers

Your guide to the world-class

research carried out by Notre Dame

faculty at the Boler-Parseghian Center

for Rare and Neglected Diseases

Page 11

In this issue

Inaugural CRND award for

excellence in rare and neglected

diseases research

Outstanding Notre Dame Student and

Postdoc winners are recognized for

their excellent work

Page 6

A year in review for the RareND

student club

Raising awareness at Notre Dame and

throughout Indiana

Page 7

Visit us online at www.nd.edu/~crnd

3 Signal : July, 2015

Lorem Ipsum

2014-2015 Academic year in review

Investing in people Impacting lives

support faculty research and develop therapies for diseases that have been over-looked by the pharmaceutical industry

What we do

build partnerships among the diverse stakeholders of the rare and the neglected disease communities

1

2

A “dedication” to rare and neglected diseases

Members of the Boler and Parseghian families with Dr. Kasturi Haldar and Dean Greg Crawford during the dedication ceremony for the Boler-Parseghian Center for Rare and Neglected Diseases

On Sunday October 11th, 2014, the

University of Notre Dame celebrated

the dedication and remaing of CRND

to the “Boler-Parseghian Center for

Rare and Neglected Diseases”.

We thank the Parseghian family for

their long tradition is supporting

research in rare diseases and the

Boler family whose gift allows us to

expand the research that ranges

from developing drugs in lysosomal

disorders and neglected infectious

diseases to rare cancers.

We thank the faculty, students, fellows

and staff for their hard work, the

academic and alumni leadership, our

community partners and patient families

for their support of rare and neglected

diseases research.

4 Signal : July, 2015

“there are roughly 7,000 rare diseases, diagnosis usually takes about 5-7 years and treatments are uncommon or even nonexistent”

Rare Disease Day Celebration a community forum

bringing together researchers, students, clinicians and patient families to raise awareness and find cures

by Jayme Russell

The Boler-Parseghian Center for Rare

and Neglected Diseases held a two-day

Rare Disease Symposium (February 13-

14, 2015) and invited researchers,

patients, families, physicians, and

advocacy groups to speak about their

personal experiences with rare

diseases. The symposium anticipated

Rare Disease Day, recognized

worldwide on the last day of February.

Organized by Barbara Calhoun, nurse

practitioner and outreach coordinator

for the Boler-Parseghian Center, the

event featured research presentations

as well as discussion panels focused on

patient experiences. Because there are

roughly 7,000 rare diseases, diagnosis

usually takes about 5-7 years and

treatments are uncommon or even

nonexistent. These diseases are

emotionally hard to cope with, so it is

important for patients and families to

find others who struggle with the same

illnesses for support.

Students from the RareND Club played a

big part in the symposium. Many

members of the club are students who

have personal experience with rare

diseases and those who wish to pursue

careers in healthcare. The RareND Club

organized a quiz, which was answered

through texts from the audience, to

demonstrate the difficulty in diagnosis

of rare diseases.

Dr. Elizabeth Berry-Kravis, a clinician

researcher at Rush University and Notre

Dame alumna, spoke about her work

exploring delivery of an experimental

drug to patients suffering from

Niemann-Pick Type C (NPC) disease, a

devastating neurodegenerative

disorder. Following her talk, Dr. Berry-

Kravis joined families of the patients

Barbara Calhoun, RN, MSN, PNP Outreach Coordinator

5 Signal : July, 2015

fatal, degenerative disease which

typically begins in childhood. As well,

clinician Elizabeth Berry-Kravis, M.D.

discussed her current tests with new

investigational drugs to treat NPC.

Berry-Kravis has seen positive results

in stabilizing patients, and her work is

showing promising progress. In

addition, ESTEEM student Robert

Power spoke about Diagnostics in

Neurological Diseases, including NPC.

Shahir Rizk, the center’s director of

external programs and research

assistant professor of biological

sciences, discussed Non-Ketotic

Hyperglycinemia; Zhangali Peng,

professor of mechanical and

biomolecular engineering, modeled the

dynamics of red blood cells in sickle cell

anemia; and professor of biological

sciences Jeff Schorey discussed

Mycobacteria Avium, a rare infection

that compromises the immune system.

The research talks, which spanned a

number of genetic disorders and

infections, were streamed live through

the Boler-Parseghian website, so

patient families from the US and Europe

who could not travel were able to see

the progress in rare disease research at

Notre Dame.

under her care in a panel, where they

discussed with the audience the

challenges of caring for someone with a

rare disease and the hopes for a cure. In

addition, Karen Quandt, a nurse,

advocate and NPC mother spoke about

helping clinicians better diagnose the

disease.

Local pediatrician Dr. Carol Luzzi

presented information on the

differences she has seen in children

who have rare neurological versus

behavioral disorders. She focused on

the nuances of diagnosis and shared

patient success stories.

Other presentations and panels

featured a number of Notre Dame

students. Bernie Grey, alumnus ’14 and

master’s candidate in mathematics,

spoke about his own experience with

Common Variable Immune Deficiency.

Two computer science majors Dan

McCormack and Bradley Stalcup

discussed how they are applying their

work with databases to aid in diagnosis

and management of rare diseases.

Friday’s research presentations focused

on current rare disease research at the

university and in the

community. Robert Stahelin, professor

of chemistry and biochemistry,

and Basar Bilgicer, professor of

chemical and biomolecular engineering

and professor of chemistry and

biochemistry, held two in-depth

discussions on Ebola, the mechanism of

infection, and improvements that can be

made in methods of detection.

Purdue University professor of

biology, David H. Thompson explained

new drug treatments for patients with

Niemann-Pick Type C (NPC) disease, a

Both days of the symposium involved

student engagement. “Since last year,

we have structured the event as a

course for Notre Dame students

interested in participating

in rare disease research or advocacy. It

has been a great success because it

allows the students to interact directly

with patients and their families. This is

an extremely valuable experience for

Notre Dame students who are not

typically exposed to clinical research,

especially those considering a career in

medicine,” said Shahir Rizk.

Twenty-nine students registered for the

course this year. The symposium

complements the class taught by

Kasturi Haldar, Rev. Julius Nieuwland,

C.S.C. Professor of Biological Sciences,

titled Clinical Research in Rare and

Neglected Diseases, which allows

students to work with real patient

records, identify symptoms of rare

diseases, and score the severity of

disease progression. In connection with

the class, a small group of computer

science students are working with

Barbara Calhoun to establish the Rare

Health Exchange (RHE), a database of

the information collected by the

students.

“a great experience for Notre Dame students interested in a pursuing a career in medicine to get exposed to clinical research”

6 Signal : July, 2015

The winners will receive a $1,000 cash prize and a plaque recognizing their outstanding

achievements in rare and neglected diseases research

Winners of the Inaugural

CRND Award

Dr. Cassandra Buchheit & Dr. Alassane Mbengue receive the 1st CRND Award for excellence in Rare & Neglected Diseases Research

The winners of the 2015 inaugural Boler-Parseghian CRND award for

excellence in rare and neglected diseases were announced in May.

Dr. Cassandra Buchheit (Schafer lab) and

Dr. Alassane Mbengue (Haldar Lab)

Dr. Buchheit is the graduate student winner, for her outstanding work

on a rare cancer known as inflammatory breast cancer. See Cassie’s

recent published paper on ‘Anoikis evasion in inflammatory breast

cancer cells is mediated by Bim-EL sequestration’ published in the

journal Cell Death and Differentiation in December 2014. The work was

supported by the Elsa U. Pardee Foundation, the Coleman Foundation

and the American Cancer Society, as well as graduate fellowship support

to Cassie from CRND.

Dr. Mbengue is the postdoctoral scholar winner for his outstanding

work in drug resistance in malaria. See Alassane’s recent published

study on , “A molecular mechanism of artemisinin resistance

in Plasmodium falciparum malaria,” published in Nature in the journal

April 2015. The work was supported by the National Institutes of

Health and Notre Dame International.

The CRND award for excellence in rare and neglected diseases will be

made annually. To be considered for the award, applicants must be

nominated by their advisor and provide additional information as

required by the guidelines. Each application is then evaluated by

independent reviewers with appropriate expertise and scored in four

categories pertinent to research training and productivity. We were

excited that in the first year, we had a very strong

pool of applicants. We thank all the participants

for their excellent contributions. The winners will

receive a $1,000 cash prize and a plaque

recognizing their outstanding achievements in

rare and neglected diseases research.

7 Signal : July, 2015

Below: RareND club at the “five guys” fundraiser, rasing awareness for rare diseases among the ND student community

On Tuesday April 28, 2015, the

Notre Dame RareND club

gathered for dinner at Five Guys

restaurant at Eddy St. Commons.

As part of this organized activity,

the restaurant donated a

percentage of its profits from

that day to the club. Since it

gained its club status by the SAO,

RareND has been engaged in a

number of activities on and off

campus to raise awareness

among ND students and in the

community at large for rare

diseases. Following a strong

showing for Notre Dame day, the

Five Guys fundraiser will help

RareND student club wraps up another year of outreach and awareness

To learn more about upcoming events, check out the RareND Facebook page: https://www.facebook.com/rareNDclub

support the club activities in

spreading the word about rare

diseases.

The club has also reached out to

families of rare diseases patients.

The club also welcomed the family

of Skylar Sevison, a brave 1 year

old with Neurofibromatosis. The

students had a chance to learn

about the disease, which is

associated with large benign

tumors and skin pigmentation, and

heard from Skylar’s mom about

living with the disease and the

need for developing treatments

and raising awareness.

Above: RareND club with the family of Skylar Sevison who has a rare disorder known as

neurofibromatosis type 1 Left: Baby Skylar

Thanks to the RareND club, Indiana now recognizes February

28th as Rare Disease Day

8 Signal : July, 2015

Boler-Parseghian researchers led an

international team to identify a

molecular mechanism responsible for

making malaria parasites resistant to

artemisinins, the leading class of

antimalarial drugs.

According to the World Health

Organization’s 2014 World Malaria

Report, there are an estimated 198

million cases of malaria worldwide

with 3.3 billion people at risk for

contracting the infection. Although the

impact of malaria is still significant, the

statistics reflect a considerable

reduction in the global malaria burden.

Since 2010, disease transmission has

been reduced by 30 percent and

mortality due to malaria has decreased

by almost half.

Artemisinins are powerful drugs that

CRND Researchers identify molecular mechanism responsible for making malaria parasites drug-resistant

by Stephanie Healey

The Preah Vihear, a Hindu temple at the border between Thailand and Cambodia: at this border Plasmodium falciparum the most dangerous of malaria parasites are highly resistant to drugs including frontline artemisinin drugs.

have the most rapid action of all

current drugs against Plasmodium

falciparum, the parasite species that

causes the most dangerous form of

malaria. Artemisinin combination

therapies (ACTs) are now standard

treatment worldwide for P. falciparum

malaria. Unfortunately, resistance to

artemisinin has been detected in five

countries across Southeast Asia. Along

the Cambodia-Thailand border, P.

falciparum is now resistant to most

available antimalarial drugs.

Artemisinin resistance poses a serious

global threat to malaria control and

elimination.

“There are two phases of blood stage

malaria infection. In the first phase,

the ‘ring’ parasite stage circulates in

the bloodstream, and in the second

phase, the ‘mature’ parasite stage

sequesters in the tissues of the body,”

explained Kasturi Haldar, the Rev.

Julius A. Nieuwland Professor of

Biological Sciences and the James C.

Parsons and Carrie Ann Quinn

Director of the Boler-Parseghian

Center for Rare and Neglected

Diseases. “Artemisinins are highly

effective in treating malaria quickly

because they target the first ring stage.

When patients take the medication,

their fevers reduce quickly, and the

parasite is eliminated rapidly.”

Although artemisinins have been

widely used and investigated, no one

fully understood how they worked or

why clinical resistance has emerged.

Laboratory studies showed that

artemisinins were always active

against the mature parasite stages that

sequester in tissues, but clinicians

were observing resistant infections

from patients who were still in early

stage of infections. In addition,

previous genome wide association

studies of P. falciparum identified

genes associated with artemisinin

resistance, but it was unknown how

the genes worked. This Notre Dame-

led study identified both the target of

artemisinins in the clinically affected

ring stages and how a gene named

PfKelch13, a dominant marker used to

track the parasite’s resistance, causes

artemisinin resistance.

“We observed that levels of a lipid

called phosphatidylinositol-3-

9 Signal : July, 2015

“Artemisinins are powerful drugs with most rapid action against

malaria. Artemisinin resistance poses a serious global threat to

malaria eradication efforts”

Elevated levels of the enzyme PfPI3K help the parasite make more of a certain lipid, ultimately overcoming the effects of artemisinin, the most

effective drug currently used against malaria

Image by Kimbra Turner

phosphate (PI3P) were higher in

artemisinin-resistant P. falciparum than

artemisinin-sensitive strains,” said

Alassane Mbengue, a postdoctoral associate

in biological sciences and co-first author on

the study. “This lipid is produced by an

enzyme called PfPI3K. We found that

artemisinins block this kinase from

producing PI3P lipids.”

“We also discovered that the amount of the

kinase present in the parasite is controlled

by the gene PfKelch13,” Mbengue said.

“Mutation in the gene increases the kinase

levels, which in turn increases PI3P lipid

levels. The higher the level of PI3P lipids

present in the parasite, the greater

the level of artemisinin resistance.

We also studied the lipid levels in

parasites without the gene

mutation and observed that when

PI3P lipid levels were increased

artificially, the parasites still

became proportionately resistant.”

“Our results are especially

significant because we studied

clinical parasites from Cambodia,

where artemisinin resistance is

highly prevalent,” explained Souvik

Bhattacharjee, research assistant

professor of biological sciences and

co-first author of the paper. “We

collaborated with researchers and

clinicians in Asia, Europe and the

U.S. This was true cooperation over

several years at both the

international and the local levels.”

Other Notre Dame collaborators on

the study included Rob

Stahelin at Indiana University

School of Medicine-South

Bend, Olaf Wiest in the Department of

Chemistry and Biochemistry,

theComputer Assisted Molecular Design

Core, Shahir Rizk in the Department of

Biological Sciences, and the Genomics

and Bioinformatics Core.

When asked about the next steps for

this research, Bhattacharjee said, “There

are presently two options for

overcoming artemisinin resistance.

Working with our colleagues at Notre

Dame, Eli Lilly & Co. and the Medicines

for Malaria Venture, we need to find

drugs that kill the parasite by blocking

the function of the kinase from making

the PI3P lipid or disrupting the

production of the kinase itself.”

The study, “A molecular mechanism of

artemisinin resistance in Plasmodium

falciparum malaria,” was published

online in Nature on Wednesday (April

15). This work was supported by the

National Institutes of Health, the

Parsons-Quinn Endowment and Notre

Dame International.

10 Signal : July, 2015

Registration now open

The Midwest Neglected Infectious Diseases Conference

the only regional meeting in the Midwest that

features forefront research focused on the

pathogenesis of fungal and parasitic diseases Register at www3.nd.edu/~crnd/

August 28-29 McKenna

Conference Center

Keynote Speaker:

Chandy John, MD Ryan White Professor of Pediatrics Professor of Microbiology & Immunology Indiana University School of Medicine

MNID ‘15

11 Signal : July, 2015

Extraordinary research

carried out by Notre Dame

scientists developing

therapies for rare and

neglected diseases

Meet the Researchers

12 Signal : July, 2015

Dr. Miguel Morales Biological Sciences

Dr. Miguel Morales Developing therapies for tropical

diseases with a global impact

Roughly 90% of the world’s health

care resources are spent on diseases

that affect only 10% of the world’s

population. Neglected Tropical

Diseases (NTDs) are a group of

diseases that cause substantial illness

for more than one billion people

globally. Several of these NTDs are

caused by trypanosomatids such as

Leishmania spp and Trypanosoma

cruzi. My research program explores

multiple angles of signaling events in

these parasites, including stress

response, differentiation, drug

resistance, virulence, infectivity,

validation of pathways as drug targets

and transcriptional control.

Leishmaniasis is a major public health

problem in several areas of the world.

The disease is fatal if untreated and

currently ranks second to malaria in

terms of mortality and disability.

Chagas’ disease is a zoonotic

infection caused by the protozoan

parasite T. cruzi and it represents a

health threat to almost 20 million

people worldwide. Whereas originally

the disease was confined mostly to

Latin American countries, current

international migration patterns have

drastically changed Chagas’

epidemiology.

14 million people from countries

where the disease is endemic have

moved to the United States, Europe,

Japan and Australia. Notably, it is

estimated that more than 300,000

people harboring a T. cruzi infection

live in the United States. Drug therapy

is the only way to control and treat

these diseases due to the lack of a

human safe vaccine. However, this

strategy is seriously threatened by

rampant increase of resistance against

standard clinical drugs. Therefore it is

urgent to identify new drugs and new

drug targets.

I have extensive experience in

Leishmania and Trypanosoma

molecular biology, proteomics and

epidemiology and I have successfully

trained graduate students, technicians,

and post-doctoral fellows. We are

utilizing state-of-the-art molecular

techniques to elucidate the relevance

of an important molecular from the

parasite known as mitogen-activated

protein kinase (MAPK). We analyze

the role of the MAPK signaling

pathway in intracellular infection,

stress response, drug resistance and as

new targets for therapeutic

intervention. For instance new links

between signaling events in

Leishmania and tolerance to new

drugs such as miltefosine will allow

us to better understand and define new

resistance markers before clinical

resistance becomes a worldwide

problem.

MEET THE RESEARCHERS

13 Signal : July, 2015

“Inflammatory Breast Cancer (IBC) is rare and frequently misdiagnosed. Prognosis for women with IBC is often poor.”

We got interested in inflammatory

breast cancer after discussing the

objectives of the Boler-Parseghian

Center with Dr. Kasturi Haldar

several years ago. This got us

thinking about IBC. It is a rare

subtype of breast cancer where not

much is known regarding the

underlying basic biology. IBC is

unique because there is no palpable

primary tumor formation and

instead IBC cancer cells lodge in the

dermal lymphatic vessels of the

mammary gland. My background is in

studying cell death and specifically

how cancer cells survive in unnatural

environments, so understanding how

IBC cells survive in the dermal

lymphatic vessels was a natural fit.

The project took off from there with

a grant from the Elsa U. Pardee

foundation and support from the

Boler-Parseghian Center.

Inflammatory breast cancer (IBC) has

a very unique disease progression

that causes women to be frequently

Dr. Zach Shafer:

Understanding a Rare Breast Cancer

Left: Dr. Zach Shafer with members of his lab

misdiagnosed. Instead of starting as

a lump in the breast, IBC manifests

as reddened skin that is often

mistaken for an infection. In fact,

this reddening is due to IBC cancer

cells lodging in the lymphatic

vessels under the skin. It is

inherently aggressive and the fact

that it is frequently misdiagnosed

exacerbates problems for the

patient. Prognosis for women with

IBC is often poor.

In our recent study we found that

IBC cells have elevated levels of the

protein Bim-EL. This protein

typically would either be eliminated

rapidly or, conversely, localized in

the cell to cause cell death.

However, in IBC cells, this protein

binds to two other proteins (Beclin-

1 and LC8) in a fashion that

prevents it from causing cell death.

This appears to be a unique

mechanism utilized by IBC cells.

The fact that Bim-EL, a protein that can

cause cells to die, is present in high

levels in IBC cells represents an

attractive therapeutic target.

Our next step is to better ascertain if we

can utilize the high levels of Bim-EL

found in IBC cells to develop a strategy

to specifically eliminate IBC cells. We

are currently collaborating with

investigators at MD Anderson Cancer

Center to investigate the quantities of

Bim-EL present in a diverse collection

of IBC patients samples and are

preparing investigate the possibility of

using high Bim-EL levels as a

therapeutic strategy.

Boler-Parseghain Center for Rare and Neglected Diseases

107 Galvin Hall of Science Notre Dame, Indiana, 46556

Congratulations to the Boler-Parseghian Center for Rare and Neglected Diseases and Bristol

Street Pediatrics for winning the Ganey Award to help improve care

for children with rare diseases in the South Bend/Elkhart community