Research Strategy

Our research strategy includes overall principles and criteria to guide prioritisation of the research focus and identify specific areas of priority.

Visit here for details on 2021 CBS deficiency Research Grants.

Our Research Strategy aims to:

Define key priorities for future research for Classical Homocystinuria (CBS deficiency); and
Guide prioritisation and evaluation of research grants funded by HCU Patient Community Groups.

Key Focus Areas

Several areas of unmet need in the diagnosis and management of Classical Homocystinuria have been identified through advice from academic researchers and clinical experts. We have defined 3 key priority focus areas for future research and patient advocacy:

We expect our near-term Research Strategy to focus primarily on advancement of new treatment modalities, in order to maximize the benefit to patients and lesson the burden of strict dietary control. We will use 3 guiding criteria for prioritisation and evaluation of research grants:

Potential risk/benefit of approach to improve patient care.
Probability research in this area would move forward without funding by HCU Network Australia and HCU Network America (HCUNAs). Lower priority placed on an area if industry funding available.
Probability funding a project in this area would contribute significantly to progressing research in this area, including potentially attaining proof of concept to motivate industry funding.

Background

HCU Network Australia and HCU Network America have agreed to collaborate in specific areas that can benefit from global perspective and coordination. One such area is to promote research for Classical Homocystinuria, which is supported by a global Scientific Advisory Board. Over time, we hope to include patient groups from other countries and to be able to expand focus beyond classical homocystinuria to include cobalamin deficiencies and methylation disorders that also cause elevated homocysteine levels.

Therapeutic Avenues

The current therapeutic objective is described in the Guidelines for the diagnosis and management of cystathionine beta-synthase deficiency. Click here to view the Guidelines.

There are several approaches being investigated for the treatment of classical homocystinuria. See our Investigational Therapies Research Map.

Enzyme Replacement Therapy (ERT) – Replace CBS enzyme

Enzyme Replacement Therapy (ERT)

What is it?

Enzyme replacement therapy (ERT) is a medical treatment, which replaces an enzyme in a patient where the enzyme is defective due to a genetic defect. The product currently in development for classical homocystinuria is a synthetic version of the enzyme and is expected to be administered by a subcutaneous injection.

The safety and effectiveness of ERT has been shown in the treatment of some lysosomal storage diseases including Gaucher disease type I, Fabry disease, MPS I (Hurler syndrome), MPS II, MPS VI and Pompe. ERT does not correct the underlying genetic defect and is not a curative approach but rather requires lifelong administration.

Gene Therapy – Deliver DNA to enable body to produce CBS enzyme

Gene Therapy

What is it?

Gene therapy is a treatment approach that involves delivering genetic material (DNA) into a person’s cells to compensate for defective genes. The process involves using a vector (e.g. the adenovirus or common cold vector which is inactivated and has no biologic activity) to deliver the genetic material into the body. The cells in the body (in the case of classical HCU, the liver cells) will then transcribe the DNA and produce the enzyme. It is unknown how long the product will last and whether readministration will need to occur over time.

Alternative Enzymes– Use alternative enzymes to degrade

Methionine (Met) or Homocysteine (Hcy)

What is it?

There are other synthetic enzymes in development that are designed to degrade methionine (so that it is not converted to homocysteine) or directly degrade homocysteine. These are expected to require infusions, most likely on a monthly basis.

CBS Protein Activation: Administer small molecules to restore faulty

CBS enzyme function or activation

What is it?

Small molecules can be chemically synthesized and often taken in tablet or capsule form, in contrast to enzymes or other “biologics”, which are made via living organisms and too “large” to be taken in tablet or capsule form so require injection or infusion. There are a few small molecules being researched for HCU that would either activate the function of the CBS enzyme (which is a protein) or prevent its degradation, thereby increasing its effectiveness in lowering homocysteine levels.

Metabolic Pathway Modification:

Use nutrition or dietary supplements to address metabolic imbalances caused by HCU

What is it?

There are other approaches to modify the metabolic pathway through modulating sulphur containing amino acids through diet and/or supplements, but this approach needs to be validated in clinical trials to demonstrate any advantages over the current approach of protein restriction and supplementation with non-methionine amino acids.

Metabolic Compounds

What is it?

Research has shown that the administration of different metabolic compounds (not yet disclosed) can reduce levels of homocysteine in mice, and especially when combined with betaine. A new study in mice is being conducted by Ken Maclean at the University of Colorado, with a grant from HCU Network America and HCU Network Australia, to determine whether treatment with specific metabolic compounds combined with betaine could dramatically improve clinical outcome in HCU and conceivably remove the need for a methionine-restricted diet. (Dr. Maclean is also utilizing funding from the William R. Hummel Homocystinuria Research Fund to supplement this grant.)

Taurine

What is it?

Taurine is a naturally occurring sulfinic acid that acts to increase tissue levels of the major cellular antioxidant glutathione by exerting a cysteine sparing effect. In an animal model of HCU, the co-administration of taurine acted to normalize blood-clotting parameters, decrease inflammation in the vasculature and increased the effectiveness of the betaine response. In a recent short-term human pilot trial, taurine reversed endothelial dysfunction in human subjects with HCU. Further studies of taurine are being considered.

Here is a schematic overview showing the biochemical cascade and how emerging therapeutic interventions address the biochemical or disease process.

Current Research Avenues

Classical homocystinuria was first reported by American physician D. A. Carson in 1962 followed by H. Mudd describing the enzyme defect in 1964. Since his discovery much research has gone into both understanding the disease and investigating approaches for effective therapeutic treatments.

The HCU Networks sought to identify the therapeutic approaches under investigation for classical homocystinuria and characterise clinical and preclinical stage technologies in development. The Investigational Therapies Research Map aims to summarise the treatment approaches being studied by academia and industry covering pre-clinical and clinical stage technologies.

The Research Map was developed based on information available in the public domain and provided by academic and industry researchers. Interviews with leading researchers and clinicians served to expand and validate the Research Map and to provide expert input on the Research Strategy.

Expert input included:

Viktor Kozich – Project Advisor
Kimberley Chapman
Bart deGeest
Henk Blom
Jan Kraus
Warren Kruger
Andrew Morris
Bridget Wilcken
Johan Van Hove/Cynthia Frehauf*

Industry input included:

Aeglea Biotech*
Erytech*
Orphan Technologies*

*Provided input on specific program

Investigational Therapies Research Map

Our Research Map focuses on one of our key priorities: Advance New Treatment Modalities. The Research Map is not intended to be an exhaustive list of research activities around the world and does not include analysis on existing and emerging tools for diagnosis and disease monitoring. Click here to view our Investigational Therapies Research Map.

For a description on the different types of investigational therapies for Classical Homocystinuria please see Therapeutic Avenues.

To read about strengths and weaknesses of each approach view the Global Research Map: CBS deficient homocystinuria presentation by Margie McGlynn, President HCU Network America. Note: the evaluation of each program is based on a compilation of input from expert interviewees and does not represent a consensus.

Scientific Advisory Board

A Scientific Advisory Board has been convened to advise the HCU Networks on key priorities and guide which specific projects should be funded.

The current members of the Scientific Advisory Board Include:

	Professor Viktor Kožich, (Chair of SAB); MD, PhD, Professor of Medical Genetics and Head of Institute of Inherited Metabolic Disorders, General University Hospital in Prague and Charles University-First Faculty of Medicine, Prague, Czech Republic. Read Professor Kožich’s bio
	Professor Bridget Wilcken AM, MD, FRACP, FRCPA (hon), FHGSA, emeritus consultant at the Children’s Hospital, Westmead, Sydney; part-time metabolic physician, Sydney Children’s Hospital, Australia. Read Professor Wilcken’s bio
	Professor Matthias R. Baumgartner, Prof. Dr. med., Head of Division for Metabolic Diseases and Medical Director of the Swiss Newborn Screening Program, Kinderspital, Zürich, Switzerland. Read Professor Baumgartner’s bio
	Professor Henk Blom, PhD, Laboratory Specialist, Clinical Genetics, Erasmus University Medical Center, Rotterdam, Netherlands. Read Professor Blom’s bio
	Professor Warren Kruger, Ph. D, Full professor, Cancer Biology program at Fox Chase Cancer Center, Philadelphia, PA, U.S. Read Professor Kruger’s bio
	Dr Andrew Morris, MD, Consultant and Senior Lecturer in Paediatric Metabolic Medicine. Willink Metabolic Unit, Central Manchester University Hospital, UK. Read Dr Morris’ bio
	Dr Kimberly Chapman, MD, Ph.D., attending physician in Genetics and Metabolism, Children’s National: Assistant Professor of Pediatrics and Integrated Systems Biology, George Washington University, U.S. Read Dr Chapman’s bio

Patient Representatives:

	Tara Morrison, BA LLB, Director & Chair, HCU Network Australia
	Margaret McGlynn, R. Ph., Ph. D. (hon), President of Board, HCU Network America

Past Members of Scientific Advisory Board

The Late Professor Jan Kraus, Ph. D, Professor Pediatrics / Cell and Developmental Biology, University at Colorado U.S. Read Professor Kraus’ bio

Responsibilities of the Scientific Advisory Board

The responsibilities of the Scientific Advisory Board include:

Work with HCU Network Australia and HCU Network America (HCUNAs) (and other patient groups interested in funding grants) to develop research strategy and identify key priorities for funding.
Provide non-binding but informed guidance on matters specific to HCUNAs research and funding strategies, including opportunities for new programs or clinical trials.
Provide peer review for applications submitted to HCUNAs for funding and provide recommendations on specific projects to be funded.
Support any grant applications submitted by HCUNAs to other funding bodies.
Participate in periodic reviews of HCUNAs Research Strategy.

Download a copy of the Scientific Advisory Board’s Terms of Reference.

HCU Network America and HCU Network Australia are currently calling for Expressions of Interest (EOI) for:

New therapies to treat classical homocystinuria and remethylation disorders by exploring novel mechanisms to obtain proof of concept to enable progression to clinical trials
Technologies to improve early detection of classical homocystinuria and remethylation disorders, particularly via primary markers for newborn screening

Research Grant awards are up to $40,000 USD though exceptional applications may be funded at a higher amount if the budget request is justified. Research Grants support projects to produce proof of concept that would facilitate more substantial funding from federal agencies, foundations or corporations.

Important Dates:

EOI deadline for submission: August 31, 2021
Notification of successful EOI: October 15, 2021
Deadline for full applications: December 15, 2021
Funding decisions will be made by April 15, 2022

How to apply for a Research Grant:

Download the Expression of Interest instructions here for information.

EOIs will be reviewed by the Scientific Advisory Board, in consultation with HCU Network America and HCU Network Australia, and applicants will be notified by October 15, 2021 if they are invited to submit a full application.

Full applications are due by December 15, 2021 and will subsequently be reviewed by our Scientific Advisory Board. HCU Network America and HCU Network Australia Board of Directors will make the final funding decision on each grant application taking into consideration the advice of the Scientific Advisory Board and direct donor input.

For more information, please email: Margie McGlynn at margie@themcglynns.net or Tara Morrison at tara@hcunetworkaustralia.org.au

Apply today for the HCU Travel Fellowship 2021

hcu-travel-fellowship

Application Guidelines / Terms and Conditions

HCU Network Australia welcome applications for its 2021 research and education travel fellowships. These grants are intended to foster professional development and continued learning opportunities for scientists and/or health professionals to improve the health and wellbeing of children and adults with Homocystinuria (HCU).

The principal aim is to encourage education, research and professional development for those interested in obtaining further HCU education or presenting relevant work at national or international conferences. Nurses, scientists, clinicians and other health care professionals working in either a clinical or research environment in Australia are eligible to apply.

Applications will be called for once per year, with up to $3,000 available. The maximum amount that will be awarded to an individual for travel in Australia or New Zealand will be $750 and the maximum for travel to other overseas locations will be $3,000. The Fellowship(s) awarded are at the sole discretion of HCU Network Australia’s Executive Committee.

Deadline for submission of applications

Travel Fellowship 2020: 31st January 2021 for travel in the following 12 months.

The applications must meet the criteria described below. They will be reviewed by HCU Network Australia’s Executive Committee, whose decision will be final. No further discussion with the applicants will take place. It is expected that decisions on the fellowships will be made within four weeks of applications closing.

The Fellowship may be used for costs of flights, accommodation, or meeting registration. It will be paid in a single installment following receipt of proof in the form of receipts or directly to suppliers at the discretion of the approving group. Applicants are expected to purchase economy class airfares and choose cheaper accommodation options if appropriate. Anticipated expenditure on individual items must be clearly specified in the application.

We understand that these Fellowships may not cover the entire costs of the travel and we encourage applicants to supplement them by applying to other funding bodies, seeking conference travel grants, utilizing professional development allowances or other personal funding.

The following guidelines should be considered before submitting the application:

The conference/meeting/workshop for which grants are sought must have a substantial HCU component.
Applicants attending conferences, meetings or workshops for the purpose of educational development or training must clearly explain in the application how this event will help them develop professional skills required for their care of HCU patients or help them in their work aimed at helping those living with HCU.
Applicants attending conferences for purpose of presenting research or clinical findings need to submit proof of abstract acceptance for oral or poster presentation and must be the presenting author. Any presentation given needs to acknowledge funding support from HCU Network Australia.
Applicants should be willing to present at HCU Network Australia-sponsored events and share the knowledge they have gained with other health care professionals and the HCU community.
Applicants must provide a 2 page lay language report about the conference/training for the HCU Network Australia newsletter/website/media promotion within 1 month of returning.

Applications

Applications must consist of:

A CV no longer than 4 pages that must include the following details:

Name of applicant
Current position (i.e. clinician, nurse, researcher)
Institution
Supervisor
Education background (highest previous qualification/date of award/institution and current degree being pursued if applicable)
List of publications or clinical experience relating to working with HCU
Previous grants and awards if available

A covering letter from the applicant which includes:

Proposed dates, the cost of travel, accommodation and/or registration and a statement regarding relevant financial reasons for requesting meeting travel support.
Information about any other approved or outstanding applications to other funding bodies for the same travel.
For a conference: A description of the conference, a copy of any submitted abstract, and a personal statement highlighting how the applicant’s research/development would be enhanced by attending the conference.
For education/training activities: A description of the topics that will be covered during the meeting, how they relate to HCU, why is it important for the applicant to attend and how those topics would benefit the professional development of the individual and future care of patients with HCU.
A description of how the applicant proposes to share the knowledge that will be gained with other health care professionals and the HCU community.

A brief letter of support from the applicant’s supervisor addressing the above guidelines and a statement of eligibility. Any funding towards travel obtained from the applicant’s department/supervisor/institution should be confirmed in the letter of support.

Submission details

Applications should be sent to: The President, HCU Network Australia, PO Box 7484 BAULKHAM HILLS NSW 2153 or emailed to: tara@hcunetworkaustralia.org.au

We would like to acknowledge DEBRA for their generosity in allowing HCU Network Australia to adopt their Travel Fellowship Terms and Conditions.
You can read more about DEBRA at www.debra.org.au

Research news

We acknowledge the scientists, researchers and clinicians both past and present who have dedicated their professionals lives to achieving the best possible health outcomes for those with Homocystinuria.

Our Projects

HCU Network Australia together with HCU Network America are pleased to announce their first Research Grant was awarded in 2018. The HCU Network Australia Grant is made possible by people within our community who raise funds on our behalf. HCU Network Australia thanks the community first and foremost for making these Grants possible. The HCU Network America Grant is through the Hempling Foundation for Homocystinuria Research, established in memory of Judy and Susie Hempling, two young girls from Buffalo, NY whose lives were cut short by HCU in the 1970s.

The HCU Networks extend a warm thanks to our Scientific Advisory Board for generously giving their time and expertise to review the Research Grant Applications and a special thanks is extended to the independent reviewers of these Applications for their valuable insight and expertise in their evaluation of the Grant Applications.

You can read more about our Research Strategy and Research Grants program.

The HCU Networks plan to continue this Grant Program through issuing calls for Expressions of Interest on a periodic basis. The next call is planned first half of 2019.

Research Grant 2019

Project title: Evaluation of benefits of thiol-based reductants in classical homocystinuria
Principal Investigator: Tomas Majtan, PhD
Amount: $USD 40,000
Status: Active

The HCU Networks have awarded funding to a research project to evaluate benefits of thiol-based reductants in classical homocystinuria (HCU). The research, entitled Evaluation of benefits of thiol-based reductants in classical homocystinuria, will be carried out by Assistant Research Professor Tomas Majtan at the University of Colorado Anschutz Medical Campus, Aurora.

According to the principal investigator, Tomas Majtan, this project aims to explore whether existing FDA-approved compounds that are thiol-based reductants may prevent binding of homocysteine to cysteine and cysteine residues, which could lead to increased cysteine retention and better elimination of homocysteine from the bloodstream. In addition, anticipated increased availability of homocysteine in plasma could further improve the efficacy of enzyme therapies for homocystinuria that are in development. Tomas Majtan said “The research grant from HCU Network America and HCU Network Australia will allow us to better understand the balance between different forms of homocysteine and how it could be exploited towards better management of CBS-deficient homocystinuria. We are very grateful for this support as we continue our work on expanding therapeutic options for this devastating disease.”

Founder and director of the HCU Network Australia, Tara Morrison said “It was pleasing to receive an increased response to our second call for Expressions of Interest in our 2019 global grants round. We are delighted to announce the recipient of this round, Dr Majtan, and we look forward to his research efforts contributing further to the field. Moreover, we are hopeful this work can lead to the development of a treatment approach that could potentially reduce the need for a protein-restricted diet, which could ease the burden on the affected individual and the people who care for them”.

President of HCU Network America, Margie McGlynn said “We are pleased to provide a grant through the second round of our global grants process to explore this potential new mechanism. Dr. Majtan has been very involved in research on other therapies to address HCU, including a pharmacological chaperone therapy and, more importantly, a potential enzyme replacement therapy, OT-58, under the leadership of his postdoctoral mentor, Jan Kraus. Jan, unfortunately, lost his life to lung cancer in July 2019, and would be so proud to see Tomas being awarded this grant”.

The HCU Networks plan to continue this grant program though issuing calls for Expressions of Interest on a periodic basis. The next call will be announced by fourth quarter of 2020.

You can read the Press Release here.

Tomas Majtan, PhD

University of Colorado Anschutz Medical Campus, Aurora.

Tomas Majtan received his PharmD in 2003 from the Faculty of Pharmacy, Comenius University in Bratislava studying novel antimicrobial compounds and disinfectants using Salmonella pathogens. He then pursued postgraduate training in microbiology at Slovak Medical University and in 2006 he received a PhD in molecular biology working at the Institute of Molecular Biology of the Slovak Academy of Sciences. During this period, he studied epidemiology and genetics of Salmonella virulence factors and antibiotic resistance markers and deciphered gene expression of bacteriophage during infection of an important industrial strain producing amino acid lysine. In 2007, he started postdoctoral training on enzymology and biochemistry of cystathionine beta-synthase (CBS) in Professor Jan Kraus group at the University of Colorado School of Medicine, Aurora, Colorado. In 2013, he was promoted to Assistant Research Professor at the Department of Pediatrics, Section of Genetics and Metabolism, University of Colorado School of Medicine and continues working on understanding molecular mechanisms behind inborn errors of metabolism and developing new treatments with a focus on homocystinuria.

His contributions to the field include uncovering the mechanism of how missense pathogenic mutations impair CBS function, understanding how CBS cofactors work and affect folding and stability of the WT and mutant enzyme, solving several crystal structures of full-length human CBS to gain structural insight into homocystinuria or clarifying the role of CBS as hydrogen sulfide producing enzyme in health and disease. He utilized his intimate knowledge about CBS and has been working with the late Professor Jan Kraus and Orphan Technologies on enzyme replacement therapy for homocystinuria since 2010.

Dr. Majtan has been a mentor and supervisor of several graduate and postgraduate students or research associates. He is an author of over 40 peer-reviewed papers published in international journals as well as several patents, book chapters and monographs. He regularly presents his research on various conferences and meetings. In addition, he serves as a reviewer for multiple scientific journals and several funding agencies.

Research Grants 2018

Project title: New Metabolic strategies for improving treatment of homocystinuria due to CBS deficiency and remethylation defects
Principal Investigator: Kenneth N. Maclean, PhD
Amount: $USD 40,000
Status: Active

The HCU Networks have awarded funding to a research project to investigate the potential usage of metabolic compounds to treat CBS deficient homocystinuria (HCU). The research, entitled New Metabolic strategies for improving treatment of homocystinuria due to CBS deficiency and remethylation defects, will be carried out by Professor Kenneth N. Maclean at the University of Colorado School of Medicine, Denver.

According to principal investigator, Kenneth Maclean, “ A number of lines of evidence have led us to hypothesize that improving our understanding of the regulation of the betaine metabolic pathway in HCU may hold the key to improving treatment in all forms of homocystinuria with a view towards reducing dependence upon methionine restriction and improving clinical outcome”, said Dr. Maclean. “Preliminary work in our laboratory using an animal model of HCU has indicated that this approach has the potential to deliver near normal levels of homocysteine in the presence of a normal protein diet which would represent a highly significant advance in treatment for this condition”. A lot more work is required to capitalize upon these promising early findings and the grant from HCU Network America and HCU Network Australia constitutes an essential first step in that process.”

Founder and director of the HCU Network Australia, Tara Morrison said “the Network is excited to be providing support to this research project which offers the potential to develop a new treatment for the disorder. A treatment approach that could potentially relax or remove the need for a protein-restricted diet is much-needed in this community and would ease the burden on the affected individual and the people who care for them”.

President of HCU Network America, Margie McGlynn said: “It is exciting to award our first grant and to explore this potential new mechanism, and we look forward to expanding our grants program to help improve the diagnosis and treatment of this challenging disease”.

You can read the Press Release here.

Kenneth N. Maclean, PhD

Kenneth N. Maclean, PhD, Professor of Pediatrics, Ehst-Hummel-Kaufman Family Endowed Chair in Inherited Metabolic Disease, Department of Pediatrics, University of Colorado School of Medicine, Denver.

Professor Maclean did his undergraduate degree and PhD in genetics and biochemistry at the University of Greenwich in the United Kingdom. This was followed by a research fellowship at the Hungarian academy of Sciences in Szeged and a post-doc at the Royal London Hospital. Since coming to America in 1997, he has worked primarily on investigating the pathogenic mechanisms involved in cystathionine beta-synthase deficient homocystinuria with a view towards the rational design of novel treatment strategies for this condition.

Participating in the Program

Your participation in the Data Collection Program is one of the most important and critical efforts you can do. Patient reported outcomes can accelerate research and the development of future treatments and cures.

Rare Disease Research

Are you a stakeholder interested in using patient data to further your homocystinurias research?

Join the Program

Being part of the Data Collection Program means you can contribute to disease understanding which paves the way for a brighter future for the homocystinurias community.