What We’re Working On

Frequency study
New mutation research
Anti-sense oligos – new mutation

HTS
Peptide Computational peptide design
Prepanolin drug development
Potential impact of apbd research on other diseases

b. Glycogen synthase (GS)

HTS
Guaiacol
Turpin
GS Inhibitors
CRISPR’s (AAV9 virus)

Registry
Mouse Model preservation- Jackson lab
Potential impact of apbd research on other diseases
Breadth of all work APBDRF is supporting

1) Genetics

Frequency study

Research team: H. Orhan Akman, PhD

New mutation research

Research team: H. Orhan Akman, PhD

2) Drug Research

Two drug strategies are currently being studied: lower polyglucosans by lowering glycogen synthase or lower polyglucosans by increasing glycogen branching enzyme. Polyglucosans are an abnormal form of glycogen that cannot be broken down and used for energy in the body. These abnormal glycogen molecules accumulate within cells and cause damage.

High Throughput Screening is used to develop medications. It allows a researcher to quickly conduct millions of chemical, genetic or pharmacological tests. Through this process active compounds, antibodies or genes that affect a particular biomolecular pathway can be rapidly identified. The results of these experiments provide starting points for drug design and for understanding the role of a particular biochemical process in the human body. Tens of thousands of compounds are being tested and will be shared with other centers that are testing an additional 20,000 compounds.

a. Glycogen branching enzyme (GBE)

Drugs are being tested that will lower polyglucosan bodies by increasing glycogen branching enzyme (GBE) activity. GBE is an enzyme that plays a part in converting glucose to glycogen. Small molecules that bind to and stabilize the mutated GBE will be identified in order to correct the deficiency that results in APBD. A “library” of chemical compounds that are already being used to treat other disorders will be screened to find those that stabilize GBE. This should result in decreased levels of polyglucosans, representing a new treatment approach for APBD and a cure.

Associated GBE Projects under way:

HTS

Research Team: Berge Minassian, MD, Wyatt Yue

Peptide Computational peptide design

The computational chemist Amit Michaeli from Hebrew University is designing peptides (short amino acid sequences) that can either 1) bind to the mutated Glycogen Branching Enzyme (GBE) and stabilize it, or 2) destabilize the enzyme Glycogen Synthase (GS). Dr. Tropak plans to test the effects of GBE stabilizing peptides on GBE activities. He also plans to test whether peptides predicted to stabilize GBE enable it to resist change in its chemical or physical structure at relatively high temperatures. This would suggest the ability to stabilize GBE and thus counter the effect of the Y329S gene mutation in APBD.

Research Team: Or Kakhlon, PhD

Prepanolin drug development

Dr. Escribá’ s focus in the last 15 years has been on discovering the dynamic role of the cellular membrane in the different functions of the cell. He is now Testing of molecules that may regulate Glycogen Branching Enzyme (GBE1).

Research Team: Pablo Escribá, PhD

Potential impact of apbd research on other diseases

APBD (Adult Polyglucosan Body Disease) is an elusive genetic disorder. One study estimates that one in 34.5 Jews of Ashkenazi descent carry the Y329S genetic mutation that causes APBD.

APBD has many similarities to other disorders and is often mis-diagnosed. Symptoms in both men and woman begin as early as age 35 and are shared with other illnesses such as Prostate Cancer, ALS, Alzheimer’s, Multiple Sclerosis, Peripheral Neuropathy, Benign Prostatic Hyperplasia (BPH), and Spinal Stenosis.

b. Glycogen synthase (GS)

The enzyme glycogen synthase is involved in converting glucose into glycogen. Finding a small molecule medication that safely slows down the enzyme glycogen synthase will provide a treatment for APBD. By slowing further buildup of glycogen it is hoped that the body will then be able to clear polyglucosans that have already formed. Thus, stopping the disease would not only be a treatment, but could ultimately be a cure.

Projects under way:

CRISPR’s (AAV9 virus)

Antisense

Recently Approved Gene Therapy

Using an FDA-approved method, the goal of this research is to reduce polyglucosan bodies in patients with APBD in order to safely slow down the progression of the disease. Polyglucosans are an abnormal form of glycogen that cannot be broken down and used for fuel in the body. Instead they build up to form clumps that can damage cells, especially nerve cells.

Antisense oligonucleotides (ASO).
ASOs are small sequences of DNA that block disease processes by interfering with the production of a particular protein that is their target. In APBD, ASOs would be injected directly into the central nervous system where they can knock down their specific target, glycogen synthase (an enzyme involved in converting glucose to glycogen).

The ASO sequences discovered by ISIS Pharmaceuticals will be injected into APBD mouse models generated by Dr. Akman and Lafora Disease mouse models generated by Dr. Minassian. The goal is to use ASOs in periodic injections for APBD patients to reduce the buildup of polyglucosan bodies by glycogen synthase and thus slow down the disease

Research Team: H. Orhan Akman, PhD

Our three research centers are working on High Throughput Screening. Columbia University, Hadassah University Hospital and Toronto University Sick Kids Hospital. Isis pharma

https://www.scientificamerican.com/custom-media/inside-view-the-remarkable-sense-of-antisense/

Triple-helix-forming oligos (TFO)

These are very stable molecules that bind specifically to the DNA sequence they target. TFOs will be used in the same way as ASOs but will have highly specific targeted effects, giving them tremendous potential as gene therapy

Research Team: Or Kakhlon, PhD
Hadassah University Hospital.
GeneArrest

Clinical trials

Triheptantoin

Dr. Raphael Schiffmann is conducting a study in patients with APBD to test whether an insufficient supply of energy from glycogen to brain cells is a cause of APBD. While the role of glycogen is to supply energy, the abnormal glycogen that accumulates in patients with APBD cannot be broken down to supply this energy to cells.

The treatment being tested is an oil called triheptanoin or C7 which will be used instead of glycogen to supply energy to brain cells. In an initial study, five patients were stabilized and their ability to walk improved while taking C7. Based on these results a double-blind randomized controlled trial to compare C7 oil with regular vegetable oil will be done in at least 18 patients. This 3-year study funded by the Baylor Research Institute will be conducted in Dallas, Texas with sites in Israel and France.

Ultragenyx Pharmaceutical, Inc of Novato CA has purchased licensing rights for triheptanoin, the oil used in the study (A Treatment Trial of Triheptanoin in Patients with Adult Polyglucosan Body Disease) being conducted here at Baylor Research Institute. As part of the agreement, the company has agreed to provide travel funds for study subjects (those currently enrolled and any future participants) as well as providing a more purified form of triheptanoin for the study. We are excited to have Ultragenyx support and would appreciate the APBD research foundation sharing this new information with the APBD community.

More human trials are coming up in the foreseeable future. Please read more about Human Trials

https://clinicaltrials.gov/ct2/about-studies/learn

Research Team: Raphael Schiffmann, MD, MHS

Other

Registry

The APBD contact registry consists of a secure database to store contact information and basic clinical data on APBD patients. Registries can be used to compare people with APBD who are treated with those who are untreated in order to speed up FDA approval for new treatments and drugs. Dr. Edwin Kolodny speaks about the importance of creating patient registries here. Join the APBD patient registry.

Mouse Model preservation- Jackson lab

Developing and preserving APBD mouse models are critical in discovering the genetic basis for preventing and curing APBD.

Research Team: H. Orhan Akman, PhD

Potential impact of apbd research on other diseases

APBD (Adult Polyglucosan Body Disease) is an elusive genetic disorder. One study estimates that one in 34.5 Jews of Ashkenazi descent carry the Y329S genetic mutation that causes APBD.

Breadth of all work APBDRF is supporting

Therapeutic approaches that the APBDRF is supporting to cure APBD can be divided into targeted (1) and non-targeted (2).

Targeted agents can be subdivided into:
- Agents designed to lower GS levels and activity:
  i.      Antisense Oligonucleotides (ASO):  Isis Pharmaceuticals – Tamar R Grossman
  ii.      Triple Helix Forming Oligonucleotides (TFO): Gene Arrest- Anwar Rya
  iii.      New compounds discovered by GS solvent mapping in Boston University by Dima Kozakov
  iv.      Dr. Minassian’s collaborative work on amylase and using the CRISPR/Cas9 technology
- Agents designed to stabilize GBE
  i.      Peptides predicted to fill the small cavity generated by the Y329S mutation:      Amit Michaeli- Pepticom.
  ii.      Small molecules screened by Differential Scanning Fluorimetry (DSF) for their capacity to increase the melting temperature of recombinant wild type GBE and GBE Y329S proteins. Both recombinant protein production and the DSF are done in the lab of Dr. Wyatt Yue at the University of Oxford who specializes in using in vitro and structural methods to evaluate small molecule binding to proteins and the specificity of this binding
  iii.      Lipid membranes. Their interaction with and effect on GBE and GBE Y329S (the mutation causing APBD) is investigated by Dr Pablo Escriba and his team at University of the Balearic Islands of Mallorca, Spain. Dr. Escriba’s research is aimed at the design and synthesis of new lipid molecules whose efficacy for the treatment of APBD in cell and/or animal models could be investigated.

Non-targeted approach consists of our high-throughput screenings done at Prof. Miguel Weil’s Cell Screening Facility in Tel Aviv University managed by Dr. Leonardo Solmesky. In this facility, libraries of small molecules with diverse structures are screened for their capacity to lower polyglucosans regardless of the mechanism. In this non-targeted approach we are only interested in the end result – lowering of polyglucosan bodies. SEE VIDEO. Positive hits discovered by this high-throughput screenings will then be further studied in order to elucidate their mode of action. For example, in theory they could be GS inhibitors or GBE stabilizers, but might also be molecules which “open” polyglucosans, thus enabling their degradation by the enzyme which normally degrades glycogen (phosphorylase a). These positive hits will also be tested and validated in cell and animal models of APBD by Dr Berge Minassian (Sick Kids Hospital, University of Toronto) and Dr Orhan Akman (Columbia University).

The take home message is that no single approach is expected to provide a foolproof therapeutic on its own. We anticipate that a final therapeutic will consist of a combination of, for instance, a GBE stabilizer co-administered with GS-targeting ASO injection. This is why our effort is multifactorial.