Hereditary Inclusion Body Myopathy (hIBM).

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1). Advancement of Research for Myopathies

2). Hereditary inclusion body myopathy: The Middle Eastern genetic cluster

3). Article from the Jewish Journal of Greater Los Angeles (on-line)

4). Brothers in Search of a Cure

5). 2006 hIBM Research (also see research updates on the main IBM page).

6). For the classification of the different types, see: aboutibm1.htm#2B:

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1). Advancement of Research for Myopathies.

See: http://www.hibm.org/

and: Advancement of Research for Myopathies: http://www.hibm.org/arm/

What is A.R.M?
A.R.M. is an abbreviation of Advancement of Research for Myopathies, a non-profit 501(c)(3) organization with the primary goal of speeding up bio-medical research on IBM2, the Autosomal Recessive form of Hereditary Inclusion Body Myopathies (HIBM).

What is HIBM?
HIBM (Hereditary Inclusion Body Myopathies) are a group of genetic disorders that cause progressive muscle wasting and weakness. The autosomal recessive form (IBM2 or DMRV) is very common among people of Middle Eastern & Jewish heritage. You can read more about this disorder at the OMIM database.

What does IBM2 do?
It causes progressive wasting of the arm and leg muscles starting from the ages of 18 - 45. Although the progression is slow, it typically leads to severe disability within 10 to 15 years. In most cases, the quadriceps seem to remain strong until later in the disease course.

How does it affect me?
Since the disorder is recessive (both alleles of the gene are damaged), anyone may become affected, even with healthy parents and parental families. Besides genetic testing, there is no way to tell who will be affected next. The chances of being affected is much higher if you are from Middle Eastern and Jewish background.

Is there a treatment?
There are no effective treatments for IBM2 yet. Researchers around the world are working towards finding an effective treatment. With extra funds, we can speed up the research significantly.

Where do I get more information?
You can find a lot of information here on our Web Site. If you would like to speak with a physician regarding HIBM, you may call (818) 789-1044. This disorder was first called "Vacuolar Myopathy Sparing the Quadriceps" by Sadeh, et al, in a paper published in the medical journal, Brain, 1993 (116: pages 217-232). You may obtain a copy of this paper from any medical library.

What can I do to help?
Your financial support can help speed up the research, and your vocal support can help in educating your friends and loved ones. With the current rapidly advancing genetic science and medical technology, it is not unlikely to develop an effective treatment and/or intervention in the very near future. Please inform all your loved ones and friends regarding our efforts. Help others to become more aware of a problem that can devastate our children, as it has for decades. Your awareness, and your social and moral support, is very important to our success. Your financial support can significantly speed up the development of an effective treatment. Please send your donations to:

PO BOX 261926,
ENCINO, CA 91426-1926

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2). Hereditary inclusion body myopathy: The Middle Eastern genetic cluster
Authors: Z. Argov, MD; I. Eisenberg, MSc; G. Grabov-Nardini, BA; M. Sadeh, MD; I. Wirguin, MD; D. Soffer, MD; and S. Mitrani-Rosenbaum, PhD

Abstract-Background: Recessively inherited hereditary inclusion body myopathy (HIBM) with quadriceps sparing was initially described only in Jews originating from the region of Persia. The recent identification of the gene responsible for this myopathy and the common "Persian Jewish mutation" (M712T) enabled the re-evaluation of atypical phenotypes and the epidemiology of HIBM in various communities in the Middle East. Objective: To test for the M712T mutation in the DNA from HIBM patients in the Middle East. Methods: DNA from all suspected HIBM patients was tested for the M712T mutation. Unaffected members of families with genetically proven HIBM were studied too. In the majority of families, haplotype construction with markers spanning the 700-kb region of the HIBM gene was performed. Results: One hundred twenty-nine HIBM patients of 55 families (Middle Eastern Jews, Karaites, and Arab Muslims of Palestinian and Bedouin origin) were homozygous for the M712T mutation, and all carried the same haplotype. Five clinically unaffected subjects were also homozygous for the common mutation and haplotype, including two older adults (ages 50 and 68 years). Atypical features with this same mutation were marked quadriceps weakness in five patients, proximal weakness only in two patients, facial weakness in three patients, and a muscle biopsy showing perivascular inflammation in one patient. Conclusions: The phenotypic spectrum of recessive HIBM is wider than previously described, and the diagnostic criteria for this myopathy must be changed. The Middle Eastern cluster is the result of a founder mutation, with incomplete penetrance, that is approximately 1,300 years old and is not limited to Jews.
Source: NEUROLOGY 2003;60:1519-1523 (May 13, 2003)

Hereditary inclusion body myopathy (HIBM) is the term currently used for "vacuolar myopathy sparing the quadriceps." Diagnostic criteria for HIBM have been the following: 1) a primary skeletal muscle disease, presenting usually with distal muscle weakness in the legs; 2) sustained quadriceps sparing despite marked weakness of all other hip muscles; 3) onset in late teenage years or early adulthood; 4) the presence of at least two affected members in the same family; 5) modest elevation of serum creatine kinase (CK); 6) numerous rimmed vacuoles with few other pathologic changes in the fibers; 7) detection of 14- to 18-nm tubofilamentous inclusions by electron microscopy; and 8) lack of inflammation in affected muscle biopsy. Our recent identification of the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) as the disease-causing gene of HIBM5 allows the reevaluation of the above criteria. Since our first report, several different GNE mutations were identified in numerous families with similar phenotypes from various parts of the world.6-8 However, there is only one genetically genetically uniform cluster of HIBM: a single homozygous missense mutation (M712T at exon 12 of this gene), shared by all Jewish HIBM patients originating in the Middle East and neighboring countries. Testing for this specific mutation enabled us to identify phenotypic variants of the disorder and gather additional epidemiologic and genetic data concerning this regional cluster of HIBM. This new information will affect the diagnosis of and counseling for the whole group of GNE related myopathies.

Discussion. In the cohort of HIBM patients reported in this study, all with a single homozygous GNE mutation, several atypical phenotypes of this myopathy were identified. The most problematic is that of major quadriceps involvement, which appears to contradict the past characterization of the disorder as "quadriceps-sparing myopathy." Belonging to the specific ethnic cluster or the identification of other affected relatives with the typical weakness pattern may be highly suggestive for the diagnosis of HIBM due to GNE mutation even in this circumstance. However, if a single patient presents with a more diffuse proximal weakness, including the quadriceps, the diagnosis of HIBM may be less apparent. Previous reports already suggested partial sparing (i.e., weak quadriceps, but to a lesser degree than all other proximal leg muscles) in HIBM. The lack of quadriceps sparing has grave consequences for these atypical patients' walking abilities, as the tempo of loss of ambulation is much faster. The presence of this atypical phenotype in 4% of patients should, however, not mask the fact that quadriceps sparing, a unique phenomenon in clinical myology, is maintained throughout the disease life span and even in bedridden subjects in the vast majority of patients. Another confusing phenotype is the lack of distal leg musculature involvement. Distal weakness is prominent and appears in the initial phases of the disease in the vast majority of HIBM patients, usually as bilateral foot drop. Gastrocnemius weakness may also be present at onset. The lack of distal involvement, even by CT, made the clinical diagnosis more difficult in one of our families. The crucial finding that indicated the diagnosis of HIBM was the preservation of quadriceps strength with weakness of all surrounding hip muscles. It is suggested that distal weakness and quadriceps sparing should bear less weight in the clinical criteria of HIBM and that facial weakness cannot serve as an exclusion criterion for HIBM. Inflammation is absent in the majority of biopsies of patients with recessive HIBM. Interestingly, reports of cases of "noninflammatory inclusion body myositis" exist. It is possible that some of these patients may have been isolated cases of recessive HIBM, especially those with a younger age at onset. The finding of perivascular infiltrates in our patient, who had no family history of HIBM, made the diagnostic consideration more complicated. In a probable context of HIBM, the presence of perivascular inflammation should, however, not deny this diagnosis. It should be noted that this patient had higher than usual levels of serum CK for HIBM. We suggest that any patient (whatever the phenotype) with a biopsy showing rimmed vacuoles should be considered for GNE testing. The possibility of incomplete penetrance suggested by our findings demands strong caution on disease prediction during genetic counseling in HIBM. The age at onset in our cohort of 129 patients ranges from 17 to 48 years. Thus, the 50-year-old individual homozygous for the disease's mutation and haplotype may still be considered "presymptomatic." However, the finding of a 68-year-old healthy woman with this genetic profile raises the issue of penetrance of this mutation. Theoretically, this woman could eventually develop symptoms in her 7th decade of life or later, but this seems unlikely. We suggest that the recessive M712T mutation may not have full penetrance. A similar situation was found in one Japanese patient homozygous for another GNE mutation.7 The causes of such situations in general, and especially in this defined recessive myopathy, are unknown. Initially, we thought that the Persian Jewry carries a founder mutation that is specific for this community and its close tributes only. Later we found it to be widely distributed in Jews from Uzbekistan (one patient recently diagnosed by us) in the northeast through the eastern and central region of Persia-Afghanistan-Iraq and reaching the western part of the Middle East (Egypt), but still possibly spreading by Jewish immigrations. However, the finding of families with this same mutation in its homozygous form among Karaites and Muslims broadens the distribution of this founder effect and may give some indication about its age. The Karaites are followers of a movement that broke away from mainstream Judaism around the 8th century in Persia. This movement rejects the Jewish "oral law," as embodied in the Talmud, and accepts only the written Bible as the sole authentic font of religious doctrine and practice. The religious debate between them and mainstream Judaism resulted in their segregation, as Jews were forbidden from marrying Karaites during the Middle Ages. Their communities proliferated mainly in Islamic countries (including Egypt) between the 9th and the 11th century. They remained a minority sect through later history, and approximately 10,000 Karaites, mostly of Egyptian origin, live today in several small communities in Israel. At least one more hereditary neurologic disease (Huntington's chorea) is very common among them. However, it is not clear that there were no marriages between Jews and Karaites through the generations, especially in Egypt; thus, the founder effect could still be limited to Jews. Unlike the situation with the Karaites, one cannot easily assume marriages between Jews and Muslims after the 7th century, a period when Islam emerged. However, the two Muslim families also share the same M712T mutation in its homozygous form. Even more surprising is the finding of the common "Persian Jewish" HIBM haplotype in the Palestinian Muslim family. Furthermore, the Bedouin patients can also be considered to carry the same common "Middle Eastern" haplotype. This is because allele 7 and 1 of the D9S1791 are just 2 bases apart (a difference of one CA repeat at this polymorphic site that normally spans from 168 to 190 base pairs); thus, allele 7 is very likely generated by a slippage mechanism. If this is so, then the homozygous haplotype of the Bedouins, identical in all other spanning markers, further extends the founder borders of the M712T mutation. Whereas we have not formally studied the estimated age of this mutation, historical perspective suggests that it is probably as old as 1,300 years.

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3). Article from the Jewish Journal of Greater Los Angeles (on-line)
Dated: 2002/11/22
Muscular Disorder Won't Stop Siblings
by Nancy Sokoler Steiner, Contributing Writer

As young adults, brothers Babak and Daniel Darvish, born less than two years apart, were avid athletes, music lovers and medical students who planned to become surgeons. But about five years ago, they discovered that they shared something besides their hobbies and professional aspirations. Both were diagnosed with hereditary inclusion body myopathy (HIBM), a rare muscular disorder experienced by only about 500 individuals worldwide.

Babak first detected something amiss as a third-year medical student. "I was an avid guitar player ... and realized I was having progressively more difficulty [playing]." Around the same time, Daniel, by then doing his medical residency, noticed he wasn't running and bounding up the hospital steps as quickly as usual.

Putting their knowledge to work, the brothers searched the medical literature and finally discovered a few research papers that seemed to describe their condition. HIBM, they learned, typically strikes in the 20s or 30s, gradually weakens the muscles of the limbs and eventually leads to total disability. The disease predominantly affects Iranian Jews, who have a 5 percent to 10 percent chance of carrying the gene mutation responsible for HIBM. Still, even if both parents carry the gene, their children have a 75 percent chance of eluding the disease.

Once they realized what they were facing, the brothers traveled to Israel with blood samples in hand to meet with professor Zohar Argov and Dr. Stella Mitrani-Rosenbaum. The Israeli researchers were among the few scientists investigating this condition. (They subsequently identified the gene that causes HIBM last year.)

Babak and Daniel returned home determined to generate support for research on HIBM. The two spoke extensively at Hadassah events and other venues to raise funds and awareness within the Iranian community. They were among the few willing to put a face to a disease that many preferred to keep under wraps. At the same time, they began to contact and catalogue those who had HIBM, or seemed to exhibit symptoms. Their efforts generated visibility and financial support, but a research breakthrough remained elusive.

"The daunting limitations that threatened scientific progress became apparent," Babak noted. "There were not enough patients known to provide blood samples for research. There was inadequate awareness of the disease, and due to its small target population, little to no interest in the wider general and medical communities.... This was an orphan disease, in an orphan community."

Frustrated with the lack of progress toward a cure, the Darvish brothers decided to step up their own activities. In 1997, they joined with the Iranian Jewish Federation (IJF) to found Advancement of Research for Myopathies (ARM.), a nonprofit entity dedicated to raising funds and providing grants to promising research around the globe. ARM subsequently broke off from IJF. Photographer Mansour Pouretehad currently serves as ARM's president and is also a major benefactor. In addition, last year the Darvishes created the HIBM Laboratory. Located in an Encino medical building, the lab collects and analyzes blood samples and acts as a clearinghouse for HIBM research. As Daniel explains, "Our goal is to get to clinical trials - and ultimately, treatment - as soon as possible."

Although Daniel said the laboratory performs "ancillary research," he and his colleagues have discovered four previously unknown genetic mutations that cause HIBM. Their findings were published in this month's issue of the scientific publication Molecular Genetics and Metabolism.

Meanwhile, ARM, has awarded more than $270,000 in grants so far this year to researchers at UC San Diego, USC and Hadassah Hospital in Israel.

Living with HIBM derailed the Darvish brothers' plans to become surgeons, but set them in new career directions. Babak, who is now married, works in physical medicine and rehabilitation at the West Los Angeles VA Medical Center. Daniel changed his specialty to internal medicine, and now devotes all his time to running the HIBM lab.

"We don't know who is next," Babak said. "There are people in their teenage years that have no clue what's in store for them.... People need to have a sense of urgency and feel that this [cause] belongs to our community and really work as a team toward finding a cure."

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4). Brothers in Search of a Cure
By: Doreen Shenassa
Los Angeles Chronicle, December 2, 2004
He's told the story dozens of times. About how he started showing symptoms when he was 28 toward the end of medical school. About the unusual weakness he felt in his fingers that made it difficult to play his guitar. About how it became harder and harder to go up a flight of stairs. It's the story he's told numerous times about the rare genetic disease he shares with his brother that has confined them to a wheelchair and will continue to waste away at their muscles, unless they find a cure.

Babak Darvish, MD, 35, sat comfortably in his powered wheelchair at the VA Hospital on Wilshire Boulevard. He is a staff physician and the Director of the Inpatient and Geriatric Rehabilitation Consult Service.

He described his disease, Hereditary Inclusion Body Myopathy or HIBM, with much ease, as his mini entourage consisting of a few family friends and staff strolled in and out of his office to hand him a document or bring in his dinner, almost in a celebrity-like fashion.

HIBM is a rare condition that affects middle-eastern Jews, like Babak, an Iranian Jew, causing progressive muscle wasting and weakness. Symptoms usually begin between the ages of 20-40 and may entail 10-15 years to fully develop, typically leading to total disability. Two copies of the mutated gene are needed to develop HIBM since it is recessively inherited. Thus, when both parents are carriers, each of their offspring has a 25 percent chance of developing it.

Danny is Babak's older brother. Though 2 years apart, they developed symptoms around the same time. The brothers were symptom-free throughout their teenage lives; fit, athletic and active. Apprehension loomed when their limbs grew weak in their late 20s. "No medical professional could give us a satisfactory answer." Explains Babak. "At that point, it was clear to me what needed to be done." As medical students initially drawn toward subspecialty fields of surgery, their new mission was to be the last ones affected by the debilitating disease.

The disease was uncommon and unidentified at the time, which stimulated their initiative to fully embrace the concept of finding a cure. Danny has since stopped practicing medicine altogether and dedicates his time solely to HIBM research.

Advancement of Research for Myopathies, (ARM), was founded in 1997 to fund HIBM research. They raise public awareness, award grants to scientists who are willing to help with biomedical research, and who in 2001, located the gene mutation responsible for HIBM.

ARM was gathered in Babak's office that night for their weekly meeting. Everyone was exceptionally attentive, available to tend to his every need, "Hey Bobby, you need anything?" There was an occasional knock at his office door from a member checking up or having a 'quick question.'

Babak seems healthy and well, but when he makes certain movements, his difficulties are apparent. He has trouble reaching for objects or raising his arm, but can hold a pen, write, and shake hands when introducing himself. "I stopped driving 2 years ago as it became progressively more difficult to keep control of the vehicle. I felt I was no longer safe on the road."

HIBM was often misdiagnosed for Multiple Sclerosis or Muscular Dystrophy. They might have similar symptoms but they function very differently.

Multiple Sclerosis (MS) is an inflammatory disease of the Central Nervous System, which includes the brain and spinal cord. Predominantly, it is a disease of the "white matter" tissue. The white matter is made up of nerve fibers, which are responsible for transmitting communication signals both internally within the CNS and between the CNS and the nerves supplying the rest of the body.

In general, people with MS can experience partial or complete loss of any function that is controlled by, or passes through, the brain or spinal cord.

Muscular Dystrophy, (MD) is a disease in which the muscles of the body get weaker and weaker and slowly stop working. It affects muscles throughout the body including the heart, where HIBM does not affect the heart at all.

The dystrophin gene is carried on the X-chromosome, therefore young men are more susceptible to dystrophin damage because they have only one X-chromosome.

MD affects all muscles because Dystrophin is found on all types of muscle tissue including 'cardiac' (of the heart) and 'smooth' (of the digestive tract). Unlike skeletal muscle, these muscles are involuntary, meaning that they cannot be moved at will. HIBM, on the other hand, only affects skeletal muscles. It is the most common genetic disorder in people of Iranian-Jewish descent. Yet, most primary care physicians have never heard about it. Because it only affects a few hundred patients worldwide, it is considered a rare 'orphan' disease.

Many people with the disease or those who have loved ones with HIBM do not endorse Danny and Bobby's efforts to go public. After all, it is a social stigma to have a genetic disease in the Persian Jewish community. One patient lies about why he limps to ensure that his daughters will marry while another was shamed and compelled to move to another state to avoid disgracing his family.

There are those affected, however, who keep their heads held high, at least to the best of their ability.

'I'm not ashamed. Why would I be ashamed?' Helen Shirazi, 47, is in the advanced stages of the disease, unable to move any part of her body except her fingers, mouth and eyes. Her grandfather was Iranian, but she was born in Israel. Helen was referred to the Darvish's only several months ago and was recently diagnosed with HIBM. Doctors could not make a proper diagnosis tracing back to the time she started dragging her feet at 20 years old. 'One doctor told me I had one year to live.' She started to choke up, but held back her tears. 'He destroyed my spirit, my soul.'

She met and married Shalom after her first marriage collapsed. Shalom is a cheerful man with a loud sense of humor who moves about doing little things for his wife, making her laugh and keeping her inspired.

'Before we were married, he offered to wash me, to bathe me. He read my thoughts, he felt me.' She completely lost her ability to walk by the time they wed, so his role in the marriage quickly took shape; cooking, cleaning and doing all the household chores as well as helping his disabled wife cope, even when he suffered from severe back pain. They hired a helper just two years ago when Shalom needed surgery.

'There's nothing wrong with her, she's healthy and normal.' Shalom believes his own words despite the unfortunate truth that his wife's limp body can only lie there, bed-ridden, motionless, helpless, with a limited view of what's directly in front of her. Helen confesses to her moments of grief, but is motivated and mentally active for the most part.

'I'm not disabled, and I'm not in denial either. I can move the world.' She has undeniably moved her own world, majoring in Psychology at Cal State Northridge, faced with the challenge of getting to class, relying on her helper to take notes and dictating her assignments to any student willing to take the time.

Her wish is to write an inspirational biography about how everything could be taken away except the spirit and the mind. 'Don't underestimate me.'

Helen is one of the few patients eager to share her tale or 'come out.' There are patients in Iran, Israel, across Europe, and on the East and West Coasts, but only about 500 known cases worldwide, which is why the availability of public funding for research is extremely limited. HIBM is too rare for pharmaceutical companies to deem it as a lucrative investment.

Fortunately, ARM funding helps operate and maintain the HIBM Research Group in Encino, the lab, where in addition to facilitating the genetic engineering and the ultimate production of the animal model for HIBM in mice, serves as a central suppository of research samples, tissues, reagents, and late-breaking developments of antibodies, for use by all investigators involved in HIBM Research. This levels the playing field and stimulates collaboration among the different researchers, who are sponsored by ARM to move research forward.

Although there is no treatment so far, the Darvish's are hopeful that in the next decade there will be a treatment to prevent or inhibit the process of HIBM.

'I am optimistic that this won't exist in the next generation. There are teen-agers who have no idea what's in store for them. If I could prevent a young girl or boy from ending up in a wheelchair like me, I've done my job.' Babak predicts HIBM will be treatable in 5-10 years.

Two extraordinary women who have contributed to making Danny and Bobby's jobs and lives much less troublesome are Sandra and Sheila, their wives. Babak's first marriage failed because his wife at the time could not deal with the progression of his illness.

But Sandra has been passionate and sympathetic since they met in Canada in 2002. At the time Bobby was already in a wheelchair, attending a medical conference in Vancouver to promote HIBM research, while Sandra had taken a part-time job as a tour guide.

'She showed me around the city and I knew I never wanted to be away from her.'

Sandra is devoted and kind, showering her husband with unconditional love. But as Bobby so clearly puts it, 'if it isn't unconditional, it isn't love!' Sandra helps Bobby dress, use the restroom and is usually only an earshot away. HIBM has not tainted their desires to carry on a normal life either.

'We want kids and we're half way there.' Apparently, HIBM has no influence on intimacy. 'You just have to be a creative lover.' Though confined to a wheelchair, HIBM sufferers are not paralyzed. It is not a disease that affects the nerves, therefore sensation is maintained throughout the body.

Babak is the more social and optimistic of the siblings. Danny is upbeat, but more often reminisces of active times when he could ski, or walk to the mailbox, or even get out of bed. He misses the abilities he once had that the rest of the world takes for granted.

'Most people in a wheelchair have a static condition. They know it won't get any worse. But HIBM is progressive.' Babak explains.

'The minute you get used to one dysfunction, another one kicks in.' Danny finishes his brother's thought.

Danny and Sheila have a sacred marriage, as Sheila is also an incredibly tender, warm and energetic woman from the Philippines. It seems that Sheila and Sandra have found a support system in one another; they have much in common caring for physically dependent men.

'My arm is getting stronger because I have to turn him over several times in the middle of the night.' Sheila jokes as Sandra giggles in agreement.

'Me too!'

Sandra and Sheila have embarked on their husbands' goals and work hard on a daily basis whether it is in the lab, going to meetings or just being emotionally available for their spouses.

Another female backbone in Danny and Bobby's lives is their mother, Shuku. Not only is she ARM's co-founder and spokesperson, but she also engages in day-to-day planning and fund raising.

In the meantime, Bobby and Danny are still physically able to walk with a great deal of help though they take comfort in their wheelchairs.

'I walk around more than you do Bob!' His younger brother shrugs it off. 'Okay, okay, I'm lazy.' But witnessing Danny walk is painful. He struggles with every movement like a one-year-old taking his first steps, unbalanced and unsure of whether he will tip over before reaching his destination.

The remarkable thing about the Darvish brothers is that they are working toward finding a cure for their own disease. Their initial drive created ARM, which supplies the funds needed to carry out research. Their continued persistence helped find the gene responsible for HIBM. Without their involvement, the gene would most likely still be lost. Their sustained ambition will further medical advancements. The disease would have remained stagnant without them.

Donations, funds and contributions are vital in speeding up HIBM research and developing an effective treatment. Community awareness and support is key to moving the research forward.

Finding a cure for Hereditary Inclusion Body Myopathy can ultimately result in healing related diseases in the world, but financial help is critical.

Bobby's advice for all patients with a severe medical condition: 'All I can say to anyone with any kind of a disability is 'make exceptional use of what you have.'' Danny agrees: 'Life doesn't have to be so bitter or any worse.'

But the reality lingers: time is running out.

Please help Daniel and Babak as well as hundreds of others fight HIBM by donating to: Advancement of Research for Myopathies, PO Box 261926, Encino, CA 91436

For more information on HIBM, go to: http://www.hibm.org/

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5). 2006 hIBM Research (also see research updates on main IBM page).

Grant 008
Principal investigator: Jacques P. Tremblay, PhD
Abbreviated Title of Research Proposal: Transplantation of genetically modified myoblasts from patients with IBM2.
Lay Summary:

The long-term benefit of this proposal is to develop a treatment for LBM2. The treatment is based on the autologous transplantation to the patients of their own myoblasts genetically corrected in vitro, i.e. introduction of the normal GNE gene with a viral vector. My research group became interested in the Hereditary Inclusion Body Myopathy (HTBM) following several e-mail messages from Dr. Daniel Darvish inquiring about our myoblast transplantation results. We have already cloned the GNE-cDNA by RT-PCR. Since there is no antibody available for the GNE protein, we have attached a code for a epitope tag (called V5) for which there is a commercially available antibody. This will permit us to do some preliminary experiments while developing polyclonal and monoclonal antibody. We have recently made a retroviral vector containing the GNE-V5 gene. We would now like to test this retroviral vector on human cells human patient myoblasts. We have thus recently obtained the permission from the human ethic committee the permission to obtain muscle biopsies from IBM2 patients. The genetically modified IBM2 myoblasts will be transplanted to SCID mice to verify the presence of muscle fibers expressing the transgene (GNE-V51). Although this initial grant proposal does not include the re-transplantation of the genetically corrected myoblasts to the patients, this grant will permit to develop all the tools (i.e., viral vectors and antibodies) required to start such a clinical trial subsequently.

Grant 015
Principal investigator: Jacques P. Tremblay, PhD
Abbreviated Title of Research Proposal: Preparation of a clinical trial of transplantation of genetically modified myoblasts to HIBM patients.

Lay Summary:

The long-term aim of this proposal is to develop a treatment for IBM2. The potential treatment is based on the autologous transplantation to the patients of their own myoblasts genetically corrected in culture, i.e., introduction of the normal GNE with a vector to complement the mutated GNE gene in the patient's own cells. My research group became interested in Hereditary Inclusion Body Myopathy (HIBM) following several e-mail messages from Dr. Daniel Darvish inquiring about our myoblast transplantation results. We have already produced retroviral and lentiviral vector containing the GNE gene. Some of these vectors contain markers to sort out genetically corrected cells. We will now test these vectors on myoblasts obtained from patients and from a knock-in mouse (HIBM mouse) made by Dr. Darvish. The genetically modified IBM2 myoblasts will be transplanted to IBM2 or SCID mice. This will permit us to verify whether the genetically corrected myoblasts can fuse with the existing mouse muscle fibers leading to the expression of the GNE enzyme. We will also verify whether this leads to the correction of the phenotype of the IBM2 mice. Although this grant proposal does not include the retransplantation of the genetically corrected myoblasts to the patients, this grant will permit to develop all the tools required to start such a clinical trial subsequently.

Grant 017
Principal investigator: Stella Mitrani-Rosenbaum, PhD
Abbreviated Title of Research Proposal:
In vitro and in vivo models for HIBM

Lay Summary:

Hereditary inclusion body myopathy (HIBM) is a unique group of neuromuscular disorders characterized by adult-onset, slowly progressive distal and proximal muscle weakness, and a typical muscle pathology, including rimmed vacuoles and filamentous inclusions. The prototype HIBM is a form of the disease particularly frequent in Middle Eastern Jews presenting an additional unique feature, the sparing of the quadriceps. The gene responsible for the disease, which encodes the enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosanine kinase (GNE), was identified in our laboratory and found to carry a homozygous missense mutation in all Middle Eastern HIBM patients, while other patients worldwide have usually different mutations in the same gene. GNE is the key enzyme in sialic acid biosynthesis, which is involved in a variety of biological interactions, such as cell adhesion and migration.

In order to understand the pivotal role of GNE in the onset and progression of HIBM, we will introduce the most prominent human mutations identified in the GNE gene of HIBM patients in already available murine GNE-deficient embryonic stem cells. These cells will be analyzed morphologically and biochemically and will be further used to generate transgenic mice with GNE mutations in an endogenous GNE-free in vivo system.
In addition, we will generate a mouse where the GNE gene could be switched off only in muscle tissue.

We anticipate that these studies will contribute to unravel the function of GNE and sialic acid metabolism in particular in muscle cells and reveal possible pathogenic mechanisms leading to HIBM. In addition, this animal model could be used for the assessment of therapeutic approaches.

Mail Bill: btillier@shaw.ca