I just found this site where mr. baniya is asking for his kids help.......lets contribute some fund here for his kids treatment as well guys.

visit.http://www.childhelp.lovelypokhara.com/

pls. just visit once to see why u need to help

http://www.childhelp.lovelypokhara.com
Do you know about a strange disease called Osteogenesis Imperfecta (OI)? It makes our body bones so brittle that it cracks or brakes even if you are hugged or embraced. A slight dash is enough to bring deformity. One becomes ?touch me not? person.

Surendra Baniya is suffering from brittle bone disease since the age of 10 months. In 17 years his limbs fractured 27 times. His deformity restricts walking to few feet with walker. American doctors believe, if operated before 18 years, he can spend normal life. Today, he is 17 years 3 months old. Confined to indoor life he is fighting against time and luck. He still believes someone will come forward to help him. His sister Shova who is having same disease and his father Shiva Bahadur Baniya are surprised at boy?s strong faith. Shova?s spinal cord is slightly titled on right side and vertebrae length is reduced. Her legs were fractured 13 times. They live in Pokhara Sub Metropolitan City, Ward No.15, Kantipur Marg, Nepal.

Prof. Dr. Ashok K. Banskota, M.D; F.A.C.S. (Chief of Orthopaedic) of B & B Hospital, Kathmandu, Nepal and Dr. Ram Kewal Shah, (Chief of Orthopaedic) of Nepal Medical College advised us to treat both children outside Nepal as treatment is not available. We went to Sir Ganga Ram Hospital, New Delhi (India) and Dr. V.T.K. Titus, M.S. (Ortho) of Christian Medical Hospital, Vellore, (India) and found that India is not equipped to treat OI disease. Did few more inquiries and consulted other countries doctors through Net, websites and found Kennedy Krieger Institute (Johns Hopkins Hospital), Baltimore 707, USA, can do surgery and treat my children. Dr. Jay Shapiro, MD, of aforesaid hospital gave us the appointment of 11/07/2004 which was later postponed to 12/15/2004 due to Visa obstruction.

The entire treatment cost of US $ 109,696.00 for each patient was arranged and initial deposit was also paid to above hospital. I sold my land, household jewelry, borrowed from relatives, took personal as well as bank loans and arranged treatment cost of my children. But, the American Embassy refused to issue Visa. The consular bluntly insulted our country saying, ?Nepalese cannot afford treatment in USA.? They insisted that we must bring foreign sponsors for treatment. The consular even ignored the fact that my son will be permanently handicapped if he is not treated within eight months. It is just unbelievable for me to think that a country like USA who proclaims Human Rights will have such an irresponsible, anti-Nepal representative at their Embassy.

Now, my children fate has become more precarious. Without sponsors they cannot be treated in American hospital. I hereby request doctors, hospitals, philanthropists, NGOs and INGOs to guide me. Please refer to medical certificates, X-rays & Reports given on this website and inform if any hospital can treat them.

My financial condition is not good and beside Kennedy Krieger Institute (KKI), (Johns Hopkins Hospital), Baltimore 707, USA, I don?t know whether any other country?s hospital can treat them. Considering very limited time at disposal, I request every philanthropist and social organization to extend their helping hands and sponsor my children treatment cost. Thank you and waiting for your help. Kindly send your donations to Mr. Shiva Bahadur Baniya, Account No.1210017500013, Nabil Bank Limited, Pokhara Branch, Nepal. (ABA) Bank Swift Code: NARBNPKA or N.C.C. Bank Ltd; Pokhara Branch, Nepal, Account No.013005361 C, (ABA) Swift Code: NBOCNPKA.

I want to specially thank Mr. Andrew F. Egan, Prof. Ph.D. (The University of MAINE - USA)
visiting Fulbright Scholar (Institute of Forestry Pokhara, Nepal) under whose guidance children treatment at (KKI) was arranged. My family is grateful to him. He returned to USA.
Please Send Your Donation To :

Nabil Bank Limited
(Pokhara- Branch, Nepal)
Shiva Bahadur Baniya
A/C No. : 1210017500013 (Saving)
(ABA) Bank Swift Code No. : NARBNPKA

Miss. Shova Baniya
Age: 23

Mr. Surendra Baniya
Date of Birth
September 1, 1987

Thanks to Moneyminded bro and Urbi .I hope that anyone who can, will help Mr. Baniya and his family.


Just adding sumthing about Osteogenesis Imperfecta.

----> Mr. Baniya's children suffer frm OI type III, which is quite rare.

1)Frequency of OI in the USA.

Type I - One per 30,000 live births
Type II - One per 60,000 live births
TYPE III - One per 70,000 live births
Type IV - Rare

2)Causes: It is an inherited disorder.

Type I is autosomal dominant.
Type II is autosomal dominant with new mutation.
TYPE III is autosomal dominant with new mutation. Rarely, recessive forms also are observed.
Type IV is autosomal dominant.

3)Age of onset of symptoms (ie, fractures) varies depending on the type;

Type I - Infancy
Type II - In utero
TYPE III - Half the cases in utero, and other half in the neonatal period
Type IV - Usually in infancy

can we all do something??

Let us contribute generously to save lives. The entire treatment cost of US $ 109,696.00 for each patient. I belive this can start from sajha but has to go beyond sajha to collect anywhere close to this required amount. Any medical advice or opinion ?

http://www.childhelp.com.np

Cant we like all contribute here and then later send it back home. Khai maybe ne0 can help us with this.

Dear all

I sympathize with the parents and the kids. I am willing to contribute for the benefit.

I do have some concerns.


1. The disease is not treatable at least the root cause because of the autosomal in nature. The key here to improve the quality of life by preventing future fractures.
If 100,000 plus if spent on this patient (and I understand the agony of the patients and the parents) what is the prognosis?

2. Dr Banskota and Dr. Shah and others say there is no treatment available:

"Prof. Dr. Ashok K. Banskota, M.D; F.A.C.S. (Chief of Orthopaedic) of B & B Hospital, Kathmandu, Nepal and Dr. Ram Kewal Shah, (Chief of Orthopaedic) of Nepal Medical College advised us to treat both children outside Nepal as treatment is not available. We went to Sir Ganga Ram Hospital, New Delhi (India) and Dr. V.T.K. Titus, M.S. (Ortho) of Christian Medical Hospital, Vellore, (India) and found that India is not equipped to treat OI disease. Did few more inquiries and consulted other countries doctors through Net, websites and found Kennedy Krieger Institute (Johns Hopkins Hospital), Baltimore 707, USA, can do surgery and treat my children. Dr. Jay Shapiro, MD, of aforesaid hospital gave us the appointment of 11/07/2004 which was later postponed to 12/15/2004 due to Visa obstruction."

What surgery is going to be done? Surgery can correct the current deformities but I don't think it is the treatment. The key again is the prevention of future fractures and increase the quality of life.

3. What about other Nepalese who do not have the previledge of access like Mr. Bania? Are we going to think about them too?

Tell me if I look insensitive to these unfortunate children...I am just trying to be realistic.

there are hopes but the said amount will not be enough.
I did a quick mediline search and found lots of articles on OI.

Here is one of them with Rx options:
Advances in Osteogenesis Imperfecta
[SECTION I SYMPOSIUM: Genetics of Childhood Diseases]
Cole, William G. PhD
From the Division of Orthopaedics, The Hospital for Sick Children, Toronto, Ontario, Canada.
Some of the work referred to in this paper was undertaken with the support of a grant from the Canadian Institutes of Health Research.
Reprint requests to William G. Cole, PhD, Division of Orthopaedics, The Hospital for Sick Children, 555 University Ave., Toronto, Ontario, Canada M5G 1X8.
DOI: 10.1097/01.blo.0000022190.37246aa




Output...
583 K
Links...
Library HoldingsDocument Delivery



History...

Outline
? Abstract
? Classification
? Etiology and Pathogenesis
? Natural History
? Treatment
? Improving Bone Mass
? Bisphosphonates
? Mesenchymal Stromal Cells and Somatic Gene Therapy
? Surgery
? Orthotics
? Future Directions
? Glossary
? References
? Section Description

Graphics
? Table 1
? Fig 1

Abstract
Considerable progress has been made in many aspects of osteogenesis imperfecta. The international Sillence classification of osteogenesis imperfecta is being expanded to include a greater range of subgroups of patients. Attempts are being made to identify the genes causing forms of osteogenesis imperfecta and related syndromes that are not caused by mutations of the Type I collagen genes. In medium-term studies, bisphosphonate treatment has been shown to be the first method of treatment to improve the clinical course of the disease significantly. Somatic cell therapy, using allogeneic bone marrow and mesenchymal stromal cell transplantation, are in their early phases of development for use in humans with osteogenesis imperfecta. Somatic gene therapy, which aims to inactivate the mutation, is being evaluated in laboratory and animal studies.



List of Abbreviations Used: DNA deoxyribonucleic acid, ECM extracellular matrix, mRNA messenger ribonucleic acid, MSC mesenchymal stem cell, RNA ribonucleic acid
Osteogenesis imperfecta is one of the best known skeletal dysplasias. 74 It is characterized by clinical anomalies of the Type I collagen-containing tissues that include bone, ligaments, tendons, skin, sclera, and dentin. The clinical features include osteoporosis with fractures, joint laxity, grey-blue scleral color, dentinogenesis imperfecta, and premature deafness. The current author will summarize key aspects of the classification, etiology, pathogenesis, and treatment of osteogenesis imperfecta.
Classification
Osteogenesis imperfecta is a clinically heterogeneous disorder. 74 The most commonly used classification (Table 1) was developed by Sillence et al 74 from a comprehensive study of all cases of osteogenesis imperfecta in the state of Victoria, Australia. Osteogenesis imperfecta Type IA refers to the common autosomal dominant form that is characterized by grey-blue scleral color, osteoporosis with mild to moderate skeletal fragility, ligament laxity, normal dentitition, and premature hearing loss. Osteogenesis imperfecta Type IB is similar but with dentinogenesis imperfecta. Osteogenesis imperfecta Type II refers to a heterogeneous group of very severely affected babies who die in the perinatal period or during the following months. Osteogenesis imperfecta Type III is the form best known to orthopaedic surgeons. It is the progressively deforming form of the condition. The children have severe osteoporosis with progressive deformities and numerous fractures. The scleral color is bluish at birth but becomes white during childhood. These children have dwarfism because of spinal compression fractures, deformities of the limbs, and disruption of the growth plates. Dentinogenesis imperfecta usually is severe. Osteogenesis imperfecta Type IV is similar to the Type I form except that the scleral color is white rather than grey-blue. Dentinogenesis imperfecta is present in osteogenesis imperfecta Type IVB but not in osteogenesis imperfecta Type IVA.

Many cases of osteogenesis imperfecta do not fit easily into any of the four categories described. Consequently, Glorieux et al 34 added a Type V category to include a group of individuals with osteoporosis, interosseous membrane ossification of the forearms and legs, and a high frequency of hypertrophic calluses. Other osteogenesis imperfecta variants include the osteoporosis-pseudoglioma, Bruck, and Cole-Carpenter syndromes. 5,20,72 Osteoporosis-pseudoglioma syndrome, which includes bone fragility and blindness, is attributable to mutations of the gene encoding the low density lipoprotein receptor-related protein 5. 35 Bruck syndrome, which includes bone fragility and congenital joint contractures, is an autosomal recessive condition caused by mutations in the bone specific collagen Type I telopeptide lysyl hydroxylase enzyme. 5 The gene locus is not known for Cole-Carpenter syndrome.
Etiology and Pathogenesis
Approximately 80% to 90% of patients with osteogenesis imperfecta who fit into the Sillence Type I to Type IV categories have mutations of one of the two Type I collagen genes. 15 The COL1A1 gene encodes the pro-[alpha]1(I) protein chain and the COL1A2 gene encodes the pro-[alpha]2(I) protein chain of Type I procollagen. 14 The etiologies of the remaining 10% to 20% of cases are unclear. Many hundreds of unique mutations of the Type I collagen genes have been identified in individuals with osteogenesis imperfecta. Very few individuals or families share the same mutation. The mutation details are provided in public databases. 89,90
Individuals with osteogenesis imperfecta Type IA, the common classic autosomal dominant type, only express the normal copy, also called the normal allele, of the COL1A1 gene. 88 The mutant COL1A1 allele introduces a signal into the RNA transcript that would be expected to prematurely stop the translation of the pro-[alpha]1(I) collagen protein chain. However, the cell nucleus has a quality control mechanism that enables it to detect and to destroy RNA transcripts that contain the latter type of mutation. The mutant COL1A1 allele, therefore, is rendered functionless or null. Consequently, only normal collagen, but in reduced amounts, is synthesized by the Type I collagen-producing cells of individuals with osteogenesis imperfecta Type IA. Despite the similarity of the molecular genetic mechanisms observed in different families, there is considerable interfamilial and intrafamilial variation in the severity of the clinical osteogenesis imperfecta Type IA phenotypes. 88 For example, one affected individual may have grey-blue sclera but no fractures whereas another affected member of the same family may have the same scleral color and numerous fractures. These phenotypic variations likely are attributable to unknown environmental and genetic factors that modify the expression of the mutant collagen allele. The modifying genes are likely to be identified in genetic linkage studies of large families and inbred mice strains with osteogenesis imperfecta. 63 New DNA chip technology also offers the opportunity to identify genes that are expressed abnormally by cultured osteogenesis imperfecta fibroblasts and osteoblasts. 16
Null mutations of the COL1A1 and COL1A2 genes presumably occur with similar frequency. However, there is one report of individuals who are heterozygous for null mutations of the COL1A2 gene. 53 The paucity of such reports is likely to reflect the mild osteoporotic phenotype produced by the latter mutation.

Most babies with osteogenesis imperfecta Type II, the perinatal lethal form, have expressed mutations of the COL1A1 or COL1A2 genes. 7,8,15 The Type I collagen-producing cells synthesize approximately equal amounts of the normal and mutant collagen mRNAs and protein chains. For expressed mutations of the COL1A2 gene, approximately 50% of the Type I collagen molecules contain one normal pro-[alpha]2(I) chain whereas the other 50% contain one mutant pro-[alpha]2(I) chain. Some of the mutant molecules are degraded so the concentration of Type I collagen in the tissue is reduced. The remainder of the mutant Type I collagen is incorporated into the ECM where it impairs the structure and function of the tissue. 6 For expressed mutations of the COL1A1 gene, approximately 75% of the Type I collagen molecules contain one or two mutant pro-[alpha]1(I) chains. As with the COL1A2 mutations, variable proportions of the mutant molecules are degraded or incorporated into the ECM.
A major deletion within one allele of the COL1A1 gene was the first reported mutation in a baby with osteogenesis imperfecta Type II. 18 A mutation of this type seemed to fit well with the severe phenotype of the baby. However, a subsequent study showed that the mutations more commonly produced single amino acid substitutions or small peptide deletions in the pro-[alpha]1(I) or pro-[alpha]2(I) chains. 15 The production of transgenic mouse models of osteogenesis imperfecta confirmed that one glycine substitution was sufficient to produce the disease. 77 The glycine substitutions identified in humans with osteogenesis imperfecta Type II involve one of the more than 300 glycine residues that occupy every third position of the triple helical domain of each collagen chain. These glycine residues are included in repeating Gly-X-Y triplets in which X and Y can be any amino acid. Substitution of glycine, the smallest amino acid, by other amino acids such as arginine, cysteine, serine and alanine, impairs the formation and stability of the collagen triple helix.
Autosomal recessive inheritance initially was proposed as the mechanism responsible for the birth of multiple affected babies with osteogenesis imperfecta Type II in families with clinically healthy parents. 74 However, most babies were heterozygous rather than homozygous for their mutation. 15 The recurrence of osteogenesis imperfecta in the families was shown to be caused by DNA mosaicism in one parent. 19 The parent with mosaicism, who usually was healthy clinically, carried the mutation in a small number of their gonadal and somatic cells. Because of the occurrence of genetic mosaicism in some families, the overall risk of recurrence of osteogenesis imperfecta Type II is approximately 7% with each pregnancy. 19
Many individuals with osteogenesis imperfecta Types IB, III, IVA, and IVB have expressed COL1A1 or COL1A2 mutations similar to those in babies with osteogenesis imperfecta Type II. 15 Studies of genotype-phenotype correlation have shown that the severity of the osteogenesis imperfecta phenotype generally is worse if the mutation is expressed, with the production of a mutant protein, than if the mutation is not expressed. 15 The expressed osteogenesis imperfecta mutations alter the amino acid sequences of the main helical domain or the carboxy-terminal domain of the pro-[alpha]1(I) or pro-[alpha]2(I) chains of Type I procollagen. However, the severity of the osteogenesis imperfecta phenotype correlates poorly with the type and site of the expressed mutations.
Specific types of mutations of the Type I collagen genes also can produce Ehlers-Danlos syndrome, a tissue laxity syndrome. Some individuals with the Type VII form of the syndrome, with multiple joint dislocations and mild skeletal fragility, are heterozygous for mutations involving exon 6 of the COL1A1 or COL1A2 genes. 17,24,31,84 These mutations result in the loss of a peptide bond that normally is cleaved during the removal of the amino-propeptide of the Type I procollagen chains in the conversion of procollagen to collagen. No expressed mutations involving the aminopropeptides of Type I collagen have been reported in patients with osteogenesis imperfecta. 15 Some individuals with the classic Type I form of Ehlers-Danlos syndrome, with joint laxity and scarred, fragile, and stretchy skin have mutations of an arginine amino acid residue in the helical domain of the pro-[alpha]1(I) chain. 55 The arginine residue, which normally occupies the X position of one of the Gly-X-Y triplets, is replaced by cysteine. Amino acid substitutions involving the X or Y positions of the numerous Gly-X-Y triplets within the main triple helix have not been reported in patients with osteogenesis imperfecta. Additional studies are needed to obtain a clearer understanding of the factors that contribute to the type and severity of osteogenesis imperfecta, Ehlers-Danlos syndrome, or mixed phenotypes resulting from mutations of the COL1A1 and COL1A2 genes.

Analyses of osteoblast cultures and bone from individuals with osteogenesis imperfecta showed anomalies in the metabolism of collagen and noncollagenous proteins. 12,30,79,80 These findings indicate that the osteogenesis imperfecta phenotype likely results from a complex interplay of primary and secondary metabolic events in Type I collagen-producing cells.
Histologic evaluation of bone from babies with perinatal lethal osteogenesis imperfecta Type II showed a lack of cortical bone and sparse trabecular bone. The trabeculae contain woven bone with large immature osteoblasts. 25,26 Quantitative histomorphometric evaluation of iliac crest bone from patients with osteogenesis imperfecta Types I, III, and IV showed that the lamellar structure was maintained. Irrespective of the underlying collagen mutation, the biopsy specimens from the iliac crest showed that the cortical widths and cancellous bone volumes were reduced whereas bone remodeling was increased. 70 The decreased cancellous bone volumes were attributable to the formation of fewer trabeculae and to a lack of thickening of trabeculae with growth. Children with osteogenesis imperfecta Type I had higher cancellous bone volumes than children with osteogenesis imperfecta Types III and IV. The differences in cancellous bone volumes were attributable to the higher number of trabeculae in children with Type I osteogenesis imperfecta whereas the thickness of the trabeculae was similar in children with osteogenesis imperfecta Types I, III, and IV. The histomorphometric parameters of bone formation and bone resorption indicated that cancellous bone metabolism was increased markedly. The yearly turnover of cancellous bone was estimated to be 40% and 120% higher in patients with osteogenesis Types I and III, respectively, than in controls. 11,43,70 The latter findings showed that there was a direct relationship between the increase in bone turnover and the severity of the bone disease.
Natural History
Individuals with classic osteogenesis imperfecta Type I have normal longevity. 58,59,61 Fractures commence when the child starts to stand and bone fragility persists throughout life. 74 Although fractures may seem to cease in adolescence, they can recur after inactivity, after childbirth, and with aging. During the last trimester of pregnancy and during early breast feeding, approximately 6% of the mother?s bone mass is transferred to her baby. 74 Consequently, fractures may recommence after pregnancies. The fracture frequency also increases dramatically after menopause in woman and beyond the fifth decade in men with osteogenesis imperfecta Type I. 60 Joint hypermobility, particularly in the hands, wrists, and feet can produce pain and disability. 75 Hearing impairment also is common.
The longevity of babies with the perinatal lethal Type II form of osteogenesis imperfecta is dependent on the integrity of the thorax. 58 All bones contain multiple fractures in varying stages of healing. 25 The bones are severely osteoporotic, deformed, and often lack cortical bone. The vertebrae are flattened.
Children with the progressively deforming osteogenesis imperfecta Type III are the most frequent group to need orthopaedic care. 21 Standing and walking often are impossible because of severe osteoporosis, progressive deformities, and recurring fractures. Progressive scoliosis with severe platyspondyly also is common. Dentinogenesis imperfecta is common and hearing impairment also can occur. Longevity is limited by the progressive thoracic deformities and the occurrence of repeated episodes of pneumonia. 58,61
Children with osteogenesis imperfecta Type IV vary considerably in their clinical severity. 74 Their severity often is intermediate between the severities of osteogenesis imperfecta Types I and III. Basilar impression, attributable to the descent of the skull on the cervical spine with consequent brain stem compression occurs in approximately 70% of children with osteogenesis imperfecta Type IV. 38,73 It is less frequent in children with other forms of osteogenesis imperfecta.
Treatment
Many endocrinologic, surgical, and orthotic methods have been used to improve the natural history of osteogenesis imperfecta. Until recently, the correction of deformities, intramedullary rodding of long bones, orthotic support, muscle strengthening and mobility devices, such as wheelchairs, were the mainstays of treatment. 21 However, the treatment of patients with osteogenesis imperfecta is undergoing major changes as a result of new approaches to improving bone mass and bone strength. 13
Improving Bone Mass
Many endocrine and related methods have been used to increase bone mass and to reduce the frequency of fractures. Early methods included the use of sodium fluoride, calcitonin, anabolic steroids, flavanoids, vitamin C, and vitamin D. 23 The efficacy of these agents was unclear because of the small and uncontrolled nature of the trials. More recently, recombinant human growth hormone has been used because of its anabolic effects on bone. 1,48,49,81,82 Overall, these endocrine and related treatments produced minimal or no demonstrable improvement in the bone mass and natural history of the condition.
Two new approaches to improving the bone mass are, however, undergoing continuing evaluation. The first approach involves the use of bisphosphonates to decrease the resorption of bone and to increase the formation of bone. 32 The second approach is the use of bone marrow transplantation as means of introducing normal MSCs that have the capacity to differentiate into normal osteoblasts. 40
Bisphosphonates
Bisphosphonates are synthetic analogs of pyrophosphate and are potent inhibitors of bone resorption. 33 They are used widely in the treatment of osteoporosis in adults but until recently they have been used infrequently in children. During the past decade, bisphosphonates have been shown in cohort studies to be highly effective in improving bone mass in children with severe forms of osteogenesis imperfecta. 3,9,32,33,46 Cyclic intravenous pamidronate is given in a dosage of 7.5 mg/kg/year at 4-to 6-monthly intervals. 33 The treatment resulted in biochemical, histomorphometric, and radiographic evidence of decreased bone resorption and increased bone formation when compared with pretreatment and historic control values. The increase in bone formation mainly was subperiosteal with consequent thickening of the bone cortices. The bone mineral density also was improved significantly and the fracture rate was reduced significantly. The treatment did not alter fracture healing or the appearance of the growth plates. Longitudinal growth seemed to be better than in controls. The amount of growth between the doses of pamidronate was measured easily from the growth lines (Fig 1) that were visible on the radiographs. 27,33 All patients who were treated reported substantial relief of chronic pain and fatigue. Dependence on mobility aids was reduced in half of the children and was unaltered in the other half. Apart from the well-known acute phase reaction of fever and bone pain after the first infusion cycle, the pamidronate treatment did not have any side effects at the dosage given.

Intravenous pamidronate is most effective when given to babies and can be given shortly after birth to severely affected babies. 65 The treatment rapidly improves pain, which is a major problem in the initial treatment of babies with severe osteogenesis imperfecta. Radiographs show considerable remodeling of the bones with thickening of the cortices. For example, crumpled femurs and flattened vertebrae resume more normal shapes and cortical thicknesses.
The results to date suggest that intravenous pamidronate is an effective form of treatment for severe forms of osteogenesis imperfecta, particularly when commenced in infancy and in early childhood. The treatment is not a cure for osteogenesis imperfecta and does not alter the underlying genetic causes of the disease. Randomized trials are likely to provide more quantitative information about the reported gains. It seems however, that intravenous pamidronate favorably affects the natural history of the severe forms of the disease irrespective of the underlying collagen mutations. However, there are many remaining questions that need to be resolved including the long-term efficacy and safety of the treatment, the duration of treatment, and the use of alternative intravenous and oral bisphosphonates, and the indications for treatment of children and adults with the milder osteogenesis imperfecta Type I.
Mesenchymal Stromal Cells and Somatic Gene Therapy
Bone marrow contains nonhematopoietic precursor cells that can differentiate into mature mesenchymal cells. 69 The precursor cells, referred to as mesenchymal stromal or stem cells, have the capacity to differentiate in vitro and in vivo into osteogenic, chondrogenic, fibrogenic, and adipogenic lineages. 62,64,67,68 These observations underlie the investigation of unmodified and modified MSCs for cell therapy or somatic gene therapy of osteogenesis imperfecta.
In an average human bone marrow graft, there are only two to five MSCs per 1 ? 106 mononuclear cells. 76 Consequently, it is not surprising that only low levels of engraftment, approximately 1% to 2%, were observed after allogeneic whole bone marrow transplantation in a small group of children with osteogenesis imperfecta. 39 An alternative approach is to expand the number of MSCs in ex vivo cultures and then to infuse them into the recipient. 28,45,68 Pereira et al 62 infused normal mouse MSCs into irradiated transgenic mice with osteogenesis imperfecta. In bone, the cells differentiated into osteocytes and produced normal collagen with partial correction of the osteogenesis bone phenotype. The cell therapy produced stromal chimerism in which some cells were normal and some carried the osteogenesis imperfecta mutation. A higher proportion of engrafted normal cells is required, however, to achieve the level of stromal chimerism necessary to functionally correct the osteogenesis imperfecta phenotype.
A similar approach also has been used in a pilot study of children with osteogenesis imperfecta. 40 Transplanted allogeneic MSCs bearing a gene marker showed a higher level of engraftment than was observed after whole bone marrow transplantation in the same children. There are, nonetheless, many obstacles to be overcome before allogeneic MSC therapy can be considered to be as safe and as effective as the bisphosphonates in the treatment of severe types of osteogenesis imperfecta. The principal obstacle involves the prevention of graft rejection and graft versus host reaction. Assuming that the latter matters can be prevented, then the next major obstacle is to optimize the cell therapy so that the bone phenotype is improved significantly. A high level of engraftment likely is to be needed but the optimal level may vary in each child depending on the degree of expression of the mutant allele and the growth characteristics of the mutant osteoblasts and mutant osteoblast precursors.

Autografting of genetically-modified bone marrow-derived mesenchymal stromal cells is undergoing laboratory and animal investigation to determine the feasibility of using it in the treatment of osteogenesis imperfecta in humans. 13,54,57,69,78 Autografting overcomes the allogeneic transplantation issues but introduces others relating to the safety and effectiveness of genetically-modified stromal cells. In this approach, bone marrow is harvested and ex vivo the mesenchymal stromal cells are isolated, expanded in numbers, and genetically modified, after which they then are reinfused into the donor. 54,57,62
Three types of genetic modification are being investigated in vitro and in rodents. In the first type, additional normal copies of the mutant gene are introduced into osteogenesis imperfecta mesenchymal stromal cells. 62,68,69 No attempt is made to inactivate the mutant allele. In the second type, the genetic modifications specifically are targeted to inactivate the mutant allele. 36,50,71,83 The latter approach likely will require a separate solution for each family with osteogenesis because few families and individuals share the same mutation. In the third type, other genes such as the human growth gene may be introduced into the osteogenesis imperfecta MSCs. 78 Genetically-modified MSCs have not been evaluated in humans with osteogenesis imperfecta.

here is the surgery part:

Surgery
Fractures in patients with osteogenesis imperfecta Type IA usually are treated in the same way as similar fractures in healthy children. 21 The main difference is that the period of immobilization is shortened. It is important to avoid malunions, particularly in the proximal femur because recurrent fractures, requiring realignment osteotomy and intramedullary rodding, may follow. Progressive scoliosis in adolescence may require spinal fusion with instrumentation. 37 Adults with osteogenesis imperfecta Type IA may have many fractures develop after a period of inactivity or after pregnancies and menopause. 74 Oral bisphosphonates may be needed to improve bone mass. Some children may have recurring fractures as a result of the severity of their osteopenia. Such children also may need to be considered for bisphosphonate treatment although to date, the use of this drug has been confined to patients with the severe forms of the disease.
In the prebisphosphonate era, corrective osteotomies and intramedullary roddings often were done to prevent progressive deformities and recurrent fractures in children with severe forms of osteogenesis imperfecta. 10,21 Such surgery often was done in children who were confined to wheelchairs. The surgical technique of fragmentation and rodding has been modified over several decades. 4,85?87 Currently, corrective osteotomies are done through small incisions to preserve the blood supply to the bone and to maximize healing. 22,47,85 Expanding intramedullary rods are used whenever possible. Although many technical problems have been reported, some centers have reported a low rate of complications. 42,44,52,66,85
Randomized trials are needed to determine the indications for and the type of surgery in patients receiving bisphosphonates for severe forms of osteogenesis imperfecta. Current results of bisphosphonate treatment indicate that walking and running can be expected in many children who previously would have died within the first year of life or have been confined to a wheelchair. 3,9,33,46,65 Increased activity levels also have been observed in moderately affected children receiving bisphosphonates. In these children, malunions of subtrochanteric fractures of the femur are common and consequently there is a continuing need to realign the femur and internally support it with a rod. In the prebisphosphonate era, expanding rods were used in preference to nonexpanding rods to stop the distal femur from bowing anteromedially with growth beyond the end of the rod. 66 It is unclear whether it still is necessary to use expanding rods because the new bone formed during growth will have been exposed to bisphosphonates and may no longer bow anteromedially. Intramedullary rodding is used much less frequently in other bones. It may be needed in the tibia, forearm, or humerus.
Progressive spinal deformities and basilar impression are two major problems in children with moderate and severe forms of osteogenesis imperfecta. 2,37,38,51,73 Surgical treatment often is difficult or impossible because of the severity of the deformities and the fragility of the spine. 29,37,41,56 It is to be hoped that the early commencement of bisphosphonate treatment will prevent these serious deformities.

Orthotics
Orthotics often are used to stabilize lax joints, such as the ankle and subtalar joints, and to prevent progressive deformities and fractures. 10 Commonly used devices include ankle-foot, knee-ankle-foot, and forearm orthoses. The role of orthotics in the bisphosphonate era needs to be reevaluated.
Future Directions
Future advances are likely to include the identification of additional genes that cause osteogenesis imperfecta. New insights into the primary and secondary genetic consequences of the mutations should provide a better understanding of the pathogenesis of osteogenesis imperfecta and its related and overlapping syndromes. The latter advances will enable the classification of osteogenesis imperfecta to be improved and enable treatment trials to be stratified accordingly. The treatment options also are likely to expand with new or modified pharmaceutical, cell therapy, and gene therapy protocols. As these advances occur, it is likely that the role of surgery, orthotics, and physical therapy will diminish.
Glossary
COL1A1 = the gene encoding the pro-[alpha]1(I) protein chain.
COL1A2 = the gene encoding the pro-[alpha]2(I) protein chain.
Gly-X-Y = the repeating amino acid triplet of the helical domain of the collagen chains in which GLY is the amino acid glycine whereas X and Y can be any amino acid.
Pro-[alpha]1(I) and pro-[alpha]2(I) = the proteins chains of Type I collagen.

References
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