Summary of Research Efforts:
Achondroplasia is a genetic condition that results from the mutation of a single gene - the gene for FGFR3 - an important negative regulator of bone growth. The mutation exaggerates the function of FGFR3 to inhibit linear bone growth. Following identification of the “achondroplasia gene/mutation” in 1994, there has been mounting effort to develop drug therapies aimed at reducing the negative effects of FGFR3 on bone growth. Potential therapies range from those targeted to the overactive FGFR3 protein to those directed at the mutant FGFR3 gene to those that act indirectly by interfering with the “pathways” through which FGFR3 regulates bone growth. Humans have two copies of the FGFR3 gene and achondroplasia is caused by a mutation of only one copy. Future therapies may be able to target only the mutant copy of the gene or its protein. The adverse effect of overactive FGFR3 on skeletal growth begins before birth, but because growth continues through puberty, experts believe effective therapy will be able to influence a child’s growth pattern over this period. Since potential drug therapies for achondroplasia depend on natural growth, which ends at puberty, they would not be effective in adults. A major goal of potential drug therapies is to minimize or even eliminate the need for surgical intervention in children and respective adults with achondroplasia, who often need surgery to address complications of skeletal deformities that arose during childhood. Based on the current advancements on therapies we expect to see a safe, effective drug in 5 to 10 years.
History and Current Status: The first commercial effort was started in 1996 by an Israeli company named Prochon whose founder had a child with achondroplasia. Since the mid 2000s, however, Prochon has moved its focus away from achondroplasia. Most recently, university research based in Japan showed that a naturally occurring protein called C-type natriuretic peptide (CNP) counteracts the inhibitory effects of FGFR3 on bone growth potentially representing a strategy for treating achondroplasia. This strategy has been adopted and refined independently by two pharmaceutical companies, Chugai in Japan and BioMarin in the USA. In addition to enhancing the growth of bones that contribute to stature, CNP has potential to promote growth at the base of the skull enough to reduce the need for decompression surgery in the subset of achondroplastic infants with a very small foramen magnum. Clinical trials for CNP based drug therapy are expected to begin in 2012. Several years will be needed to establish the safety and effectiveness of CNP treatment for achondroplasia.
Emerging Opportunities:
Despite the promise of CNP, achondroplasia drug treatment is still early in its evolution. So it seems prudent to explore additional treatment strategies that could complement, constitute viable alternatives to or even surpass CNP based treatments. Below are some strategies in layman terms that are currently being pursued by researchers. The list below is just a subset of strategies. Many other strategies are being explored by researchers worldwide.
1. Block expression of the mutant FGFR3 gene so it does not produce the mutant protein. There are several variations on this theme all of which interfere with conversion of (erroneous) genetic information to (mal) functioning protein.
a. This strategy leverages billions of dollars of research focused on finding drugs for viruses.
b. Technical term example = siRNA
2. Neutralize function of mutant protein. FGFR3 functions by initiating chemical signals that affect behavior of growing cells. This strategy blocks (excessive) signal initiation.
a. This strategy leverages billions of dollars of research focused on finding drugs for cancer
b. Technical term example = tyrosine kinase inhibitor
3. Reduce lifespan of the mutant protein in growing cells. Proteins function as long as they survive within a cell and mutant FGFR3 has a longer lifespan that average FGFR3. This strategy promotes destruction of (mutant) proteins as a means to reduce its impact on cell growth.
a. This strategy leverages billions of dollars of research focused on finding drugs for cancer
b. Technical term example = Hsp90 inhibitor
4. Alter how FGFR3 is processed within a growing cell. Proteins are often modified or “processed” over their lifetimes within a cell and these modifications affect their function and can contribute to disease. Because processing steps are often shared by unrelated proteins, drugs developed to affect protein processing in one disease may work for other diseases which share a processing disturbance.
a. Achondroplasia shares a common processing disturbance with Alzheimers disease and may be responsive to drugs developed for this condition.
b. This strategy leverages billions of dollars of research focused on finding drugs for Alzheimers disease.
Other resources:
For more details about research from labs supported by Growing Stronger please review the individual blogs from each lab and Dr. Morry
For questions on how will drug therapies may look like, how non-profit funding helps discover drugs and more, please see the learn page on www.growingstronger.org
For research papers related to achondroplasia please review http://www.ncbi.nlm.nih.gov/pubmed?term=achondroplasia
Government sponsored information about achondroplasia is at: http://rarediseases.info.nih.gov/GARD/Condition/8173/Achondroplasia.aspx
Genetics Home Reference – Achondroplasia is at: http://ghr.nlm.nih.gov/condition/achondroplasia
Achondroplasia is a genetic condition that results from the mutation of a single gene - the gene for FGFR3 - an important negative regulator of bone growth. The mutation exaggerates the function of FGFR3 to inhibit linear bone growth. Following identification of the “achondroplasia gene/mutation” in 1994, there has been mounting effort to develop drug therapies aimed at reducing the negative effects of FGFR3 on bone growth. Potential therapies range from those targeted to the overactive FGFR3 protein to those directed at the mutant FGFR3 gene to those that act indirectly by interfering with the “pathways” through which FGFR3 regulates bone growth. Humans have two copies of the FGFR3 gene and achondroplasia is caused by a mutation of only one copy. Future therapies may be able to target only the mutant copy of the gene or its protein. The adverse effect of overactive FGFR3 on skeletal growth begins before birth, but because growth continues through puberty, experts believe effective therapy will be able to influence a child’s growth pattern over this period. Since potential drug therapies for achondroplasia depend on natural growth, which ends at puberty, they would not be effective in adults. A major goal of potential drug therapies is to minimize or even eliminate the need for surgical intervention in children and respective adults with achondroplasia, who often need surgery to address complications of skeletal deformities that arose during childhood. Based on the current advancements on therapies we expect to see a safe, effective drug in 5 to 10 years.
History and Current Status: The first commercial effort was started in 1996 by an Israeli company named Prochon whose founder had a child with achondroplasia. Since the mid 2000s, however, Prochon has moved its focus away from achondroplasia. Most recently, university research based in Japan showed that a naturally occurring protein called C-type natriuretic peptide (CNP) counteracts the inhibitory effects of FGFR3 on bone growth potentially representing a strategy for treating achondroplasia. This strategy has been adopted and refined independently by two pharmaceutical companies, Chugai in Japan and BioMarin in the USA. In addition to enhancing the growth of bones that contribute to stature, CNP has potential to promote growth at the base of the skull enough to reduce the need for decompression surgery in the subset of achondroplastic infants with a very small foramen magnum. Clinical trials for CNP based drug therapy are expected to begin in 2012. Several years will be needed to establish the safety and effectiveness of CNP treatment for achondroplasia.
Emerging Opportunities:
Despite the promise of CNP, achondroplasia drug treatment is still early in its evolution. So it seems prudent to explore additional treatment strategies that could complement, constitute viable alternatives to or even surpass CNP based treatments. Below are some strategies in layman terms that are currently being pursued by researchers. The list below is just a subset of strategies. Many other strategies are being explored by researchers worldwide.
1. Block expression of the mutant FGFR3 gene so it does not produce the mutant protein. There are several variations on this theme all of which interfere with conversion of (erroneous) genetic information to (mal) functioning protein.
a. This strategy leverages billions of dollars of research focused on finding drugs for viruses.
b. Technical term example = siRNA
2. Neutralize function of mutant protein. FGFR3 functions by initiating chemical signals that affect behavior of growing cells. This strategy blocks (excessive) signal initiation.
a. This strategy leverages billions of dollars of research focused on finding drugs for cancer
b. Technical term example = tyrosine kinase inhibitor
3. Reduce lifespan of the mutant protein in growing cells. Proteins function as long as they survive within a cell and mutant FGFR3 has a longer lifespan that average FGFR3. This strategy promotes destruction of (mutant) proteins as a means to reduce its impact on cell growth.
a. This strategy leverages billions of dollars of research focused on finding drugs for cancer
b. Technical term example = Hsp90 inhibitor
4. Alter how FGFR3 is processed within a growing cell. Proteins are often modified or “processed” over their lifetimes within a cell and these modifications affect their function and can contribute to disease. Because processing steps are often shared by unrelated proteins, drugs developed to affect protein processing in one disease may work for other diseases which share a processing disturbance.
a. Achondroplasia shares a common processing disturbance with Alzheimers disease and may be responsive to drugs developed for this condition.
b. This strategy leverages billions of dollars of research focused on finding drugs for Alzheimers disease.
Other resources:
For more details about research from labs supported by Growing Stronger please review the individual blogs from each lab and Dr. Morry
For questions on how will drug therapies may look like, how non-profit funding helps discover drugs and more, please see the learn page on www.growingstronger.org
For research papers related to achondroplasia please review http://www.ncbi.nlm.nih.gov/pubmed?term=achondroplasia
Government sponsored information about achondroplasia is at: http://rarediseases.info.nih.gov/GARD/Condition/8173/Achondroplasia.aspx
Genetics Home Reference – Achondroplasia is at: http://ghr.nlm.nih.gov/condition/achondroplasia
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